Relationships Between Times to Testosterone and Prostate-Specific Antigen Rises During the First Off-Treatment Interval of Intermittent Androgen Deprivation are Prognostic for Castration Resistance in Men With Nonmetastatic Prostate Cancer

Results

Between June 1996 and September 2006, 100 patients were accrued to the IAD trial. Of those, 62 were eligible for this exploratory analysis ( Figure 2 ). Characteristics of the eligible patients are presented in Table 1 . At diagnosis, the median age was 61.2 years (range, 48.3-74.8 years), with a median PSA of 9.7 ng/mL (range, 3.9-130.5 ng/mL). The median Gleason score was 3 + 4 (range, 6-9). The treatment choices were as follows: 47 patients underwent radical prostatectomy, 14 received definitive radiation therapy, and 1 patient received primary AD. Of the 14 patients who received radiation, 13 experienced biochemical recurrence, fulfilling the contemporary Phoenix criteria. ⁶ Median time from primary treatment to biochemical recurrence was 3.3 years (range, 0.5-14.6 years).

Figure 2 Consort Diagram. The Diagram Displays the Rationale for the Selection of the 62 Patients From the Clinical Trial for this Exploratory Analysis Abbreviations: AD = androgen deprivation; IAD = intermittent androgen deprivation; PSA = prostate-specific antigen; T = testosterone.

At study entry, the median age was 66.2 years (range, 51.2-81.1 years), with median baseline pre-study PSA and T levels of 3.9 ng/mL (range, 0.46-152.4 ng/mL) and 350 ng/dL (range, 140-640 ng/dL), respectively ( Table 1 ). There were 52 patients who achieved a PSA nadir of < 0.1 ng/mL during the first treatment cycle, whereas the remaining 10 patients had a median PSA nadir of 0.2 ng/mL (range, 0.1-0.4 ng/mL). During the first off-treatment interval, the median time of recovery to first T > 50 ng/dL was 3.1 months (range, 0-5.1 months). The median time to PSA rise was 4.5 months (range, 0.9-92.3 months), and the median time to PSA rise after first T > 50 ng/dL was 1.0 month (range, −0.9 to 88.5 months). The median duration of the first off-treatment interval was 9.5 months (range, 3.4 to more than 47.5 months). At the time of this report, 5 patients were still in their first off-treatment interval because they had not yet reached the PSA threshold for initiating the second cycle of IAD, and 3 of these patients still had an undetectable PSA; for these patients, the times to CRPC and PCM were censored at the date of the last clinic visit. The median PSAdt during the first off-treatment period starting from the first PSA rise was 1.2 months (range, 0-8.3 months).

Of 62 patients, 40 are alive (23 remain on IAD, 11 have CRPC, and 6 are off study), and 22 have died. Of the 22 patients who died, 13 (59%) died of progressive CRPC and 9 (41%) died of other causes. There were 39 patients who came off study at some point after completing the first full cycle: 29 patients owing to progression to CRPC and 10 for other reasons. After the first full cycle, median time to CRPC was 4.0 years (range, 0.5-8.6 years), and median time to death was 6.6 years (range, 2.9-13.0 years). Median times from primary treatment to CRPC and to death were 9.7 years (range, 4.0-21.0 years) and 12.8 years (range, 5.5-21.6 years), respectively.

Results of the Cox proportional hazard models are presented in Table 2 . There is moderate evidence that time to PSA rise and time to PSA rise after T > 50 ng/dL were each associated with time to CRPC after controlling for age at study entry and Gleason category (P = .02 and .05, respectively). Each 30-day increase in the time to PSA rise was associated with a 21% decrease in the risk of CRPC (95% CI, 3%-36%). If a patient had a time to PSA rise of ≥ 60 days after their first T > 50 ng/dL, this was associated with a 71% decrease in the risk of CRPC (95% CI 92% decrease to 2% increase). A sensitivity analysis found that the association was similar for patients who had a time to PSA rise of ≥ 30 days after their first T > 50 ng/dL (57% decrease; 95% CI, 85% decrease to 28% increase) and for patients who had a time to PSA rise of ≥ 90 days after their first T > 50 ng/dL (69% decrease; 95% CI, 93% decrease to 37% increase). Associations between time to T > 50 ng/mL and PSAdt and time to CRPC are consistent with clinically important prognostic markers (each 30-day increase in time to T > 50 ng/dL is associated with a 32% decrease in the risk of CRPC, and each 30-day increase in PSAdt is associated with a 39% decrease in the risk of CRPC); however, this study had insufficient power to conclude statistical significance. No time intervals were associated with PCM. Figure 3 shows Kaplan-Meier survival curves predicted from the Cox models for time to CRPC and time to PCM for each time interval of interest.

Figure 3 Kaplan-Meier Curves. The Curves Show Time to Castration-Resistant Prostate Cancer (Left Panels) and Prostate Cancer Mortality (Right Panels) Predicted by 4 Time Intervals (Panel Rows) Above (Gray) and Below (Black) the Marker Median Values or, for Time From T > 50 ng/dL to PSA Rise, < 60 Days (Gray) versus ≥ 60 Days (Black) Abbreviations: PSA = prostate-specific antigen; T = testosterone.

Discussion

Recent randomized phase III trial data support the concept that IAD is not inferior in terms of survival compared with CAD for men with biochemically recurrent disease after definitive or salvage radiation. ¹ Patients on IAD have a net improved quality of life with fewer hot flashes, reduced sexual adverse effects, and long-term preservation of bone mineral density.^{1, 7, 8, 9, and 10}Given the significant heterogeneity in long-term response to IAD, prognostic markers that distinguish those with indolent versus aggressive disease would be useful. Patients with early PSA rise could be considered for novel clinical trial designs, given that this study's data indicate that they have a worse prognosis if they simply continue on intermittent ADT. Those patients with late PSA rise might require less therapy and be apt to experience mortality from other causes, rather than prostate cancer. Therefore, early identification of these patients not only may stratify risk groups but also could affect future treatment.

Previously, the present authors found that the duration of the first off-treatment interval is prognostic for both time to CRPC and death in this patient population. ³ Drawbacks to using the duration of the first off-treatment interval as a prognostic factor are that it requires waiting for the off-treatment interval to end and it does not take into account the biologic relationship between T and PSA. Knowing that changes in PSA levels over time have been found to be an important prognostic factor in other prostate cancer disease states,^{11, 12, 13, 14, 15, and 16}and hoping to find earlier indicators of prognosis than the duration of the first off-treatment interval, the present authors sought to evaluate the kinetics and relationships of PSA and T rise during the first off-treatment period.

The present analysis found that there is a significant association between a longer time to PSA rise during the first off-treatment interval and a longer time to CRPC. This is not surprising, given the prior results that defined the duration of the first off-treatment interval as prognostic for both CRPC and death. However, the time to PSA rise occurs at an earlier time point and can be used to inform subsequent treatment decisions. This analysis also found that those with a longer time (eg, ≥ 60 days) to PSA rise after first T > 50 ng/dL experience a longer time to CRPC. This is an important finding, because it confirms that a delay in PSA rise with a noncastrate T level is “good” and that a longer time from first T > 50 ng/dL to PSA rise has improved outcomes.

Although it is intuitive that a greater interval between T and PSA rise would lead to improved quality of life and long-term outcomes, this is the first study in which the concept has been confirmed. However, the explanation for this relationship is unclear. A simple explanation is that patients with a smaller overall tumor burden require greater overall stimulation from T to produce enough PSA to reach the threshold to start the next IAD cycle. Another more biologically relevant explanation relies on the known intratumoral production of androgens.^{17 and 18}It is possible that those tumors that respond very quickly to T with a rise in PSA are tumors that are already producing androgens, requiring very little exogenous T stimulation to produce and increase PSA, and hence are closer to the clinical definition of CRPC. Conversely, those tumors that are making little to no androgens rely more on testicular sources of T before the neoplastic cells are stimulated and PSA begins to rise.

Numerous studies have reported that PSAdt values after primary treatment,^{11, 12, 19, and 20}biochemical recurrence,^{13, 15, and 21}and in the castration-resistant^{22 and 23}and metastatic disease states^{16 and 24}are associated with poorer prognosis. Although an increased PSAdt is associated with a clinically important reduction in time to CRPC or PCM in the present data, these relationships did not meet statistical significance, owing to inadequate patient numbers. One challenge in this analysis is that PSAdt may not be accurate when calculated at very low PSA values. Additionally, PSAdt is usually calculated to indirectly measure tumor growth at steady-state androgen levels. It may be challenging to determine the effect of PSAdt in a setting in which T levels are actively rising.

A number of factors may have contributed to the lack of prognostic significance in some of the present evaluations. The patient population size was likely insufficient to find a marker of marginal or moderate significance. Furthermore, the long duration of time and heterogeneity in the course of subsequent treatments after the development of CRPC, as well as the small number of patients who had PCM (n = 13), limited the statistical power to test for prognostic time intervals for PCM. Finally, studying prognostic time intervals during IAD is challenging, because some patients progress during the first treatment cycle of AD whereas others may remain chronically castrate in the off-treatment period after only 1 treatment cycle of AD.

Owing to issues surrounding the morbidity and cost of continuous androgen deprivation (CAD), multiple randomized studies of intermittent androgen deprivation (IAD) versus CAD have been performed.^{1 and 2}Overall survival and time to castration resistance have been similar, but there is evidence of less toxicity for those treated with IAD. Recently, a large trial of IAD versus CAD for men who underwent radiation for prostate cancer found no difference in overall survival, with more prostate cancer–related deaths for those receiving IAD yet more non–prostate cancer–associated deaths for those receiving CAD. ¹ These findings suggest that IAD should be a standard of care for men treated with androgen deprivation (AD) in this setting.

There are few markers prognostic for progression to castration-resistant prostate cancer (CRPC) or prostate cancer mortality (PCM). This is particularly true for men undergoing IAD. The present authors have previously found that, when a predetermined prostate-specific antigen (PSA) threshold is used in a prospective trial of IAD, the duration from the end of AD to reaching that threshold (defining the first off-treatment interval) is prognostic for time to CRPC and death. ³ However, this prognostic time interval requires follow-up for long periods until the PSA threshold is met and AD is resumed for a second treatment cycle. An earlier biologic and prognostic marker would be useful both in the clinic and to stratify risk for future clinical trials. For this reason, this study evaluated times to testosterone (T) and PSA rises, times between these events, and PSA doubling time (PSAdt) during the first off-treatment interval of IAD as potential prognostic time intervals for time to CRPC and PCM in men with nonmetastatic castration-sensitive prostate cancer in this prospective trial of IAD.

Results

Between June 1996 and September 2006, 100 patients were accrued to the IAD trial. Of those, 62 were eligible for this exploratory analysis ( Figure 2 ). Characteristics of the eligible patients are presented in Table 1 . At diagnosis, the median age was 61.2 years (range, 48.3-74.8 years), with a median PSA of 9.7 ng/mL (range, 3.9-130.5 ng/mL). The median Gleason score was 3 + 4 (range, 6-9). The treatment choices were as follows: 47 patients underwent radical prostatectomy, 14 received definitive radiation therapy, and 1 patient received primary AD. Of the 14 patients who received radiation, 13 experienced biochemical recurrence, fulfilling the contemporary Phoenix criteria. ⁶ Median time from primary treatment to biochemical recurrence was 3.3 years (range, 0.5-14.6 years).

Figure 2 Consort Diagram. The Diagram Displays the Rationale for the Selection of the 62 Patients From the Clinical Trial for this Exploratory Analysis Abbreviations: AD = androgen deprivation; IAD = intermittent androgen deprivation; PSA = prostate-specific antigen; T = testosterone.

At study entry, the median age was 66.2 years (range, 51.2-81.1 years), with median baseline pre-study PSA and T levels of 3.9 ng/mL (range, 0.46-152.4 ng/mL) and 350 ng/dL (range, 140-640 ng/dL), respectively ( Table 1 ). There were 52 patients who achieved a PSA nadir of < 0.1 ng/mL during the first treatment cycle, whereas the remaining 10 patients had a median PSA nadir of 0.2 ng/mL (range, 0.1-0.4 ng/mL). During the first off-treatment interval, the median time of recovery to first T > 50 ng/dL was 3.1 months (range, 0-5.1 months). The median time to PSA rise was 4.5 months (range, 0.9-92.3 months), and the median time to PSA rise after first T > 50 ng/dL was 1.0 month (range, −0.9 to 88.5 months). The median duration of the first off-treatment interval was 9.5 months (range, 3.4 to more than 47.5 months). At the time of this report, 5 patients were still in their first off-treatment interval because they had not yet reached the PSA threshold for initiating the second cycle of IAD, and 3 of these patients still had an undetectable PSA; for these patients, the times to CRPC and PCM were censored at the date of the last clinic visit. The median PSAdt during the first off-treatment period starting from the first PSA rise was 1.2 months (range, 0-8.3 months).

Of 62 patients, 40 are alive (23 remain on IAD, 11 have CRPC, and 6 are off study), and 22 have died. Of the 22 patients who died, 13 (59%) died of progressive CRPC and 9 (41%) died of other causes. There were 39 patients who came off study at some point after completing the first full cycle: 29 patients owing to progression to CRPC and 10 for other reasons. After the first full cycle, median time to CRPC was 4.0 years (range, 0.5-8.6 years), and median time to death was 6.6 years (range, 2.9-13.0 years). Median times from primary treatment to CRPC and to death were 9.7 years (range, 4.0-21.0 years) and 12.8 years (range, 5.5-21.6 years), respectively.

Results of the Cox proportional hazard models are presented in Table 2 . There is moderate evidence that time to PSA rise and time to PSA rise after T > 50 ng/dL were each associated with time to CRPC after controlling for age at study entry and Gleason category (P = .02 and .05, respectively). Each 30-day increase in the time to PSA rise was associated with a 21% decrease in the risk of CRPC (95% CI, 3%-36%). If a patient had a time to PSA rise of ≥ 60 days after their first T > 50 ng/dL, this was associated with a 71% decrease in the risk of CRPC (95% CI 92% decrease to 2% increase). A sensitivity analysis found that the association was similar for patients who had a time to PSA rise of ≥ 30 days after their first T > 50 ng/dL (57% decrease; 95% CI, 85% decrease to 28% increase) and for patients who had a time to PSA rise of ≥ 90 days after their first T > 50 ng/dL (69% decrease; 95% CI, 93% decrease to 37% increase). Associations between time to T > 50 ng/mL and PSAdt and time to CRPC are consistent with clinically important prognostic markers (each 30-day increase in time to T > 50 ng/dL is associated with a 32% decrease in the risk of CRPC, and each 30-day increase in PSAdt is associated with a 39% decrease in the risk of CRPC); however, this study had insufficient power to conclude statistical significance. No time intervals were associated with PCM. Figure 3 shows Kaplan-Meier survival curves predicted from the Cox models for time to CRPC and time to PCM for each time interval of interest.

Figure 3 Kaplan-Meier Curves. The Curves Show Time to Castration-Resistant Prostate Cancer (Left Panels) and Prostate Cancer Mortality (Right Panels) Predicted by 4 Time Intervals (Panel Rows) Above (Gray) and Below (Black) the Marker Median Values or, for Time From T > 50 ng/dL to PSA Rise, < 60 Days (Gray) versus ≥ 60 Days (Black) Abbreviations: PSA = prostate-specific antigen; T = testosterone.

Discussion

Recent randomized phase III trial data support the concept that IAD is not inferior in terms of survival compared with CAD for men with biochemically recurrent disease after definitive or salvage radiation. ¹ Patients on IAD have a net improved quality of life with fewer hot flashes, reduced sexual adverse effects, and long-term preservation of bone mineral density.^{1, 7, 8, 9, and 10}Given the significant heterogeneity in long-term response to IAD, prognostic markers that distinguish those with indolent versus aggressive disease would be useful. Patients with early PSA rise could be considered for novel clinical trial designs, given that this study's data indicate that they have a worse prognosis if they simply continue on intermittent ADT. Those patients with late PSA rise might require less therapy and be apt to experience mortality from other causes, rather than prostate cancer. Therefore, early identification of these patients not only may stratify risk groups but also could affect future treatment.

Previously, the present authors found that the duration of the first off-treatment interval is prognostic for both time to CRPC and death in this patient population. ³ Drawbacks to using the duration of the first off-treatment interval as a prognostic factor are that it requires waiting for the off-treatment interval to end and it does not take into account the biologic relationship between T and PSA. Knowing that changes in PSA levels over time have been found to be an important prognostic factor in other prostate cancer disease states,^{11, 12, 13, 14, 15, and 16}and hoping to find earlier indicators of prognosis than the duration of the first off-treatment interval, the present authors sought to evaluate the kinetics and relationships of PSA and T rise during the first off-treatment period.

The present analysis found that there is a significant association between a longer time to PSA rise during the first off-treatment interval and a longer time to CRPC. This is not surprising, given the prior results that defined the duration of the first off-treatment interval as prognostic for both CRPC and death. However, the time to PSA rise occurs at an earlier time point and can be used to inform subsequent treatment decisions. This analysis also found that those with a longer time (eg, ≥ 60 days) to PSA rise after first T > 50 ng/dL experience a longer time to CRPC. This is an important finding, because it confirms that a delay in PSA rise with a noncastrate T level is “good” and that a longer time from first T > 50 ng/dL to PSA rise has improved outcomes.

Although it is intuitive that a greater interval between T and PSA rise would lead to improved quality of life and long-term outcomes, this is the first study in which the concept has been confirmed. However, the explanation for this relationship is unclear. A simple explanation is that patients with a smaller overall tumor burden require greater overall stimulation from T to produce enough PSA to reach the threshold to start the next IAD cycle. Another more biologically relevant explanation relies on the known intratumoral production of androgens.^{17 and 18}It is possible that those tumors that respond very quickly to T with a rise in PSA are tumors that are already producing androgens, requiring very little exogenous T stimulation to produce and increase PSA, and hence are closer to the clinical definition of CRPC. Conversely, those tumors that are making little to no androgens rely more on testicular sources of T before the neoplastic cells are stimulated and PSA begins to rise.

Numerous studies have reported that PSAdt values after primary treatment,^{11, 12, 19, and 20}biochemical recurrence,^{13, 15, and 21}and in the castration-resistant^{22 and 23}and metastatic disease states^{16 and 24}are associated with poorer prognosis. Although an increased PSAdt is associated with a clinically important reduction in time to CRPC or PCM in the present data, these relationships did not meet statistical significance, owing to inadequate patient numbers. One challenge in this analysis is that PSAdt may not be accurate when calculated at very low PSA values. Additionally, PSAdt is usually calculated to indirectly measure tumor growth at steady-state androgen levels. It may be challenging to determine the effect of PSAdt in a setting in which T levels are actively rising.

A number of factors may have contributed to the lack of prognostic significance in some of the present evaluations. The patient population size was likely insufficient to find a marker of marginal or moderate significance. Furthermore, the long duration of time and heterogeneity in the course of subsequent treatments after the development of CRPC, as well as the small number of patients who had PCM (n = 13), limited the statistical power to test for prognostic time intervals for PCM. Finally, studying prognostic time intervals during IAD is challenging, because some patients progress during the first treatment cycle of AD whereas others may remain chronically castrate in the off-treatment period after only 1 treatment cycle of AD.

Owing to issues surrounding the morbidity and cost of continuous androgen deprivation (CAD), multiple randomized studies of intermittent androgen deprivation (IAD) versus CAD have been performed.^{1 and 2}Overall survival and time to castration resistance have been similar, but there is evidence of less toxicity for those treated with IAD. Recently, a large trial of IAD versus CAD for men who underwent radiation for prostate cancer found no difference in overall survival, with more prostate cancer–related deaths for those receiving IAD yet more non–prostate cancer–associated deaths for those receiving CAD. ¹ These findings suggest that IAD should be a standard of care for men treated with androgen deprivation (AD) in this setting.

There are few markers prognostic for progression to castration-resistant prostate cancer (CRPC) or prostate cancer mortality (PCM). This is particularly true for men undergoing IAD. The present authors have previously found that, when a predetermined prostate-specific antigen (PSA) threshold is used in a prospective trial of IAD, the duration from the end of AD to reaching that threshold (defining the first off-treatment interval) is prognostic for time to CRPC and death. ³ However, this prognostic time interval requires follow-up for long periods until the PSA threshold is met and AD is resumed for a second treatment cycle. An earlier biologic and prognostic marker would be useful both in the clinic and to stratify risk for future clinical trials. For this reason, this study evaluated times to testosterone (T) and PSA rises, times between these events, and PSA doubling time (PSAdt) during the first off-treatment interval of IAD as potential prognostic time intervals for time to CRPC and PCM in men with nonmetastatic castration-sensitive prostate cancer in this prospective trial of IAD.

Results

Between June 1996 and September 2006, 100 patients were accrued to the IAD trial. Of those, 62 were eligible for this exploratory analysis ( Figure 2 ). Characteristics of the eligible patients are presented in Table 1 . At diagnosis, the median age was 61.2 years (range, 48.3-74.8 years), with a median PSA of 9.7 ng/mL (range, 3.9-130.5 ng/mL). The median Gleason score was 3 + 4 (range, 6-9). The treatment choices were as follows: 47 patients underwent radical prostatectomy, 14 received definitive radiation therapy, and 1 patient received primary AD. Of the 14 patients who received radiation, 13 experienced biochemical recurrence, fulfilling the contemporary Phoenix criteria. ⁶ Median time from primary treatment to biochemical recurrence was 3.3 years (range, 0.5-14.6 years).

Figure 2 Consort Diagram. The Diagram Displays the Rationale for the Selection of the 62 Patients From the Clinical Trial for this Exploratory Analysis Abbreviations: AD = androgen deprivation; IAD = intermittent androgen deprivation; PSA = prostate-specific antigen; T = testosterone.

At study entry, the median age was 66.2 years (range, 51.2-81.1 years), with median baseline pre-study PSA and T levels of 3.9 ng/mL (range, 0.46-152.4 ng/mL) and 350 ng/dL (range, 140-640 ng/dL), respectively ( Table 1 ). There were 52 patients who achieved a PSA nadir of < 0.1 ng/mL during the first treatment cycle, whereas the remaining 10 patients had a median PSA nadir of 0.2 ng/mL (range, 0.1-0.4 ng/mL). During the first off-treatment interval, the median time of recovery to first T > 50 ng/dL was 3.1 months (range, 0-5.1 months). The median time to PSA rise was 4.5 months (range, 0.9-92.3 months), and the median time to PSA rise after first T > 50 ng/dL was 1.0 month (range, −0.9 to 88.5 months). The median duration of the first off-treatment interval was 9.5 months (range, 3.4 to more than 47.5 months). At the time of this report, 5 patients were still in their first off-treatment interval because they had not yet reached the PSA threshold for initiating the second cycle of IAD, and 3 of these patients still had an undetectable PSA; for these patients, the times to CRPC and PCM were censored at the date of the last clinic visit. The median PSAdt during the first off-treatment period starting from the first PSA rise was 1.2 months (range, 0-8.3 months).

Of 62 patients, 40 are alive (23 remain on IAD, 11 have CRPC, and 6 are off study), and 22 have died. Of the 22 patients who died, 13 (59%) died of progressive CRPC and 9 (41%) died of other causes. There were 39 patients who came off study at some point after completing the first full cycle: 29 patients owing to progression to CRPC and 10 for other reasons. After the first full cycle, median time to CRPC was 4.0 years (range, 0.5-8.6 years), and median time to death was 6.6 years (range, 2.9-13.0 years). Median times from primary treatment to CRPC and to death were 9.7 years (range, 4.0-21.0 years) and 12.8 years (range, 5.5-21.6 years), respectively.

Results of the Cox proportional hazard models are presented in Table 2 . There is moderate evidence that time to PSA rise and time to PSA rise after T > 50 ng/dL were each associated with time to CRPC after controlling for age at study entry and Gleason category (P = .02 and .05, respectively). Each 30-day increase in the time to PSA rise was associated with a 21% decrease in the risk of CRPC (95% CI, 3%-36%). If a patient had a time to PSA rise of ≥ 60 days after their first T > 50 ng/dL, this was associated with a 71% decrease in the risk of CRPC (95% CI 92% decrease to 2% increase). A sensitivity analysis found that the association was similar for patients who had a time to PSA rise of ≥ 30 days after their first T > 50 ng/dL (57% decrease; 95% CI, 85% decrease to 28% increase) and for patients who had a time to PSA rise of ≥ 90 days after their first T > 50 ng/dL (69% decrease; 95% CI, 93% decrease to 37% increase). Associations between time to T > 50 ng/mL and PSAdt and time to CRPC are consistent with clinically important prognostic markers (each 30-day increase in time to T > 50 ng/dL is associated with a 32% decrease in the risk of CRPC, and each 30-day increase in PSAdt is associated with a 39% decrease in the risk of CRPC); however, this study had insufficient power to conclude statistical significance. No time intervals were associated with PCM. Figure 3 shows Kaplan-Meier survival curves predicted from the Cox models for time to CRPC and time to PCM for each time interval of interest.

Figure 3 Kaplan-Meier Curves. The Curves Show Time to Castration-Resistant Prostate Cancer (Left Panels) and Prostate Cancer Mortality (Right Panels) Predicted by 4 Time Intervals (Panel Rows) Above (Gray) and Below (Black) the Marker Median Values or, for Time From T > 50 ng/dL to PSA Rise, < 60 Days (Gray) versus ≥ 60 Days (Black) Abbreviations: PSA = prostate-specific antigen; T = testosterone.

Discussion

Recent randomized phase III trial data support the concept that IAD is not inferior in terms of survival compared with CAD for men with biochemically recurrent disease after definitive or salvage radiation. ¹ Patients on IAD have a net improved quality of life with fewer hot flashes, reduced sexual adverse effects, and long-term preservation of bone mineral density.^{1, 7, 8, 9, and 10}Given the significant heterogeneity in long-term response to IAD, prognostic markers that distinguish those with indolent versus aggressive disease would be useful. Patients with early PSA rise could be considered for novel clinical trial designs, given that this study's data indicate that they have a worse prognosis if they simply continue on intermittent ADT. Those patients with late PSA rise might require less therapy and be apt to experience mortality from other causes, rather than prostate cancer. Therefore, early identification of these patients not only may stratify risk groups but also could affect future treatment.

Previously, the present authors found that the duration of the first off-treatment interval is prognostic for both time to CRPC and death in this patient population. ³ Drawbacks to using the duration of the first off-treatment interval as a prognostic factor are that it requires waiting for the off-treatment interval to end and it does not take into account the biologic relationship between T and PSA. Knowing that changes in PSA levels over time have been found to be an important prognostic factor in other prostate cancer disease states,^{11, 12, 13, 14, 15, and 16}and hoping to find earlier indicators of prognosis than the duration of the first off-treatment interval, the present authors sought to evaluate the kinetics and relationships of PSA and T rise during the first off-treatment period.

The present analysis found that there is a significant association between a longer time to PSA rise during the first off-treatment interval and a longer time to CRPC. This is not surprising, given the prior results that defined the duration of the first off-treatment interval as prognostic for both CRPC and death. However, the time to PSA rise occurs at an earlier time point and can be used to inform subsequent treatment decisions. This analysis also found that those with a longer time (eg, ≥ 60 days) to PSA rise after first T > 50 ng/dL experience a longer time to CRPC. This is an important finding, because it confirms that a delay in PSA rise with a noncastrate T level is “good” and that a longer time from first T > 50 ng/dL to PSA rise has improved outcomes.

Although it is intuitive that a greater interval between T and PSA rise would lead to improved quality of life and long-term outcomes, this is the first study in which the concept has been confirmed. However, the explanation for this relationship is unclear. A simple explanation is that patients with a smaller overall tumor burden require greater overall stimulation from T to produce enough PSA to reach the threshold to start the next IAD cycle. Another more biologically relevant explanation relies on the known intratumoral production of androgens.^{17 and 18}It is possible that those tumors that respond very quickly to T with a rise in PSA are tumors that are already producing androgens, requiring very little exogenous T stimulation to produce and increase PSA, and hence are closer to the clinical definition of CRPC. Conversely, those tumors that are making little to no androgens rely more on testicular sources of T before the neoplastic cells are stimulated and PSA begins to rise.

Numerous studies have reported that PSAdt values after primary treatment,^{11, 12, 19, and 20}biochemical recurrence,^{13, 15, and 21}and in the castration-resistant^{22 and 23}and metastatic disease states^{16 and 24}are associated with poorer prognosis. Although an increased PSAdt is associated with a clinically important reduction in time to CRPC or PCM in the present data, these relationships did not meet statistical significance, owing to inadequate patient numbers. One challenge in this analysis is that PSAdt may not be accurate when calculated at very low PSA values. Additionally, PSAdt is usually calculated to indirectly measure tumor growth at steady-state androgen levels. It may be challenging to determine the effect of PSAdt in a setting in which T levels are actively rising.

A number of factors may have contributed to the lack of prognostic significance in some of the present evaluations. The patient population size was likely insufficient to find a marker of marginal or moderate significance. Furthermore, the long duration of time and heterogeneity in the course of subsequent treatments after the development of CRPC, as well as the small number of patients who had PCM (n = 13), limited the statistical power to test for prognostic time intervals for PCM. Finally, studying prognostic time intervals during IAD is challenging, because some patients progress during the first treatment cycle of AD whereas others may remain chronically castrate in the off-treatment period after only 1 treatment cycle of AD.

Owing to issues surrounding the morbidity and cost of continuous androgen deprivation (CAD), multiple randomized studies of intermittent androgen deprivation (IAD) versus CAD have been performed.^{1 and 2}Overall survival and time to castration resistance have been similar, but there is evidence of less toxicity for those treated with IAD. Recently, a large trial of IAD versus CAD for men who underwent radiation for prostate cancer found no difference in overall survival, with more prostate cancer–related deaths for those receiving IAD yet more non–prostate cancer–associated deaths for those receiving CAD. ¹ These findings suggest that IAD should be a standard of care for men treated with androgen deprivation (AD) in this setting.

There are few markers prognostic for progression to castration-resistant prostate cancer (CRPC) or prostate cancer mortality (PCM). This is particularly true for men undergoing IAD. The present authors have previously found that, when a predetermined prostate-specific antigen (PSA) threshold is used in a prospective trial of IAD, the duration from the end of AD to reaching that threshold (defining the first off-treatment interval) is prognostic for time to CRPC and death. ³ However, this prognostic time interval requires follow-up for long periods until the PSA threshold is met and AD is resumed for a second treatment cycle. An earlier biologic and prognostic marker would be useful both in the clinic and to stratify risk for future clinical trials. For this reason, this study evaluated times to testosterone (T) and PSA rises, times between these events, and PSA doubling time (PSAdt) during the first off-treatment interval of IAD as potential prognostic time intervals for time to CRPC and PCM in men with nonmetastatic castration-sensitive prostate cancer in this prospective trial of IAD.

Results

Between June 1996 and September 2006, 100 patients were accrued to the IAD trial. Of those, 62 were eligible for this exploratory analysis ( Figure 2 ). Characteristics of the eligible patients are presented in Table 1 . At diagnosis, the median age was 61.2 years (range, 48.3-74.8 years), with a median PSA of 9.7 ng/mL (range, 3.9-130.5 ng/mL). The median Gleason score was 3 + 4 (range, 6-9). The treatment choices were as follows: 47 patients underwent radical prostatectomy, 14 received definitive radiation therapy, and 1 patient received primary AD. Of the 14 patients who received radiation, 13 experienced biochemical recurrence, fulfilling the contemporary Phoenix criteria. ⁶ Median time from primary treatment to biochemical recurrence was 3.3 years (range, 0.5-14.6 years).

Figure 2 Consort Diagram. The Diagram Displays the Rationale for the Selection of the 62 Patients From the Clinical Trial for this Exploratory Analysis Abbreviations: AD = androgen deprivation; IAD = intermittent androgen deprivation; PSA = prostate-specific antigen; T = testosterone.

At study entry, the median age was 66.2 years (range, 51.2-81.1 years), with median baseline pre-study PSA and T levels of 3.9 ng/mL (range, 0.46-152.4 ng/mL) and 350 ng/dL (range, 140-640 ng/dL), respectively ( Table 1 ). There were 52 patients who achieved a PSA nadir of < 0.1 ng/mL during the first treatment cycle, whereas the remaining 10 patients had a median PSA nadir of 0.2 ng/mL (range, 0.1-0.4 ng/mL). During the first off-treatment interval, the median time of recovery to first T > 50 ng/dL was 3.1 months (range, 0-5.1 months). The median time to PSA rise was 4.5 months (range, 0.9-92.3 months), and the median time to PSA rise after first T > 50 ng/dL was 1.0 month (range, −0.9 to 88.5 months). The median duration of the first off-treatment interval was 9.5 months (range, 3.4 to more than 47.5 months). At the time of this report, 5 patients were still in their first off-treatment interval because they had not yet reached the PSA threshold for initiating the second cycle of IAD, and 3 of these patients still had an undetectable PSA; for these patients, the times to CRPC and PCM were censored at the date of the last clinic visit. The median PSAdt during the first off-treatment period starting from the first PSA rise was 1.2 months (range, 0-8.3 months).

Of 62 patients, 40 are alive (23 remain on IAD, 11 have CRPC, and 6 are off study), and 22 have died. Of the 22 patients who died, 13 (59%) died of progressive CRPC and 9 (41%) died of other causes. There were 39 patients who came off study at some point after completing the first full cycle: 29 patients owing to progression to CRPC and 10 for other reasons. After the first full cycle, median time to CRPC was 4.0 years (range, 0.5-8.6 years), and median time to death was 6.6 years (range, 2.9-13.0 years). Median times from primary treatment to CRPC and to death were 9.7 years (range, 4.0-21.0 years) and 12.8 years (range, 5.5-21.6 years), respectively.

Results of the Cox proportional hazard models are presented in Table 2 . There is moderate evidence that time to PSA rise and time to PSA rise after T > 50 ng/dL were each associated with time to CRPC after controlling for age at study entry and Gleason category (P = .02 and .05, respectively). Each 30-day increase in the time to PSA rise was associated with a 21% decrease in the risk of CRPC (95% CI, 3%-36%). If a patient had a time to PSA rise of ≥ 60 days after their first T > 50 ng/dL, this was associated with a 71% decrease in the risk of CRPC (95% CI 92% decrease to 2% increase). A sensitivity analysis found that the association was similar for patients who had a time to PSA rise of ≥ 30 days after their first T > 50 ng/dL (57% decrease; 95% CI, 85% decrease to 28% increase) and for patients who had a time to PSA rise of ≥ 90 days after their first T > 50 ng/dL (69% decrease; 95% CI, 93% decrease to 37% increase). Associations between time to T > 50 ng/mL and PSAdt and time to CRPC are consistent with clinically important prognostic markers (each 30-day increase in time to T > 50 ng/dL is associated with a 32% decrease in the risk of CRPC, and each 30-day increase in PSAdt is associated with a 39% decrease in the risk of CRPC); however, this study had insufficient power to conclude statistical significance. No time intervals were associated with PCM. Figure 3 shows Kaplan-Meier survival curves predicted from the Cox models for time to CRPC and time to PCM for each time interval of interest.

Figure 3 Kaplan-Meier Curves. The Curves Show Time to Castration-Resistant Prostate Cancer (Left Panels) and Prostate Cancer Mortality (Right Panels) Predicted by 4 Time Intervals (Panel Rows) Above (Gray) and Below (Black) the Marker Median Values or, for Time From T > 50 ng/dL to PSA Rise, < 60 Days (Gray) versus ≥ 60 Days (Black) Abbreviations: PSA = prostate-specific antigen; T = testosterone.

Discussion

Recent randomized phase III trial data support the concept that IAD is not inferior in terms of survival compared with CAD for men with biochemically recurrent disease after definitive or salvage radiation. ¹ Patients on IAD have a net improved quality of life with fewer hot flashes, reduced sexual adverse effects, and long-term preservation of bone mineral density.^{1, 7, 8, 9, and 10}Given the significant heterogeneity in long-term response to IAD, prognostic markers that distinguish those with indolent versus aggressive disease would be useful. Patients with early PSA rise could be considered for novel clinical trial designs, given that this study's data indicate that they have a worse prognosis if they simply continue on intermittent ADT. Those patients with late PSA rise might require less therapy and be apt to experience mortality from other causes, rather than prostate cancer. Therefore, early identification of these patients not only may stratify risk groups but also could affect future treatment.

Previously, the present authors found that the duration of the first off-treatment interval is prognostic for both time to CRPC and death in this patient population. ³ Drawbacks to using the duration of the first off-treatment interval as a prognostic factor are that it requires waiting for the off-treatment interval to end and it does not take into account the biologic relationship between T and PSA. Knowing that changes in PSA levels over time have been found to be an important prognostic factor in other prostate cancer disease states,^{11, 12, 13, 14, 15, and 16}and hoping to find earlier indicators of prognosis than the duration of the first off-treatment interval, the present authors sought to evaluate the kinetics and relationships of PSA and T rise during the first off-treatment period.

The present analysis found that there is a significant association between a longer time to PSA rise during the first off-treatment interval and a longer time to CRPC. This is not surprising, given the prior results that defined the duration of the first off-treatment interval as prognostic for both CRPC and death. However, the time to PSA rise occurs at an earlier time point and can be used to inform subsequent treatment decisions. This analysis also found that those with a longer time (eg, ≥ 60 days) to PSA rise after first T > 50 ng/dL experience a longer time to CRPC. This is an important finding, because it confirms that a delay in PSA rise with a noncastrate T level is “good” and that a longer time from first T > 50 ng/dL to PSA rise has improved outcomes.

Although it is intuitive that a greater interval between T and PSA rise would lead to improved quality of life and long-term outcomes, this is the first study in which the concept has been confirmed. However, the explanation for this relationship is unclear. A simple explanation is that patients with a smaller overall tumor burden require greater overall stimulation from T to produce enough PSA to reach the threshold to start the next IAD cycle. Another more biologically relevant explanation relies on the known intratumoral production of androgens.^{17 and 18}It is possible that those tumors that respond very quickly to T with a rise in PSA are tumors that are already producing androgens, requiring very little exogenous T stimulation to produce and increase PSA, and hence are closer to the clinical definition of CRPC. Conversely, those tumors that are making little to no androgens rely more on testicular sources of T before the neoplastic cells are stimulated and PSA begins to rise.

Numerous studies have reported that PSAdt values after primary treatment,^{11, 12, 19, and 20}biochemical recurrence,^{13, 15, and 21}and in the castration-resistant^{22 and 23}and metastatic disease states^{16 and 24}are associated with poorer prognosis. Although an increased PSAdt is associated with a clinically important reduction in time to CRPC or PCM in the present data, these relationships did not meet statistical significance, owing to inadequate patient numbers. One challenge in this analysis is that PSAdt may not be accurate when calculated at very low PSA values. Additionally, PSAdt is usually calculated to indirectly measure tumor growth at steady-state androgen levels. It may be challenging to determine the effect of PSAdt in a setting in which T levels are actively rising.

A number of factors may have contributed to the lack of prognostic significance in some of the present evaluations. The patient population size was likely insufficient to find a marker of marginal or moderate significance. Furthermore, the long duration of time and heterogeneity in the course of subsequent treatments after the development of CRPC, as well as the small number of patients who had PCM (n = 13), limited the statistical power to test for prognostic time intervals for PCM. Finally, studying prognostic time intervals during IAD is challenging, because some patients progress during the first treatment cycle of AD whereas others may remain chronically castrate in the off-treatment period after only 1 treatment cycle of AD.

Owing to issues surrounding the morbidity and cost of continuous androgen deprivation (CAD), multiple randomized studies of intermittent androgen deprivation (IAD) versus CAD have been performed.^{1 and 2}Overall survival and time to castration resistance have been similar, but there is evidence of less toxicity for those treated with IAD. Recently, a large trial of IAD versus CAD for men who underwent radiation for prostate cancer found no difference in overall survival, with more prostate cancer–related deaths for those receiving IAD yet more non–prostate cancer–associated deaths for those receiving CAD. ¹ These findings suggest that IAD should be a standard of care for men treated with androgen deprivation (AD) in this setting.

There are few markers prognostic for progression to castration-resistant prostate cancer (CRPC) or prostate cancer mortality (PCM). This is particularly true for men undergoing IAD. The present authors have previously found that, when a predetermined prostate-specific antigen (PSA) threshold is used in a prospective trial of IAD, the duration from the end of AD to reaching that threshold (defining the first off-treatment interval) is prognostic for time to CRPC and death. ³ However, this prognostic time interval requires follow-up for long periods until the PSA threshold is met and AD is resumed for a second treatment cycle. An earlier biologic and prognostic marker would be useful both in the clinic and to stratify risk for future clinical trials. For this reason, this study evaluated times to testosterone (T) and PSA rises, times between these events, and PSA doubling time (PSAdt) during the first off-treatment interval of IAD as potential prognostic time intervals for time to CRPC and PCM in men with nonmetastatic castration-sensitive prostate cancer in this prospective trial of IAD.

Results

Between June 1996 and September 2006, 100 patients were accrued to the IAD trial. Of those, 62 were eligible for this exploratory analysis ( Figure 2 ). Characteristics of the eligible patients are presented in Table 1 . At diagnosis, the median age was 61.2 years (range, 48.3-74.8 years), with a median PSA of 9.7 ng/mL (range, 3.9-130.5 ng/mL). The median Gleason score was 3 + 4 (range, 6-9). The treatment choices were as follows: 47 patients underwent radical prostatectomy, 14 received definitive radiation therapy, and 1 patient received primary AD. Of the 14 patients who received radiation, 13 experienced biochemical recurrence, fulfilling the contemporary Phoenix criteria. ⁶ Median time from primary treatment to biochemical recurrence was 3.3 years (range, 0.5-14.6 years).

Figure 2 Consort Diagram. The Diagram Displays the Rationale for the Selection of the 62 Patients From the Clinical Trial for this Exploratory Analysis Abbreviations: AD = androgen deprivation; IAD = intermittent androgen deprivation; PSA = prostate-specific antigen; T = testosterone.

At study entry, the median age was 66.2 years (range, 51.2-81.1 years), with median baseline pre-study PSA and T levels of 3.9 ng/mL (range, 0.46-152.4 ng/mL) and 350 ng/dL (range, 140-640 ng/dL), respectively ( Table 1 ). There were 52 patients who achieved a PSA nadir of < 0.1 ng/mL during the first treatment cycle, whereas the remaining 10 patients had a median PSA nadir of 0.2 ng/mL (range, 0.1-0.4 ng/mL). During the first off-treatment interval, the median time of recovery to first T > 50 ng/dL was 3.1 months (range, 0-5.1 months). The median time to PSA rise was 4.5 months (range, 0.9-92.3 months), and the median time to PSA rise after first T > 50 ng/dL was 1.0 month (range, −0.9 to 88.5 months). The median duration of the first off-treatment interval was 9.5 months (range, 3.4 to more than 47.5 months). At the time of this report, 5 patients were still in their first off-treatment interval because they had not yet reached the PSA threshold for initiating the second cycle of IAD, and 3 of these patients still had an undetectable PSA; for these patients, the times to CRPC and PCM were censored at the date of the last clinic visit. The median PSAdt during the first off-treatment period starting from the first PSA rise was 1.2 months (range, 0-8.3 months).

Of 62 patients, 40 are alive (23 remain on IAD, 11 have CRPC, and 6 are off study), and 22 have died. Of the 22 patients who died, 13 (59%) died of progressive CRPC and 9 (41%) died of other causes. There were 39 patients who came off study at some point after completing the first full cycle: 29 patients owing to progression to CRPC and 10 for other reasons. After the first full cycle, median time to CRPC was 4.0 years (range, 0.5-8.6 years), and median time to death was 6.6 years (range, 2.9-13.0 years). Median times from primary treatment to CRPC and to death were 9.7 years (range, 4.0-21.0 years) and 12.8 years (range, 5.5-21.6 years), respectively.

Results of the Cox proportional hazard models are presented in Table 2 . There is moderate evidence that time to PSA rise and time to PSA rise after T > 50 ng/dL were each associated with time to CRPC after controlling for age at study entry and Gleason category (P = .02 and .05, respectively). Each 30-day increase in the time to PSA rise was associated with a 21% decrease in the risk of CRPC (95% CI, 3%-36%). If a patient had a time to PSA rise of ≥ 60 days after their first T > 50 ng/dL, this was associated with a 71% decrease in the risk of CRPC (95% CI 92% decrease to 2% increase). A sensitivity analysis found that the association was similar for patients who had a time to PSA rise of ≥ 30 days after their first T > 50 ng/dL (57% decrease; 95% CI, 85% decrease to 28% increase) and for patients who had a time to PSA rise of ≥ 90 days after their first T > 50 ng/dL (69% decrease; 95% CI, 93% decrease to 37% increase). Associations between time to T > 50 ng/mL and PSAdt and time to CRPC are consistent with clinically important prognostic markers (each 30-day increase in time to T > 50 ng/dL is associated with a 32% decrease in the risk of CRPC, and each 30-day increase in PSAdt is associated with a 39% decrease in the risk of CRPC); however, this study had insufficient power to conclude statistical significance. No time intervals were associated with PCM. Figure 3 shows Kaplan-Meier survival curves predicted from the Cox models for time to CRPC and time to PCM for each time interval of interest.

Figure 3 Kaplan-Meier Curves. The Curves Show Time to Castration-Resistant Prostate Cancer (Left Panels) and Prostate Cancer Mortality (Right Panels) Predicted by 4 Time Intervals (Panel Rows) Above (Gray) and Below (Black) the Marker Median Values or, for Time From T > 50 ng/dL to PSA Rise, < 60 Days (Gray) versus ≥ 60 Days (Black) Abbreviations: PSA = prostate-specific antigen; T = testosterone.

Discussion

Recent randomized phase III trial data support the concept that IAD is not inferior in terms of survival compared with CAD for men with biochemically recurrent disease after definitive or salvage radiation. ¹ Patients on IAD have a net improved quality of life with fewer hot flashes, reduced sexual adverse effects, and long-term preservation of bone mineral density.^{1, 7, 8, 9, and 10}Given the significant heterogeneity in long-term response to IAD, prognostic markers that distinguish those with indolent versus aggressive disease would be useful. Patients with early PSA rise could be considered for novel clinical trial designs, given that this study's data indicate that they have a worse prognosis if they simply continue on intermittent ADT. Those patients with late PSA rise might require less therapy and be apt to experience mortality from other causes, rather than prostate cancer. Therefore, early identification of these patients not only may stratify risk groups but also could affect future treatment.

Previously, the present authors found that the duration of the first off-treatment interval is prognostic for both time to CRPC and death in this patient population. ³ Drawbacks to using the duration of the first off-treatment interval as a prognostic factor are that it requires waiting for the off-treatment interval to end and it does not take into account the biologic relationship between T and PSA. Knowing that changes in PSA levels over time have been found to be an important prognostic factor in other prostate cancer disease states,^{11, 12, 13, 14, 15, and 16}and hoping to find earlier indicators of prognosis than the duration of the first off-treatment interval, the present authors sought to evaluate the kinetics and relationships of PSA and T rise during the first off-treatment period.

The present analysis found that there is a significant association between a longer time to PSA rise during the first off-treatment interval and a longer time to CRPC. This is not surprising, given the prior results that defined the duration of the first off-treatment interval as prognostic for both CRPC and death. However, the time to PSA rise occurs at an earlier time point and can be used to inform subsequent treatment decisions. This analysis also found that those with a longer time (eg, ≥ 60 days) to PSA rise after first T > 50 ng/dL experience a longer time to CRPC. This is an important finding, because it confirms that a delay in PSA rise with a noncastrate T level is “good” and that a longer time from first T > 50 ng/dL to PSA rise has improved outcomes.

Although it is intuitive that a greater interval between T and PSA rise would lead to improved quality of life and long-term outcomes, this is the first study in which the concept has been confirmed. However, the explanation for this relationship is unclear. A simple explanation is that patients with a smaller overall tumor burden require greater overall stimulation from T to produce enough PSA to reach the threshold to start the next IAD cycle. Another more biologically relevant explanation relies on the known intratumoral production of androgens.^{17 and 18}It is possible that those tumors that respond very quickly to T with a rise in PSA are tumors that are already producing androgens, requiring very little exogenous T stimulation to produce and increase PSA, and hence are closer to the clinical definition of CRPC. Conversely, those tumors that are making little to no androgens rely more on testicular sources of T before the neoplastic cells are stimulated and PSA begins to rise.

Numerous studies have reported that PSAdt values after primary treatment,^{11, 12, 19, and 20}biochemical recurrence,^{13, 15, and 21}and in the castration-resistant^{22 and 23}and metastatic disease states^{16 and 24}are associated with poorer prognosis. Although an increased PSAdt is associated with a clinically important reduction in time to CRPC or PCM in the present data, these relationships did not meet statistical significance, owing to inadequate patient numbers. One challenge in this analysis is that PSAdt may not be accurate when calculated at very low PSA values. Additionally, PSAdt is usually calculated to indirectly measure tumor growth at steady-state androgen levels. It may be challenging to determine the effect of PSAdt in a setting in which T levels are actively rising.

A number of factors may have contributed to the lack of prognostic significance in some of the present evaluations. The patient population size was likely insufficient to find a marker of marginal or moderate significance. Furthermore, the long duration of time and heterogeneity in the course of subsequent treatments after the development of CRPC, as well as the small number of patients who had PCM (n = 13), limited the statistical power to test for prognostic time intervals for PCM. Finally, studying prognostic time intervals during IAD is challenging, because some patients progress during the first treatment cycle of AD whereas others may remain chronically castrate in the off-treatment period after only 1 treatment cycle of AD.

Owing to issues surrounding the morbidity and cost of continuous androgen deprivation (CAD), multiple randomized studies of intermittent androgen deprivation (IAD) versus CAD have been performed.^{1 and 2}Overall survival and time to castration resistance have been similar, but there is evidence of less toxicity for those treated with IAD. Recently, a large trial of IAD versus CAD for men who underwent radiation for prostate cancer found no difference in overall survival, with more prostate cancer–related deaths for those receiving IAD yet more non–prostate cancer–associated deaths for those receiving CAD. ¹ These findings suggest that IAD should be a standard of care for men treated with androgen deprivation (AD) in this setting.

There are few markers prognostic for progression to castration-resistant prostate cancer (CRPC) or prostate cancer mortality (PCM). This is particularly true for men undergoing IAD. The present authors have previously found that, when a predetermined prostate-specific antigen (PSA) threshold is used in a prospective trial of IAD, the duration from the end of AD to reaching that threshold (defining the first off-treatment interval) is prognostic for time to CRPC and death. ³ However, this prognostic time interval requires follow-up for long periods until the PSA threshold is met and AD is resumed for a second treatment cycle. An earlier biologic and prognostic marker would be useful both in the clinic and to stratify risk for future clinical trials. For this reason, this study evaluated times to testosterone (T) and PSA rises, times between these events, and PSA doubling time (PSAdt) during the first off-treatment interval of IAD as potential prognostic time intervals for time to CRPC and PCM in men with nonmetastatic castration-sensitive prostate cancer in this prospective trial of IAD.

Results

Between June 1996 and September 2006, 100 patients were accrued to the IAD trial. Of those, 62 were eligible for this exploratory analysis ( Figure 2 ). Characteristics of the eligible patients are presented in Table 1 . At diagnosis, the median age was 61.2 years (range, 48.3-74.8 years), with a median PSA of 9.7 ng/mL (range, 3.9-130.5 ng/mL). The median Gleason score was 3 + 4 (range, 6-9). The treatment choices were as follows: 47 patients underwent radical prostatectomy, 14 received definitive radiation therapy, and 1 patient received primary AD. Of the 14 patients who received radiation, 13 experienced biochemical recurrence, fulfilling the contemporary Phoenix criteria. ⁶ Median time from primary treatment to biochemical recurrence was 3.3 years (range, 0.5-14.6 years).

Figure 2 Consort Diagram. The Diagram Displays the Rationale for the Selection of the 62 Patients From the Clinical Trial for this Exploratory Analysis Abbreviations: AD = androgen deprivation; IAD = intermittent androgen deprivation; PSA = prostate-specific antigen; T = testosterone.

At study entry, the median age was 66.2 years (range, 51.2-81.1 years), with median baseline pre-study PSA and T levels of 3.9 ng/mL (range, 0.46-152.4 ng/mL) and 350 ng/dL (range, 140-640 ng/dL), respectively ( Table 1 ). There were 52 patients who achieved a PSA nadir of < 0.1 ng/mL during the first treatment cycle, whereas the remaining 10 patients had a median PSA nadir of 0.2 ng/mL (range, 0.1-0.4 ng/mL). During the first off-treatment interval, the median time of recovery to first T > 50 ng/dL was 3.1 months (range, 0-5.1 months). The median time to PSA rise was 4.5 months (range, 0.9-92.3 months), and the median time to PSA rise after first T > 50 ng/dL was 1.0 month (range, −0.9 to 88.5 months). The median duration of the first off-treatment interval was 9.5 months (range, 3.4 to more than 47.5 months). At the time of this report, 5 patients were still in their first off-treatment interval because they had not yet reached the PSA threshold for initiating the second cycle of IAD, and 3 of these patients still had an undetectable PSA; for these patients, the times to CRPC and PCM were censored at the date of the last clinic visit. The median PSAdt during the first off-treatment period starting from the first PSA rise was 1.2 months (range, 0-8.3 months).

Of 62 patients, 40 are alive (23 remain on IAD, 11 have CRPC, and 6 are off study), and 22 have died. Of the 22 patients who died, 13 (59%) died of progressive CRPC and 9 (41%) died of other causes. There were 39 patients who came off study at some point after completing the first full cycle: 29 patients owing to progression to CRPC and 10 for other reasons. After the first full cycle, median time to CRPC was 4.0 years (range, 0.5-8.6 years), and median time to death was 6.6 years (range, 2.9-13.0 years). Median times from primary treatment to CRPC and to death were 9.7 years (range, 4.0-21.0 years) and 12.8 years (range, 5.5-21.6 years), respectively.

Results of the Cox proportional hazard models are presented in Table 2 . There is moderate evidence that time to PSA rise and time to PSA rise after T > 50 ng/dL were each associated with time to CRPC after controlling for age at study entry and Gleason category (P = .02 and .05, respectively). Each 30-day increase in the time to PSA rise was associated with a 21% decrease in the risk of CRPC (95% CI, 3%-36%). If a patient had a time to PSA rise of ≥ 60 days after their first T > 50 ng/dL, this was associated with a 71% decrease in the risk of CRPC (95% CI 92% decrease to 2% increase). A sensitivity analysis found that the association was similar for patients who had a time to PSA rise of ≥ 30 days after their first T > 50 ng/dL (57% decrease; 95% CI, 85% decrease to 28% increase) and for patients who had a time to PSA rise of ≥ 90 days after their first T > 50 ng/dL (69% decrease; 95% CI, 93% decrease to 37% increase). Associations between time to T > 50 ng/mL and PSAdt and time to CRPC are consistent with clinically important prognostic markers (each 30-day increase in time to T > 50 ng/dL is associated with a 32% decrease in the risk of CRPC, and each 30-day increase in PSAdt is associated with a 39% decrease in the risk of CRPC); however, this study had insufficient power to conclude statistical significance. No time intervals were associated with PCM. Figure 3 shows Kaplan-Meier survival curves predicted from the Cox models for time to CRPC and time to PCM for each time interval of interest.

Figure 3 Kaplan-Meier Curves. The Curves Show Time to Castration-Resistant Prostate Cancer (Left Panels) and Prostate Cancer Mortality (Right Panels) Predicted by 4 Time Intervals (Panel Rows) Above (Gray) and Below (Black) the Marker Median Values or, for Time From T > 50 ng/dL to PSA Rise, < 60 Days (Gray) versus ≥ 60 Days (Black) Abbreviations: PSA = prostate-specific antigen; T = testosterone.

Discussion

Recent randomized phase III trial data support the concept that IAD is not inferior in terms of survival compared with CAD for men with biochemically recurrent disease after definitive or salvage radiation. ¹ Patients on IAD have a net improved quality of life with fewer hot flashes, reduced sexual adverse effects, and long-term preservation of bone mineral density.^{1, 7, 8, 9, and 10}Given the significant heterogeneity in long-term response to IAD, prognostic markers that distinguish those with indolent versus aggressive disease would be useful. Patients with early PSA rise could be considered for novel clinical trial designs, given that this study's data indicate that they have a worse prognosis if they simply continue on intermittent ADT. Those patients with late PSA rise might require less therapy and be apt to experience mortality from other causes, rather than prostate cancer. Therefore, early identification of these patients not only may stratify risk groups but also could affect future treatment.

Previously, the present authors found that the duration of the first off-treatment interval is prognostic for both time to CRPC and death in this patient population. ³ Drawbacks to using the duration of the first off-treatment interval as a prognostic factor are that it requires waiting for the off-treatment interval to end and it does not take into account the biologic relationship between T and PSA. Knowing that changes in PSA levels over time have been found to be an important prognostic factor in other prostate cancer disease states,^{11, 12, 13, 14, 15, and 16}and hoping to find earlier indicators of prognosis than the duration of the first off-treatment interval, the present authors sought to evaluate the kinetics and relationships of PSA and T rise during the first off-treatment period.

The present analysis found that there is a significant association between a longer time to PSA rise during the first off-treatment interval and a longer time to CRPC. This is not surprising, given the prior results that defined the duration of the first off-treatment interval as prognostic for both CRPC and death. However, the time to PSA rise occurs at an earlier time point and can be used to inform subsequent treatment decisions. This analysis also found that those with a longer time (eg, ≥ 60 days) to PSA rise after first T > 50 ng/dL experience a longer time to CRPC. This is an important finding, because it confirms that a delay in PSA rise with a noncastrate T level is “good” and that a longer time from first T > 50 ng/dL to PSA rise has improved outcomes.

Although it is intuitive that a greater interval between T and PSA rise would lead to improved quality of life and long-term outcomes, this is the first study in which the concept has been confirmed. However, the explanation for this relationship is unclear. A simple explanation is that patients with a smaller overall tumor burden require greater overall stimulation from T to produce enough PSA to reach the threshold to start the next IAD cycle. Another more biologically relevant explanation relies on the known intratumoral production of androgens.^{17 and 18}It is possible that those tumors that respond very quickly to T with a rise in PSA are tumors that are already producing androgens, requiring very little exogenous T stimulation to produce and increase PSA, and hence are closer to the clinical definition of CRPC. Conversely, those tumors that are making little to no androgens rely more on testicular sources of T before the neoplastic cells are stimulated and PSA begins to rise.

Numerous studies have reported that PSAdt values after primary treatment,^{11, 12, 19, and 20}biochemical recurrence,^{13, 15, and 21}and in the castration-resistant^{22 and 23}and metastatic disease states^{16 and 24}are associated with poorer prognosis. Although an increased PSAdt is associated with a clinically important reduction in time to CRPC or PCM in the present data, these relationships did not meet statistical significance, owing to inadequate patient numbers. One challenge in this analysis is that PSAdt may not be accurate when calculated at very low PSA values. Additionally, PSAdt is usually calculated to indirectly measure tumor growth at steady-state androgen levels. It may be challenging to determine the effect of PSAdt in a setting in which T levels are actively rising.

A number of factors may have contributed to the lack of prognostic significance in some of the present evaluations. The patient population size was likely insufficient to find a marker of marginal or moderate significance. Furthermore, the long duration of time and heterogeneity in the course of subsequent treatments after the development of CRPC, as well as the small number of patients who had PCM (n = 13), limited the statistical power to test for prognostic time intervals for PCM. Finally, studying prognostic time intervals during IAD is challenging, because some patients progress during the first treatment cycle of AD whereas others may remain chronically castrate in the off-treatment period after only 1 treatment cycle of AD.

Owing to issues surrounding the morbidity and cost of continuous androgen deprivation (CAD), multiple randomized studies of intermittent androgen deprivation (IAD) versus CAD have been performed.^{1 and 2}Overall survival and time to castration resistance have been similar, but there is evidence of less toxicity for those treated with IAD. Recently, a large trial of IAD versus CAD for men who underwent radiation for prostate cancer found no difference in overall survival, with more prostate cancer–related deaths for those receiving IAD yet more non–prostate cancer–associated deaths for those receiving CAD. ¹ These findings suggest that IAD should be a standard of care for men treated with androgen deprivation (AD) in this setting.

There are few markers prognostic for progression to castration-resistant prostate cancer (CRPC) or prostate cancer mortality (PCM). This is particularly true for men undergoing IAD. The present authors have previously found that, when a predetermined prostate-specific antigen (PSA) threshold is used in a prospective trial of IAD, the duration from the end of AD to reaching that threshold (defining the first off-treatment interval) is prognostic for time to CRPC and death. ³ However, this prognostic time interval requires follow-up for long periods until the PSA threshold is met and AD is resumed for a second treatment cycle. An earlier biologic and prognostic marker would be useful both in the clinic and to stratify risk for future clinical trials. For this reason, this study evaluated times to testosterone (T) and PSA rises, times between these events, and PSA doubling time (PSAdt) during the first off-treatment interval of IAD as potential prognostic time intervals for time to CRPC and PCM in men with nonmetastatic castration-sensitive prostate cancer in this prospective trial of IAD.

Results

Between June 1996 and September 2006, 100 patients were accrued to the IAD trial. Of those, 62 were eligible for this exploratory analysis ( Figure 2 ). Characteristics of the eligible patients are presented in Table 1 . At diagnosis, the median age was 61.2 years (range, 48.3-74.8 years), with a median PSA of 9.7 ng/mL (range, 3.9-130.5 ng/mL). The median Gleason score was 3 + 4 (range, 6-9). The treatment choices were as follows: 47 patients underwent radical prostatectomy, 14 received definitive radiation therapy, and 1 patient received primary AD. Of the 14 patients who received radiation, 13 experienced biochemical recurrence, fulfilling the contemporary Phoenix criteria. ⁶ Median time from primary treatment to biochemical recurrence was 3.3 years (range, 0.5-14.6 years).

Figure 2 Consort Diagram. The Diagram Displays the Rationale for the Selection of the 62 Patients From the Clinical Trial for this Exploratory Analysis Abbreviations: AD = androgen deprivation; IAD = intermittent androgen deprivation; PSA = prostate-specific antigen; T = testosterone.

At study entry, the median age was 66.2 years (range, 51.2-81.1 years), with median baseline pre-study PSA and T levels of 3.9 ng/mL (range, 0.46-152.4 ng/mL) and 350 ng/dL (range, 140-640 ng/dL), respectively ( Table 1 ). There were 52 patients who achieved a PSA nadir of < 0.1 ng/mL during the first treatment cycle, whereas the remaining 10 patients had a median PSA nadir of 0.2 ng/mL (range, 0.1-0.4 ng/mL). During the first off-treatment interval, the median time of recovery to first T > 50 ng/dL was 3.1 months (range, 0-5.1 months). The median time to PSA rise was 4.5 months (range, 0.9-92.3 months), and the median time to PSA rise after first T > 50 ng/dL was 1.0 month (range, −0.9 to 88.5 months). The median duration of the first off-treatment interval was 9.5 months (range, 3.4 to more than 47.5 months). At the time of this report, 5 patients were still in their first off-treatment interval because they had not yet reached the PSA threshold for initiating the second cycle of IAD, and 3 of these patients still had an undetectable PSA; for these patients, the times to CRPC and PCM were censored at the date of the last clinic visit. The median PSAdt during the first off-treatment period starting from the first PSA rise was 1.2 months (range, 0-8.3 months).

Of 62 patients, 40 are alive (23 remain on IAD, 11 have CRPC, and 6 are off study), and 22 have died. Of the 22 patients who died, 13 (59%) died of progressive CRPC and 9 (41%) died of other causes. There were 39 patients who came off study at some point after completing the first full cycle: 29 patients owing to progression to CRPC and 10 for other reasons. After the first full cycle, median time to CRPC was 4.0 years (range, 0.5-8.6 years), and median time to death was 6.6 years (range, 2.9-13.0 years). Median times from primary treatment to CRPC and to death were 9.7 years (range, 4.0-21.0 years) and 12.8 years (range, 5.5-21.6 years), respectively.

Results of the Cox proportional hazard models are presented in Table 2 . There is moderate evidence that time to PSA rise and time to PSA rise after T > 50 ng/dL were each associated with time to CRPC after controlling for age at study entry and Gleason category (P = .02 and .05, respectively). Each 30-day increase in the time to PSA rise was associated with a 21% decrease in the risk of CRPC (95% CI, 3%-36%). If a patient had a time to PSA rise of ≥ 60 days after their first T > 50 ng/dL, this was associated with a 71% decrease in the risk of CRPC (95% CI 92% decrease to 2% increase). A sensitivity analysis found that the association was similar for patients who had a time to PSA rise of ≥ 30 days after their first T > 50 ng/dL (57% decrease; 95% CI, 85% decrease to 28% increase) and for patients who had a time to PSA rise of ≥ 90 days after their first T > 50 ng/dL (69% decrease; 95% CI, 93% decrease to 37% increase). Associations between time to T > 50 ng/mL and PSAdt and time to CRPC are consistent with clinically important prognostic markers (each 30-day increase in time to T > 50 ng/dL is associated with a 32% decrease in the risk of CRPC, and each 30-day increase in PSAdt is associated with a 39% decrease in the risk of CRPC); however, this study had insufficient power to conclude statistical significance. No time intervals were associated with PCM. Figure 3 shows Kaplan-Meier survival curves predicted from the Cox models for time to CRPC and time to PCM for each time interval of interest.

Figure 3 Kaplan-Meier Curves. The Curves Show Time to Castration-Resistant Prostate Cancer (Left Panels) and Prostate Cancer Mortality (Right Panels) Predicted by 4 Time Intervals (Panel Rows) Above (Gray) and Below (Black) the Marker Median Values or, for Time From T > 50 ng/dL to PSA Rise, < 60 Days (Gray) versus ≥ 60 Days (Black) Abbreviations: PSA = prostate-specific antigen; T = testosterone.

Discussion

Recent randomized phase III trial data support the concept that IAD is not inferior in terms of survival compared with CAD for men with biochemically recurrent disease after definitive or salvage radiation. ¹ Patients on IAD have a net improved quality of life with fewer hot flashes, reduced sexual adverse effects, and long-term preservation of bone mineral density.^{1, 7, 8, 9, and 10}Given the significant heterogeneity in long-term response to IAD, prognostic markers that distinguish those with indolent versus aggressive disease would be useful. Patients with early PSA rise could be considered for novel clinical trial designs, given that this study's data indicate that they have a worse prognosis if they simply continue on intermittent ADT. Those patients with late PSA rise might require less therapy and be apt to experience mortality from other causes, rather than prostate cancer. Therefore, early identification of these patients not only may stratify risk groups but also could affect future treatment.

Previously, the present authors found that the duration of the first off-treatment interval is prognostic for both time to CRPC and death in this patient population. ³ Drawbacks to using the duration of the first off-treatment interval as a prognostic factor are that it requires waiting for the off-treatment interval to end and it does not take into account the biologic relationship between T and PSA. Knowing that changes in PSA levels over time have been found to be an important prognostic factor in other prostate cancer disease states,^{11, 12, 13, 14, 15, and 16}and hoping to find earlier indicators of prognosis than the duration of the first off-treatment interval, the present authors sought to evaluate the kinetics and relationships of PSA and T rise during the first off-treatment period.

The present analysis found that there is a significant association between a longer time to PSA rise during the first off-treatment interval and a longer time to CRPC. This is not surprising, given the prior results that defined the duration of the first off-treatment interval as prognostic for both CRPC and death. However, the time to PSA rise occurs at an earlier time point and can be used to inform subsequent treatment decisions. This analysis also found that those with a longer time (eg, ≥ 60 days) to PSA rise after first T > 50 ng/dL experience a longer time to CRPC. This is an important finding, because it confirms that a delay in PSA rise with a noncastrate T level is “good” and that a longer time from first T > 50 ng/dL to PSA rise has improved outcomes.

Although it is intuitive that a greater interval between T and PSA rise would lead to improved quality of life and long-term outcomes, this is the first study in which the concept has been confirmed. However, the explanation for this relationship is unclear. A simple explanation is that patients with a smaller overall tumor burden require greater overall stimulation from T to produce enough PSA to reach the threshold to start the next IAD cycle. Another more biologically relevant explanation relies on the known intratumoral production of androgens.^{17 and 18}It is possible that those tumors that respond very quickly to T with a rise in PSA are tumors that are already producing androgens, requiring very little exogenous T stimulation to produce and increase PSA, and hence are closer to the clinical definition of CRPC. Conversely, those tumors that are making little to no androgens rely more on testicular sources of T before the neoplastic cells are stimulated and PSA begins to rise.

Numerous studies have reported that PSAdt values after primary treatment,^{11, 12, 19, and 20}biochemical recurrence,^{13, 15, and 21}and in the castration-resistant^{22 and 23}and metastatic disease states^{16 and 24}are associated with poorer prognosis. Although an increased PSAdt is associated with a clinically important reduction in time to CRPC or PCM in the present data, these relationships did not meet statistical significance, owing to inadequate patient numbers. One challenge in this analysis is that PSAdt may not be accurate when calculated at very low PSA values. Additionally, PSAdt is usually calculated to indirectly measure tumor growth at steady-state androgen levels. It may be challenging to determine the effect of PSAdt in a setting in which T levels are actively rising.

A number of factors may have contributed to the lack of prognostic significance in some of the present evaluations. The patient population size was likely insufficient to find a marker of marginal or moderate significance. Furthermore, the long duration of time and heterogeneity in the course of subsequent treatments after the development of CRPC, as well as the small number of patients who had PCM (n = 13), limited the statistical power to test for prognostic time intervals for PCM. Finally, studying prognostic time intervals during IAD is challenging, because some patients progress during the first treatment cycle of AD whereas others may remain chronically castrate in the off-treatment period after only 1 treatment cycle of AD.

Owing to issues surrounding the morbidity and cost of continuous androgen deprivation (CAD), multiple randomized studies of intermittent androgen deprivation (IAD) versus CAD have been performed.^{1 and 2}Overall survival and time to castration resistance have been similar, but there is evidence of less toxicity for those treated with IAD. Recently, a large trial of IAD versus CAD for men who underwent radiation for prostate cancer found no difference in overall survival, with more prostate cancer–related deaths for those receiving IAD yet more non–prostate cancer–associated deaths for those receiving CAD. ¹ These findings suggest that IAD should be a standard of care for men treated with androgen deprivation (AD) in this setting.

There are few markers prognostic for progression to castration-resistant prostate cancer (CRPC) or prostate cancer mortality (PCM). This is particularly true for men undergoing IAD. The present authors have previously found that, when a predetermined prostate-specific antigen (PSA) threshold is used in a prospective trial of IAD, the duration from the end of AD to reaching that threshold (defining the first off-treatment interval) is prognostic for time to CRPC and death. ³ However, this prognostic time interval requires follow-up for long periods until the PSA threshold is met and AD is resumed for a second treatment cycle. An earlier biologic and prognostic marker would be useful both in the clinic and to stratify risk for future clinical trials. For this reason, this study evaluated times to testosterone (T) and PSA rises, times between these events, and PSA doubling time (PSAdt) during the first off-treatment interval of IAD as potential prognostic time intervals for time to CRPC and PCM in men with nonmetastatic castration-sensitive prostate cancer in this prospective trial of IAD.

Results

Between June 1996 and September 2006, 100 patients were accrued to the IAD trial. Of those, 62 were eligible for this exploratory analysis ( Figure 2 ). Characteristics of the eligible patients are presented in Table 1 . At diagnosis, the median age was 61.2 years (range, 48.3-74.8 years), with a median PSA of 9.7 ng/mL (range, 3.9-130.5 ng/mL). The median Gleason score was 3 + 4 (range, 6-9). The treatment choices were as follows: 47 patients underwent radical prostatectomy, 14 received definitive radiation therapy, and 1 patient received primary AD. Of the 14 patients who received radiation, 13 experienced biochemical recurrence, fulfilling the contemporary Phoenix criteria. ⁶ Median time from primary treatment to biochemical recurrence was 3.3 years (range, 0.5-14.6 years).

Figure 2 Consort Diagram. The Diagram Displays the Rationale for the Selection of the 62 Patients From the Clinical Trial for this Exploratory Analysis Abbreviations: AD = androgen deprivation; IAD = intermittent androgen deprivation; PSA = prostate-specific antigen; T = testosterone.

At study entry, the median age was 66.2 years (range, 51.2-81.1 years), with median baseline pre-study PSA and T levels of 3.9 ng/mL (range, 0.46-152.4 ng/mL) and 350 ng/dL (range, 140-640 ng/dL), respectively ( Table 1 ). There were 52 patients who achieved a PSA nadir of < 0.1 ng/mL during the first treatment cycle, whereas the remaining 10 patients had a median PSA nadir of 0.2 ng/mL (range, 0.1-0.4 ng/mL). During the first off-treatment interval, the median time of recovery to first T > 50 ng/dL was 3.1 months (range, 0-5.1 months). The median time to PSA rise was 4.5 months (range, 0.9-92.3 months), and the median time to PSA rise after first T > 50 ng/dL was 1.0 month (range, −0.9 to 88.5 months). The median duration of the first off-treatment interval was 9.5 months (range, 3.4 to more than 47.5 months). At the time of this report, 5 patients were still in their first off-treatment interval because they had not yet reached the PSA threshold for initiating the second cycle of IAD, and 3 of these patients still had an undetectable PSA; for these patients, the times to CRPC and PCM were censored at the date of the last clinic visit. The median PSAdt during the first off-treatment period starting from the first PSA rise was 1.2 months (range, 0-8.3 months).

Of 62 patients, 40 are alive (23 remain on IAD, 11 have CRPC, and 6 are off study), and 22 have died. Of the 22 patients who died, 13 (59%) died of progressive CRPC and 9 (41%) died of other causes. There were 39 patients who came off study at some point after completing the first full cycle: 29 patients owing to progression to CRPC and 10 for other reasons. After the first full cycle, median time to CRPC was 4.0 years (range, 0.5-8.6 years), and median time to death was 6.6 years (range, 2.9-13.0 years). Median times from primary treatment to CRPC and to death were 9.7 years (range, 4.0-21.0 years) and 12.8 years (range, 5.5-21.6 years), respectively.

Results of the Cox proportional hazard models are presented in Table 2 . There is moderate evidence that time to PSA rise and time to PSA rise after T > 50 ng/dL were each associated with time to CRPC after controlling for age at study entry and Gleason category (P = .02 and .05, respectively). Each 30-day increase in the time to PSA rise was associated with a 21% decrease in the risk of CRPC (95% CI, 3%-36%). If a patient had a time to PSA rise of ≥ 60 days after their first T > 50 ng/dL, this was associated with a 71% decrease in the risk of CRPC (95% CI 92% decrease to 2% increase). A sensitivity analysis found that the association was similar for patients who had a time to PSA rise of ≥ 30 days after their first T > 50 ng/dL (57% decrease; 95% CI, 85% decrease to 28% increase) and for patients who had a time to PSA rise of ≥ 90 days after their first T > 50 ng/dL (69% decrease; 95% CI, 93% decrease to 37% increase). Associations between time to T > 50 ng/mL and PSAdt and time to CRPC are consistent with clinically important prognostic markers (each 30-day increase in time to T > 50 ng/dL is associated with a 32% decrease in the risk of CRPC, and each 30-day increase in PSAdt is associated with a 39% decrease in the risk of CRPC); however, this study had insufficient power to conclude statistical significance. No time intervals were associated with PCM. Figure 3 shows Kaplan-Meier survival curves predicted from the Cox models for time to CRPC and time to PCM for each time interval of interest.

Figure 3 Kaplan-Meier Curves. The Curves Show Time to Castration-Resistant Prostate Cancer (Left Panels) and Prostate Cancer Mortality (Right Panels) Predicted by 4 Time Intervals (Panel Rows) Above (Gray) and Below (Black) the Marker Median Values or, for Time From T > 50 ng/dL to PSA Rise, < 60 Days (Gray) versus ≥ 60 Days (Black) Abbreviations: PSA = prostate-specific antigen; T = testosterone.

Discussion

Recent randomized phase III trial data support the concept that IAD is not inferior in terms of survival compared with CAD for men with biochemically recurrent disease after definitive or salvage radiation. ¹ Patients on IAD have a net improved quality of life with fewer hot flashes, reduced sexual adverse effects, and long-term preservation of bone mineral density.^{1, 7, 8, 9, and 10}Given the significant heterogeneity in long-term response to IAD, prognostic markers that distinguish those with indolent versus aggressive disease would be useful. Patients with early PSA rise could be considered for novel clinical trial designs, given that this study's data indicate that they have a worse prognosis if they simply continue on intermittent ADT. Those patients with late PSA rise might require less therapy and be apt to experience mortality from other causes, rather than prostate cancer. Therefore, early identification of these patients not only may stratify risk groups but also could affect future treatment.

Previously, the present authors found that the duration of the first off-treatment interval is prognostic for both time to CRPC and death in this patient population. ³ Drawbacks to using the duration of the first off-treatment interval as a prognostic factor are that it requires waiting for the off-treatment interval to end and it does not take into account the biologic relationship between T and PSA. Knowing that changes in PSA levels over time have been found to be an important prognostic factor in other prostate cancer disease states,^{11, 12, 13, 14, 15, and 16}and hoping to find earlier indicators of prognosis than the duration of the first off-treatment interval, the present authors sought to evaluate the kinetics and relationships of PSA and T rise during the first off-treatment period.

The present analysis found that there is a significant association between a longer time to PSA rise during the first off-treatment interval and a longer time to CRPC. This is not surprising, given the prior results that defined the duration of the first off-treatment interval as prognostic for both CRPC and death. However, the time to PSA rise occurs at an earlier time point and can be used to inform subsequent treatment decisions. This analysis also found that those with a longer time (eg, ≥ 60 days) to PSA rise after first T > 50 ng/dL experience a longer time to CRPC. This is an important finding, because it confirms that a delay in PSA rise with a noncastrate T level is “good” and that a longer time from first T > 50 ng/dL to PSA rise has improved outcomes.

Although it is intuitive that a greater interval between T and PSA rise would lead to improved quality of life and long-term outcomes, this is the first study in which the concept has been confirmed. However, the explanation for this relationship is unclear. A simple explanation is that patients with a smaller overall tumor burden require greater overall stimulation from T to produce enough PSA to reach the threshold to start the next IAD cycle. Another more biologically relevant explanation relies on the known intratumoral production of androgens.^{17 and 18}It is possible that those tumors that respond very quickly to T with a rise in PSA are tumors that are already producing androgens, requiring very little exogenous T stimulation to produce and increase PSA, and hence are closer to the clinical definition of CRPC. Conversely, those tumors that are making little to no androgens rely more on testicular sources of T before the neoplastic cells are stimulated and PSA begins to rise.

Numerous studies have reported that PSAdt values after primary treatment,^{11, 12, 19, and 20}biochemical recurrence,^{13, 15, and 21}and in the castration-resistant^{22 and 23}and metastatic disease states^{16 and 24}are associated with poorer prognosis. Although an increased PSAdt is associated with a clinically important reduction in time to CRPC or PCM in the present data, these relationships did not meet statistical significance, owing to inadequate patient numbers. One challenge in this analysis is that PSAdt may not be accurate when calculated at very low PSA values. Additionally, PSAdt is usually calculated to indirectly measure tumor growth at steady-state androgen levels. It may be challenging to determine the effect of PSAdt in a setting in which T levels are actively rising.

A number of factors may have contributed to the lack of prognostic significance in some of the present evaluations. The patient population size was likely insufficient to find a marker of marginal or moderate significance. Furthermore, the long duration of time and heterogeneity in the course of subsequent treatments after the development of CRPC, as well as the small number of patients who had PCM (n = 13), limited the statistical power to test for prognostic time intervals for PCM. Finally, studying prognostic time intervals during IAD is challenging, because some patients progress during the first treatment cycle of AD whereas others may remain chronically castrate in the off-treatment period after only 1 treatment cycle of AD.

Owing to issues surrounding the morbidity and cost of continuous androgen deprivation (CAD), multiple randomized studies of intermittent androgen deprivation (IAD) versus CAD have been performed.^{1 and 2}Overall survival and time to castration resistance have been similar, but there is evidence of less toxicity for those treated with IAD. Recently, a large trial of IAD versus CAD for men who underwent radiation for prostate cancer found no difference in overall survival, with more prostate cancer–related deaths for those receiving IAD yet more non–prostate cancer–associated deaths for those receiving CAD. ¹ These findings suggest that IAD should be a standard of care for men treated with androgen deprivation (AD) in this setting.

There are few markers prognostic for progression to castration-resistant prostate cancer (CRPC) or prostate cancer mortality (PCM). This is particularly true for men undergoing IAD. The present authors have previously found that, when a predetermined prostate-specific antigen (PSA) threshold is used in a prospective trial of IAD, the duration from the end of AD to reaching that threshold (defining the first off-treatment interval) is prognostic for time to CRPC and death. ³ However, this prognostic time interval requires follow-up for long periods until the PSA threshold is met and AD is resumed for a second treatment cycle. An earlier biologic and prognostic marker would be useful both in the clinic and to stratify risk for future clinical trials. For this reason, this study evaluated times to testosterone (T) and PSA rises, times between these events, and PSA doubling time (PSAdt) during the first off-treatment interval of IAD as potential prognostic time intervals for time to CRPC and PCM in men with nonmetastatic castration-sensitive prostate cancer in this prospective trial of IAD.

Results

Between June 1996 and September 2006, 100 patients were accrued to the IAD trial. Of those, 62 were eligible for this exploratory analysis ( Figure 2 ). Characteristics of the eligible patients are presented in Table 1 . At diagnosis, the median age was 61.2 years (range, 48.3-74.8 years), with a median PSA of 9.7 ng/mL (range, 3.9-130.5 ng/mL). The median Gleason score was 3 + 4 (range, 6-9). The treatment choices were as follows: 47 patients underwent radical prostatectomy, 14 received definitive radiation therapy, and 1 patient received primary AD. Of the 14 patients who received radiation, 13 experienced biochemical recurrence, fulfilling the contemporary Phoenix criteria. ⁶ Median time from primary treatment to biochemical recurrence was 3.3 years (range, 0.5-14.6 years).

Figure 2 Consort Diagram. The Diagram Displays the Rationale for the Selection of the 62 Patients From the Clinical Trial for this Exploratory Analysis Abbreviations: AD = androgen deprivation; IAD = intermittent androgen deprivation; PSA = prostate-specific antigen; T = testosterone.

At study entry, the median age was 66.2 years (range, 51.2-81.1 years), with median baseline pre-study PSA and T levels of 3.9 ng/mL (range, 0.46-152.4 ng/mL) and 350 ng/dL (range, 140-640 ng/dL), respectively ( Table 1 ). There were 52 patients who achieved a PSA nadir of < 0.1 ng/mL during the first treatment cycle, whereas the remaining 10 patients had a median PSA nadir of 0.2 ng/mL (range, 0.1-0.4 ng/mL). During the first off-treatment interval, the median time of recovery to first T > 50 ng/dL was 3.1 months (range, 0-5.1 months). The median time to PSA rise was 4.5 months (range, 0.9-92.3 months), and the median time to PSA rise after first T > 50 ng/dL was 1.0 month (range, −0.9 to 88.5 months). The median duration of the first off-treatment interval was 9.5 months (range, 3.4 to more than 47.5 months). At the time of this report, 5 patients were still in their first off-treatment interval because they had not yet reached the PSA threshold for initiating the second cycle of IAD, and 3 of these patients still had an undetectable PSA; for these patients, the times to CRPC and PCM were censored at the date of the last clinic visit. The median PSAdt during the first off-treatment period starting from the first PSA rise was 1.2 months (range, 0-8.3 months).

Of 62 patients, 40 are alive (23 remain on IAD, 11 have CRPC, and 6 are off study), and 22 have died. Of the 22 patients who died, 13 (59%) died of progressive CRPC and 9 (41%) died of other causes. There were 39 patients who came off study at some point after completing the first full cycle: 29 patients owing to progression to CRPC and 10 for other reasons. After the first full cycle, median time to CRPC was 4.0 years (range, 0.5-8.6 years), and median time to death was 6.6 years (range, 2.9-13.0 years). Median times from primary treatment to CRPC and to death were 9.7 years (range, 4.0-21.0 years) and 12.8 years (range, 5.5-21.6 years), respectively.

Results of the Cox proportional hazard models are presented in Table 2 . There is moderate evidence that time to PSA rise and time to PSA rise after T > 50 ng/dL were each associated with time to CRPC after controlling for age at study entry and Gleason category (P = .02 and .05, respectively). Each 30-day increase in the time to PSA rise was associated with a 21% decrease in the risk of CRPC (95% CI, 3%-36%). If a patient had a time to PSA rise of ≥ 60 days after their first T > 50 ng/dL, this was associated with a 71% decrease in the risk of CRPC (95% CI 92% decrease to 2% increase). A sensitivity analysis found that the association was similar for patients who had a time to PSA rise of ≥ 30 days after their first T > 50 ng/dL (57% decrease; 95% CI, 85% decrease to 28% increase) and for patients who had a time to PSA rise of ≥ 90 days after their first T > 50 ng/dL (69% decrease; 95% CI, 93% decrease to 37% increase). Associations between time to T > 50 ng/mL and PSAdt and time to CRPC are consistent with clinically important prognostic markers (each 30-day increase in time to T > 50 ng/dL is associated with a 32% decrease in the risk of CRPC, and each 30-day increase in PSAdt is associated with a 39% decrease in the risk of CRPC); however, this study had insufficient power to conclude statistical significance. No time intervals were associated with PCM. Figure 3 shows Kaplan-Meier survival curves predicted from the Cox models for time to CRPC and time to PCM for each time interval of interest.

Figure 3 Kaplan-Meier Curves. The Curves Show Time to Castration-Resistant Prostate Cancer (Left Panels) and Prostate Cancer Mortality (Right Panels) Predicted by 4 Time Intervals (Panel Rows) Above (Gray) and Below (Black) the Marker Median Values or, for Time From T > 50 ng/dL to PSA Rise, < 60 Days (Gray) versus ≥ 60 Days (Black) Abbreviations: PSA = prostate-specific antigen; T = testosterone.

Discussion

Recent randomized phase III trial data support the concept that IAD is not inferior in terms of survival compared with CAD for men with biochemically recurrent disease after definitive or salvage radiation. ¹ Patients on IAD have a net improved quality of life with fewer hot flashes, reduced sexual adverse effects, and long-term preservation of bone mineral density.^{1, 7, 8, 9, and 10}Given the significant heterogeneity in long-term response to IAD, prognostic markers that distinguish those with indolent versus aggressive disease would be useful. Patients with early PSA rise could be considered for novel clinical trial designs, given that this study's data indicate that they have a worse prognosis if they simply continue on intermittent ADT. Those patients with late PSA rise might require less therapy and be apt to experience mortality from other causes, rather than prostate cancer. Therefore, early identification of these patients not only may stratify risk groups but also could affect future treatment.

Previously, the present authors found that the duration of the first off-treatment interval is prognostic for both time to CRPC and death in this patient population. ³ Drawbacks to using the duration of the first off-treatment interval as a prognostic factor are that it requires waiting for the off-treatment interval to end and it does not take into account the biologic relationship between T and PSA. Knowing that changes in PSA levels over time have been found to be an important prognostic factor in other prostate cancer disease states,^{11, 12, 13, 14, 15, and 16}and hoping to find earlier indicators of prognosis than the duration of the first off-treatment interval, the present authors sought to evaluate the kinetics and relationships of PSA and T rise during the first off-treatment period.

The present analysis found that there is a significant association between a longer time to PSA rise during the first off-treatment interval and a longer time to CRPC. This is not surprising, given the prior results that defined the duration of the first off-treatment interval as prognostic for both CRPC and death. However, the time to PSA rise occurs at an earlier time point and can be used to inform subsequent treatment decisions. This analysis also found that those with a longer time (eg, ≥ 60 days) to PSA rise after first T > 50 ng/dL experience a longer time to CRPC. This is an important finding, because it confirms that a delay in PSA rise with a noncastrate T level is “good” and that a longer time from first T > 50 ng/dL to PSA rise has improved outcomes.

Although it is intuitive that a greater interval between T and PSA rise would lead to improved quality of life and long-term outcomes, this is the first study in which the concept has been confirmed. However, the explanation for this relationship is unclear. A simple explanation is that patients with a smaller overall tumor burden require greater overall stimulation from T to produce enough PSA to reach the threshold to start the next IAD cycle. Another more biologically relevant explanation relies on the known intratumoral production of androgens.^{17 and 18}It is possible that those tumors that respond very quickly to T with a rise in PSA are tumors that are already producing androgens, requiring very little exogenous T stimulation to produce and increase PSA, and hence are closer to the clinical definition of CRPC. Conversely, those tumors that are making little to no androgens rely more on testicular sources of T before the neoplastic cells are stimulated and PSA begins to rise.

Numerous studies have reported that PSAdt values after primary treatment,^{11, 12, 19, and 20}biochemical recurrence,^{13, 15, and 21}and in the castration-resistant^{22 and 23}and metastatic disease states^{16 and 24}are associated with poorer prognosis. Although an increased PSAdt is associated with a clinically important reduction in time to CRPC or PCM in the present data, these relationships did not meet statistical significance, owing to inadequate patient numbers. One challenge in this analysis is that PSAdt may not be accurate when calculated at very low PSA values. Additionally, PSAdt is usually calculated to indirectly measure tumor growth at steady-state androgen levels. It may be challenging to determine the effect of PSAdt in a setting in which T levels are actively rising.

A number of factors may have contributed to the lack of prognostic significance in some of the present evaluations. The patient population size was likely insufficient to find a marker of marginal or moderate significance. Furthermore, the long duration of time and heterogeneity in the course of subsequent treatments after the development of CRPC, as well as the small number of patients who had PCM (n = 13), limited the statistical power to test for prognostic time intervals for PCM. Finally, studying prognostic time intervals during IAD is challenging, because some patients progress during the first treatment cycle of AD whereas others may remain chronically castrate in the off-treatment period after only 1 treatment cycle of AD.

Owing to issues surrounding the morbidity and cost of continuous androgen deprivation (CAD), multiple randomized studies of intermittent androgen deprivation (IAD) versus CAD have been performed.^{1 and 2}Overall survival and time to castration resistance have been similar, but there is evidence of less toxicity for those treated with IAD. Recently, a large trial of IAD versus CAD for men who underwent radiation for prostate cancer found no difference in overall survival, with more prostate cancer–related deaths for those receiving IAD yet more non–prostate cancer–associated deaths for those receiving CAD. ¹ These findings suggest that IAD should be a standard of care for men treated with androgen deprivation (AD) in this setting.

There are few markers prognostic for progression to castration-resistant prostate cancer (CRPC) or prostate cancer mortality (PCM). This is particularly true for men undergoing IAD. The present authors have previously found that, when a predetermined prostate-specific antigen (PSA) threshold is used in a prospective trial of IAD, the duration from the end of AD to reaching that threshold (defining the first off-treatment interval) is prognostic for time to CRPC and death. ³ However, this prognostic time interval requires follow-up for long periods until the PSA threshold is met and AD is resumed for a second treatment cycle. An earlier biologic and prognostic marker would be useful both in the clinic and to stratify risk for future clinical trials. For this reason, this study evaluated times to testosterone (T) and PSA rises, times between these events, and PSA doubling time (PSAdt) during the first off-treatment interval of IAD as potential prognostic time intervals for time to CRPC and PCM in men with nonmetastatic castration-sensitive prostate cancer in this prospective trial of IAD.

Results

Between June 1996 and September 2006, 100 patients were accrued to the IAD trial. Of those, 62 were eligible for this exploratory analysis ( Figure 2 ). Characteristics of the eligible patients are presented in Table 1 . At diagnosis, the median age was 61.2 years (range, 48.3-74.8 years), with a median PSA of 9.7 ng/mL (range, 3.9-130.5 ng/mL). The median Gleason score was 3 + 4 (range, 6-9). The treatment choices were as follows: 47 patients underwent radical prostatectomy, 14 received definitive radiation therapy, and 1 patient received primary AD. Of the 14 patients who received radiation, 13 experienced biochemical recurrence, fulfilling the contemporary Phoenix criteria. ⁶ Median time from primary treatment to biochemical recurrence was 3.3 years (range, 0.5-14.6 years).

Figure 2 Consort Diagram. The Diagram Displays the Rationale for the Selection of the 62 Patients From the Clinical Trial for this Exploratory Analysis Abbreviations: AD = androgen deprivation; IAD = intermittent androgen deprivation; PSA = prostate-specific antigen; T = testosterone.

At study entry, the median age was 66.2 years (range, 51.2-81.1 years), with median baseline pre-study PSA and T levels of 3.9 ng/mL (range, 0.46-152.4 ng/mL) and 350 ng/dL (range, 140-640 ng/dL), respectively ( Table 1 ). There were 52 patients who achieved a PSA nadir of < 0.1 ng/mL during the first treatment cycle, whereas the remaining 10 patients had a median PSA nadir of 0.2 ng/mL (range, 0.1-0.4 ng/mL). During the first off-treatment interval, the median time of recovery to first T > 50 ng/dL was 3.1 months (range, 0-5.1 months). The median time to PSA rise was 4.5 months (range, 0.9-92.3 months), and the median time to PSA rise after first T > 50 ng/dL was 1.0 month (range, −0.9 to 88.5 months). The median duration of the first off-treatment interval was 9.5 months (range, 3.4 to more than 47.5 months). At the time of this report, 5 patients were still in their first off-treatment interval because they had not yet reached the PSA threshold for initiating the second cycle of IAD, and 3 of these patients still had an undetectable PSA; for these patients, the times to CRPC and PCM were censored at the date of the last clinic visit. The median PSAdt during the first off-treatment period starting from the first PSA rise was 1.2 months (range, 0-8.3 months).

Of 62 patients, 40 are alive (23 remain on IAD, 11 have CRPC, and 6 are off study), and 22 have died. Of the 22 patients who died, 13 (59%) died of progressive CRPC and 9 (41%) died of other causes. There were 39 patients who came off study at some point after completing the first full cycle: 29 patients owing to progression to CRPC and 10 for other reasons. After the first full cycle, median time to CRPC was 4.0 years (range, 0.5-8.6 years), and median time to death was 6.6 years (range, 2.9-13.0 years). Median times from primary treatment to CRPC and to death were 9.7 years (range, 4.0-21.0 years) and 12.8 years (range, 5.5-21.6 years), respectively.

Results of the Cox proportional hazard models are presented in Table 2 . There is moderate evidence that time to PSA rise and time to PSA rise after T > 50 ng/dL were each associated with time to CRPC after controlling for age at study entry and Gleason category (P = .02 and .05, respectively). Each 30-day increase in the time to PSA rise was associated with a 21% decrease in the risk of CRPC (95% CI, 3%-36%). If a patient had a time to PSA rise of ≥ 60 days after their first T > 50 ng/dL, this was associated with a 71% decrease in the risk of CRPC (95% CI 92% decrease to 2% increase). A sensitivity analysis found that the association was similar for patients who had a time to PSA rise of ≥ 30 days after their first T > 50 ng/dL (57% decrease; 95% CI, 85% decrease to 28% increase) and for patients who had a time to PSA rise of ≥ 90 days after their first T > 50 ng/dL (69% decrease; 95% CI, 93% decrease to 37% increase). Associations between time to T > 50 ng/mL and PSAdt and time to CRPC are consistent with clinically important prognostic markers (each 30-day increase in time to T > 50 ng/dL is associated with a 32% decrease in the risk of CRPC, and each 30-day increase in PSAdt is associated with a 39% decrease in the risk of CRPC); however, this study had insufficient power to conclude statistical significance. No time intervals were associated with PCM. Figure 3 shows Kaplan-Meier survival curves predicted from the Cox models for time to CRPC and time to PCM for each time interval of interest.

Figure 3 Kaplan-Meier Curves. The Curves Show Time to Castration-Resistant Prostate Cancer (Left Panels) and Prostate Cancer Mortality (Right Panels) Predicted by 4 Time Intervals (Panel Rows) Above (Gray) and Below (Black) the Marker Median Values or, for Time From T > 50 ng/dL to PSA Rise, < 60 Days (Gray) versus ≥ 60 Days (Black) Abbreviations: PSA = prostate-specific antigen; T = testosterone.

Discussion

Recent randomized phase III trial data support the concept that IAD is not inferior in terms of survival compared with CAD for men with biochemically recurrent disease after definitive or salvage radiation. ¹ Patients on IAD have a net improved quality of life with fewer hot flashes, reduced sexual adverse effects, and long-term preservation of bone mineral density.^{1, 7, 8, 9, and 10}Given the significant heterogeneity in long-term response to IAD, prognostic markers that distinguish those with indolent versus aggressive disease would be useful. Patients with early PSA rise could be considered for novel clinical trial designs, given that this study's data indicate that they have a worse prognosis if they simply continue on intermittent ADT. Those patients with late PSA rise might require less therapy and be apt to experience mortality from other causes, rather than prostate cancer. Therefore, early identification of these patients not only may stratify risk groups but also could affect future treatment.

Previously, the present authors found that the duration of the first off-treatment interval is prognostic for both time to CRPC and death in this patient population. ³ Drawbacks to using the duration of the first off-treatment interval as a prognostic factor are that it requires waiting for the off-treatment interval to end and it does not take into account the biologic relationship between T and PSA. Knowing that changes in PSA levels over time have been found to be an important prognostic factor in other prostate cancer disease states,^{11, 12, 13, 14, 15, and 16}and hoping to find earlier indicators of prognosis than the duration of the first off-treatment interval, the present authors sought to evaluate the kinetics and relationships of PSA and T rise during the first off-treatment period.

The present analysis found that there is a significant association between a longer time to PSA rise during the first off-treatment interval and a longer time to CRPC. This is not surprising, given the prior results that defined the duration of the first off-treatment interval as prognostic for both CRPC and death. However, the time to PSA rise occurs at an earlier time point and can be used to inform subsequent treatment decisions. This analysis also found that those with a longer time (eg, ≥ 60 days) to PSA rise after first T > 50 ng/dL experience a longer time to CRPC. This is an important finding, because it confirms that a delay in PSA rise with a noncastrate T level is “good” and that a longer time from first T > 50 ng/dL to PSA rise has improved outcomes.

Although it is intuitive that a greater interval between T and PSA rise would lead to improved quality of life and long-term outcomes, this is the first study in which the concept has been confirmed. However, the explanation for this relationship is unclear. A simple explanation is that patients with a smaller overall tumor burden require greater overall stimulation from T to produce enough PSA to reach the threshold to start the next IAD cycle. Another more biologically relevant explanation relies on the known intratumoral production of androgens.^{17 and 18}It is possible that those tumors that respond very quickly to T with a rise in PSA are tumors that are already producing androgens, requiring very little exogenous T stimulation to produce and increase PSA, and hence are closer to the clinical definition of CRPC. Conversely, those tumors that are making little to no androgens rely more on testicular sources of T before the neoplastic cells are stimulated and PSA begins to rise.

Numerous studies have reported that PSAdt values after primary treatment,^{11, 12, 19, and 20}biochemical recurrence,^{13, 15, and 21}and in the castration-resistant^{22 and 23}and metastatic disease states^{16 and 24}are associated with poorer prognosis. Although an increased PSAdt is associated with a clinically important reduction in time to CRPC or PCM in the present data, these relationships did not meet statistical significance, owing to inadequate patient numbers. One challenge in this analysis is that PSAdt may not be accurate when calculated at very low PSA values. Additionally, PSAdt is usually calculated to indirectly measure tumor growth at steady-state androgen levels. It may be challenging to determine the effect of PSAdt in a setting in which T levels are actively rising.

A number of factors may have contributed to the lack of prognostic significance in some of the present evaluations. The patient population size was likely insufficient to find a marker of marginal or moderate significance. Furthermore, the long duration of time and heterogeneity in the course of subsequent treatments after the development of CRPC, as well as the small number of patients who had PCM (n = 13), limited the statistical power to test for prognostic time intervals for PCM. Finally, studying prognostic time intervals during IAD is challenging, because some patients progress during the first treatment cycle of AD whereas others may remain chronically castrate in the off-treatment period after only 1 treatment cycle of AD.

Owing to issues surrounding the morbidity and cost of continuous androgen deprivation (CAD), multiple randomized studies of intermittent androgen deprivation (IAD) versus CAD have been performed.^{1 and 2}Overall survival and time to castration resistance have been similar, but there is evidence of less toxicity for those treated with IAD. Recently, a large trial of IAD versus CAD for men who underwent radiation for prostate cancer found no difference in overall survival, with more prostate cancer–related deaths for those receiving IAD yet more non–prostate cancer–associated deaths for those receiving CAD. ¹ These findings suggest that IAD should be a standard of care for men treated with androgen deprivation (AD) in this setting.

There are few markers prognostic for progression to castration-resistant prostate cancer (CRPC) or prostate cancer mortality (PCM). This is particularly true for men undergoing IAD. The present authors have previously found that, when a predetermined prostate-specific antigen (PSA) threshold is used in a prospective trial of IAD, the duration from the end of AD to reaching that threshold (defining the first off-treatment interval) is prognostic for time to CRPC and death. ³ However, this prognostic time interval requires follow-up for long periods until the PSA threshold is met and AD is resumed for a second treatment cycle. An earlier biologic and prognostic marker would be useful both in the clinic and to stratify risk for future clinical trials. For this reason, this study evaluated times to testosterone (T) and PSA rises, times between these events, and PSA doubling time (PSAdt) during the first off-treatment interval of IAD as potential prognostic time intervals for time to CRPC and PCM in men with nonmetastatic castration-sensitive prostate cancer in this prospective trial of IAD.

Results

Between June 1996 and September 2006, 100 patients were accrued to the IAD trial. Of those, 62 were eligible for this exploratory analysis ( Figure 2 ). Characteristics of the eligible patients are presented in Table 1 . At diagnosis, the median age was 61.2 years (range, 48.3-74.8 years), with a median PSA of 9.7 ng/mL (range, 3.9-130.5 ng/mL). The median Gleason score was 3 + 4 (range, 6-9). The treatment choices were as follows: 47 patients underwent radical prostatectomy, 14 received definitive radiation therapy, and 1 patient received primary AD. Of the 14 patients who received radiation, 13 experienced biochemical recurrence, fulfilling the contemporary Phoenix criteria. ⁶ Median time from primary treatment to biochemical recurrence was 3.3 years (range, 0.5-14.6 years).

Figure 2 Consort Diagram. The Diagram Displays the Rationale for the Selection of the 62 Patients From the Clinical Trial for this Exploratory Analysis Abbreviations: AD = androgen deprivation; IAD = intermittent androgen deprivation; PSA = prostate-specific antigen; T = testosterone.

At study entry, the median age was 66.2 years (range, 51.2-81.1 years), with median baseline pre-study PSA and T levels of 3.9 ng/mL (range, 0.46-152.4 ng/mL) and 350 ng/dL (range, 140-640 ng/dL), respectively ( Table 1 ). There were 52 patients who achieved a PSA nadir of < 0.1 ng/mL during the first treatment cycle, whereas the remaining 10 patients had a median PSA nadir of 0.2 ng/mL (range, 0.1-0.4 ng/mL). During the first off-treatment interval, the median time of recovery to first T > 50 ng/dL was 3.1 months (range, 0-5.1 months). The median time to PSA rise was 4.5 months (range, 0.9-92.3 months), and the median time to PSA rise after first T > 50 ng/dL was 1.0 month (range, −0.9 to 88.5 months). The median duration of the first off-treatment interval was 9.5 months (range, 3.4 to more than 47.5 months). At the time of this report, 5 patients were still in their first off-treatment interval because they had not yet reached the PSA threshold for initiating the second cycle of IAD, and 3 of these patients still had an undetectable PSA; for these patients, the times to CRPC and PCM were censored at the date of the last clinic visit. The median PSAdt during the first off-treatment period starting from the first PSA rise was 1.2 months (range, 0-8.3 months).

Of 62 patients, 40 are alive (23 remain on IAD, 11 have CRPC, and 6 are off study), and 22 have died. Of the 22 patients who died, 13 (59%) died of progressive CRPC and 9 (41%) died of other causes. There were 39 patients who came off study at some point after completing the first full cycle: 29 patients owing to progression to CRPC and 10 for other reasons. After the first full cycle, median time to CRPC was 4.0 years (range, 0.5-8.6 years), and median time to death was 6.6 years (range, 2.9-13.0 years). Median times from primary treatment to CRPC and to death were 9.7 years (range, 4.0-21.0 years) and 12.8 years (range, 5.5-21.6 years), respectively.

Results of the Cox proportional hazard models are presented in Table 2 . There is moderate evidence that time to PSA rise and time to PSA rise after T > 50 ng/dL were each associated with time to CRPC after controlling for age at study entry and Gleason category (P = .02 and .05, respectively). Each 30-day increase in the time to PSA rise was associated with a 21% decrease in the risk of CRPC (95% CI, 3%-36%). If a patient had a time to PSA rise of ≥ 60 days after their first T > 50 ng/dL, this was associated with a 71% decrease in the risk of CRPC (95% CI 92% decrease to 2% increase). A sensitivity analysis found that the association was similar for patients who had a time to PSA rise of ≥ 30 days after their first T > 50 ng/dL (57% decrease; 95% CI, 85% decrease to 28% increase) and for patients who had a time to PSA rise of ≥ 90 days after their first T > 50 ng/dL (69% decrease; 95% CI, 93% decrease to 37% increase). Associations between time to T > 50 ng/mL and PSAdt and time to CRPC are consistent with clinically important prognostic markers (each 30-day increase in time to T > 50 ng/dL is associated with a 32% decrease in the risk of CRPC, and each 30-day increase in PSAdt is associated with a 39% decrease in the risk of CRPC); however, this study had insufficient power to conclude statistical significance. No time intervals were associated with PCM. Figure 3 shows Kaplan-Meier survival curves predicted from the Cox models for time to CRPC and time to PCM for each time interval of interest.

Figure 3 Kaplan-Meier Curves. The Curves Show Time to Castration-Resistant Prostate Cancer (Left Panels) and Prostate Cancer Mortality (Right Panels) Predicted by 4 Time Intervals (Panel Rows) Above (Gray) and Below (Black) the Marker Median Values or, for Time From T > 50 ng/dL to PSA Rise, < 60 Days (Gray) versus ≥ 60 Days (Black) Abbreviations: PSA = prostate-specific antigen; T = testosterone.

Discussion

Recent randomized phase III trial data support the concept that IAD is not inferior in terms of survival compared with CAD for men with biochemically recurrent disease after definitive or salvage radiation. ¹ Patients on IAD have a net improved quality of life with fewer hot flashes, reduced sexual adverse effects, and long-term preservation of bone mineral density.^{1, 7, 8, 9, and 10}Given the significant heterogeneity in long-term response to IAD, prognostic markers that distinguish those with indolent versus aggressive disease would be useful. Patients with early PSA rise could be considered for novel clinical trial designs, given that this study's data indicate that they have a worse prognosis if they simply continue on intermittent ADT. Those patients with late PSA rise might require less therapy and be apt to experience mortality from other causes, rather than prostate cancer. Therefore, early identification of these patients not only may stratify risk groups but also could affect future treatment.

Previously, the present authors found that the duration of the first off-treatment interval is prognostic for both time to CRPC and death in this patient population. ³ Drawbacks to using the duration of the first off-treatment interval as a prognostic factor are that it requires waiting for the off-treatment interval to end and it does not take into account the biologic relationship between T and PSA. Knowing that changes in PSA levels over time have been found to be an important prognostic factor in other prostate cancer disease states,^{11, 12, 13, 14, 15, and 16}and hoping to find earlier indicators of prognosis than the duration of the first off-treatment interval, the present authors sought to evaluate the kinetics and relationships of PSA and T rise during the first off-treatment period.

The present analysis found that there is a significant association between a longer time to PSA rise during the first off-treatment interval and a longer time to CRPC. This is not surprising, given the prior results that defined the duration of the first off-treatment interval as prognostic for both CRPC and death. However, the time to PSA rise occurs at an earlier time point and can be used to inform subsequent treatment decisions. This analysis also found that those with a longer time (eg, ≥ 60 days) to PSA rise after first T > 50 ng/dL experience a longer time to CRPC. This is an important finding, because it confirms that a delay in PSA rise with a noncastrate T level is “good” and that a longer time from first T > 50 ng/dL to PSA rise has improved outcomes.

Although it is intuitive that a greater interval between T and PSA rise would lead to improved quality of life and long-term outcomes, this is the first study in which the concept has been confirmed. However, the explanation for this relationship is unclear. A simple explanation is that patients with a smaller overall tumor burden require greater overall stimulation from T to produce enough PSA to reach the threshold to start the next IAD cycle. Another more biologically relevant explanation relies on the known intratumoral production of androgens.^{17 and 18}It is possible that those tumors that respond very quickly to T with a rise in PSA are tumors that are already producing androgens, requiring very little exogenous T stimulation to produce and increase PSA, and hence are closer to the clinical definition of CRPC. Conversely, those tumors that are making little to no androgens rely more on testicular sources of T before the neoplastic cells are stimulated and PSA begins to rise.

Numerous studies have reported that PSAdt values after primary treatment,^{11, 12, 19, and 20}biochemical recurrence,^{13, 15, and 21}and in the castration-resistant^{22 and 23}and metastatic disease states^{16 and 24}are associated with poorer prognosis. Although an increased PSAdt is associated with a clinically important reduction in time to CRPC or PCM in the present data, these relationships did not meet statistical significance, owing to inadequate patient numbers. One challenge in this analysis is that PSAdt may not be accurate when calculated at very low PSA values. Additionally, PSAdt is usually calculated to indirectly measure tumor growth at steady-state androgen levels. It may be challenging to determine the effect of PSAdt in a setting in which T levels are actively rising.

A number of factors may have contributed to the lack of prognostic significance in some of the present evaluations. The patient population size was likely insufficient to find a marker of marginal or moderate significance. Furthermore, the long duration of time and heterogeneity in the course of subsequent treatments after the development of CRPC, as well as the small number of patients who had PCM (n = 13), limited the statistical power to test for prognostic time intervals for PCM. Finally, studying prognostic time intervals during IAD is challenging, because some patients progress during the first treatment cycle of AD whereas others may remain chronically castrate in the off-treatment period after only 1 treatment cycle of AD.

Owing to issues surrounding the morbidity and cost of continuous androgen deprivation (CAD), multiple randomized studies of intermittent androgen deprivation (IAD) versus CAD have been performed.^{1 and 2}Overall survival and time to castration resistance have been similar, but there is evidence of less toxicity for those treated with IAD. Recently, a large trial of IAD versus CAD for men who underwent radiation for prostate cancer found no difference in overall survival, with more prostate cancer–related deaths for those receiving IAD yet more non–prostate cancer–associated deaths for those receiving CAD. ¹ These findings suggest that IAD should be a standard of care for men treated with androgen deprivation (AD) in this setting.

There are few markers prognostic for progression to castration-resistant prostate cancer (CRPC) or prostate cancer mortality (PCM). This is particularly true for men undergoing IAD. The present authors have previously found that, when a predetermined prostate-specific antigen (PSA) threshold is used in a prospective trial of IAD, the duration from the end of AD to reaching that threshold (defining the first off-treatment interval) is prognostic for time to CRPC and death. ³ However, this prognostic time interval requires follow-up for long periods until the PSA threshold is met and AD is resumed for a second treatment cycle. An earlier biologic and prognostic marker would be useful both in the clinic and to stratify risk for future clinical trials. For this reason, this study evaluated times to testosterone (T) and PSA rises, times between these events, and PSA doubling time (PSAdt) during the first off-treatment interval of IAD as potential prognostic time intervals for time to CRPC and PCM in men with nonmetastatic castration-sensitive prostate cancer in this prospective trial of IAD.

Results

Between June 1996 and September 2006, 100 patients were accrued to the IAD trial. Of those, 62 were eligible for this exploratory analysis ( Figure 2 ). Characteristics of the eligible patients are presented in Table 1 . At diagnosis, the median age was 61.2 years (range, 48.3-74.8 years), with a median PSA of 9.7 ng/mL (range, 3.9-130.5 ng/mL). The median Gleason score was 3 + 4 (range, 6-9). The treatment choices were as follows: 47 patients underwent radical prostatectomy, 14 received definitive radiation therapy, and 1 patient received primary AD. Of the 14 patients who received radiation, 13 experienced biochemical recurrence, fulfilling the contemporary Phoenix criteria. ⁶ Median time from primary treatment to biochemical recurrence was 3.3 years (range, 0.5-14.6 years).

Figure 2 Consort Diagram. The Diagram Displays the Rationale for the Selection of the 62 Patients From the Clinical Trial for this Exploratory Analysis Abbreviations: AD = androgen deprivation; IAD = intermittent androgen deprivation; PSA = prostate-specific antigen; T = testosterone.

At study entry, the median age was 66.2 years (range, 51.2-81.1 years), with median baseline pre-study PSA and T levels of 3.9 ng/mL (range, 0.46-152.4 ng/mL) and 350 ng/dL (range, 140-640 ng/dL), respectively ( Table 1 ). There were 52 patients who achieved a PSA nadir of < 0.1 ng/mL during the first treatment cycle, whereas the remaining 10 patients had a median PSA nadir of 0.2 ng/mL (range, 0.1-0.4 ng/mL). During the first off-treatment interval, the median time of recovery to first T > 50 ng/dL was 3.1 months (range, 0-5.1 months). The median time to PSA rise was 4.5 months (range, 0.9-92.3 months), and the median time to PSA rise after first T > 50 ng/dL was 1.0 month (range, −0.9 to 88.5 months). The median duration of the first off-treatment interval was 9.5 months (range, 3.4 to more than 47.5 months). At the time of this report, 5 patients were still in their first off-treatment interval because they had not yet reached the PSA threshold for initiating the second cycle of IAD, and 3 of these patients still had an undetectable PSA; for these patients, the times to CRPC and PCM were censored at the date of the last clinic visit. The median PSAdt during the first off-treatment period starting from the first PSA rise was 1.2 months (range, 0-8.3 months).

Of 62 patients, 40 are alive (23 remain on IAD, 11 have CRPC, and 6 are off study), and 22 have died. Of the 22 patients who died, 13 (59%) died of progressive CRPC and 9 (41%) died of other causes. There were 39 patients who came off study at some point after completing the first full cycle: 29 patients owing to progression to CRPC and 10 for other reasons. After the first full cycle, median time to CRPC was 4.0 years (range, 0.5-8.6 years), and median time to death was 6.6 years (range, 2.9-13.0 years). Median times from primary treatment to CRPC and to death were 9.7 years (range, 4.0-21.0 years) and 12.8 years (range, 5.5-21.6 years), respectively.

Results of the Cox proportional hazard models are presented in Table 2 . There is moderate evidence that time to PSA rise and time to PSA rise after T > 50 ng/dL were each associated with time to CRPC after controlling for age at study entry and Gleason category (P = .02 and .05, respectively). Each 30-day increase in the time to PSA rise was associated with a 21% decrease in the risk of CRPC (95% CI, 3%-36%). If a patient had a time to PSA rise of ≥ 60 days after their first T > 50 ng/dL, this was associated with a 71% decrease in the risk of CRPC (95% CI 92% decrease to 2% increase). A sensitivity analysis found that the association was similar for patients who had a time to PSA rise of ≥ 30 days after their first T > 50 ng/dL (57% decrease; 95% CI, 85% decrease to 28% increase) and for patients who had a time to PSA rise of ≥ 90 days after their first T > 50 ng/dL (69% decrease; 95% CI, 93% decrease to 37% increase). Associations between time to T > 50 ng/mL and PSAdt and time to CRPC are consistent with clinically important prognostic markers (each 30-day increase in time to T > 50 ng/dL is associated with a 32% decrease in the risk of CRPC, and each 30-day increase in PSAdt is associated with a 39% decrease in the risk of CRPC); however, this study had insufficient power to conclude statistical significance. No time intervals were associated with PCM. Figure 3 shows Kaplan-Meier survival curves predicted from the Cox models for time to CRPC and time to PCM for each time interval of interest.

Figure 3 Kaplan-Meier Curves. The Curves Show Time to Castration-Resistant Prostate Cancer (Left Panels) and Prostate Cancer Mortality (Right Panels) Predicted by 4 Time Intervals (Panel Rows) Above (Gray) and Below (Black) the Marker Median Values or, for Time From T > 50 ng/dL to PSA Rise, < 60 Days (Gray) versus ≥ 60 Days (Black) Abbreviations: PSA = prostate-specific antigen; T = testosterone.

Discussion

Recent randomized phase III trial data support the concept that IAD is not inferior in terms of survival compared with CAD for men with biochemically recurrent disease after definitive or salvage radiation. ¹ Patients on IAD have a net improved quality of life with fewer hot flashes, reduced sexual adverse effects, and long-term preservation of bone mineral density.^{1, 7, 8, 9, and 10}Given the significant heterogeneity in long-term response to IAD, prognostic markers that distinguish those with indolent versus aggressive disease would be useful. Patients with early PSA rise could be considered for novel clinical trial designs, given that this study's data indicate that they have a worse prognosis if they simply continue on intermittent ADT. Those patients with late PSA rise might require less therapy and be apt to experience mortality from other causes, rather than prostate cancer. Therefore, early identification of these patients not only may stratify risk groups but also could affect future treatment.

Previously, the present authors found that the duration of the first off-treatment interval is prognostic for both time to CRPC and death in this patient population. ³ Drawbacks to using the duration of the first off-treatment interval as a prognostic factor are that it requires waiting for the off-treatment interval to end and it does not take into account the biologic relationship between T and PSA. Knowing that changes in PSA levels over time have been found to be an important prognostic factor in other prostate cancer disease states,^{11, 12, 13, 14, 15, and 16}and hoping to find earlier indicators of prognosis than the duration of the first off-treatment interval, the present authors sought to evaluate the kinetics and relationships of PSA and T rise during the first off-treatment period.

The present analysis found that there is a significant association between a longer time to PSA rise during the first off-treatment interval and a longer time to CRPC. This is not surprising, given the prior results that defined the duration of the first off-treatment interval as prognostic for both CRPC and death. However, the time to PSA rise occurs at an earlier time point and can be used to inform subsequent treatment decisions. This analysis also found that those with a longer time (eg, ≥ 60 days) to PSA rise after first T > 50 ng/dL experience a longer time to CRPC. This is an important finding, because it confirms that a delay in PSA rise with a noncastrate T level is “good” and that a longer time from first T > 50 ng/dL to PSA rise has improved outcomes.

Although it is intuitive that a greater interval between T and PSA rise would lead to improved quality of life and long-term outcomes, this is the first study in which the concept has been confirmed. However, the explanation for this relationship is unclear. A simple explanation is that patients with a smaller overall tumor burden require greater overall stimulation from T to produce enough PSA to reach the threshold to start the next IAD cycle. Another more biologically relevant explanation relies on the known intratumoral production of androgens.^{17 and 18}It is possible that those tumors that respond very quickly to T with a rise in PSA are tumors that are already producing androgens, requiring very little exogenous T stimulation to produce and increase PSA, and hence are closer to the clinical definition of CRPC. Conversely, those tumors that are making little to no androgens rely more on testicular sources of T before the neoplastic cells are stimulated and PSA begins to rise.

Numerous studies have reported that PSAdt values after primary treatment,^{11, 12, 19, and 20}biochemical recurrence,^{13, 15, and 21}and in the castration-resistant^{22 and 23}and metastatic disease states^{16 and 24}are associated with poorer prognosis. Although an increased PSAdt is associated with a clinically important reduction in time to CRPC or PCM in the present data, these relationships did not meet statistical significance, owing to inadequate patient numbers. One challenge in this analysis is that PSAdt may not be accurate when calculated at very low PSA values. Additionally, PSAdt is usually calculated to indirectly measure tumor growth at steady-state androgen levels. It may be challenging to determine the effect of PSAdt in a setting in which T levels are actively rising.

A number of factors may have contributed to the lack of prognostic significance in some of the present evaluations. The patient population size was likely insufficient to find a marker of marginal or moderate significance. Furthermore, the long duration of time and heterogeneity in the course of subsequent treatments after the development of CRPC, as well as the small number of patients who had PCM (n = 13), limited the statistical power to test for prognostic time intervals for PCM. Finally, studying prognostic time intervals during IAD is challenging, because some patients progress during the first treatment cycle of AD whereas others may remain chronically castrate in the off-treatment period after only 1 treatment cycle of AD.

Owing to issues surrounding the morbidity and cost of continuous androgen deprivation (CAD), multiple randomized studies of intermittent androgen deprivation (IAD) versus CAD have been performed.^{1 and 2}Overall survival and time to castration resistance have been similar, but there is evidence of less toxicity for those treated with IAD. Recently, a large trial of IAD versus CAD for men who underwent radiation for prostate cancer found no difference in overall survival, with more prostate cancer–related deaths for those receiving IAD yet more non–prostate cancer–associated deaths for those receiving CAD. ¹ These findings suggest that IAD should be a standard of care for men treated with androgen deprivation (AD) in this setting.

There are few markers prognostic for progression to castration-resistant prostate cancer (CRPC) or prostate cancer mortality (PCM). This is particularly true for men undergoing IAD. The present authors have previously found that, when a predetermined prostate-specific antigen (PSA) threshold is used in a prospective trial of IAD, the duration from the end of AD to reaching that threshold (defining the first off-treatment interval) is prognostic for time to CRPC and death. ³ However, this prognostic time interval requires follow-up for long periods until the PSA threshold is met and AD is resumed for a second treatment cycle. An earlier biologic and prognostic marker would be useful both in the clinic and to stratify risk for future clinical trials. For this reason, this study evaluated times to testosterone (T) and PSA rises, times between these events, and PSA doubling time (PSAdt) during the first off-treatment interval of IAD as potential prognostic time intervals for time to CRPC and PCM in men with nonmetastatic castration-sensitive prostate cancer in this prospective trial of IAD.

Results

Between June 1996 and September 2006, 100 patients were accrued to the IAD trial. Of those, 62 were eligible for this exploratory analysis ( Figure 2 ). Characteristics of the eligible patients are presented in Table 1 . At diagnosis, the median age was 61.2 years (range, 48.3-74.8 years), with a median PSA of 9.7 ng/mL (range, 3.9-130.5 ng/mL). The median Gleason score was 3 + 4 (range, 6-9). The treatment choices were as follows: 47 patients underwent radical prostatectomy, 14 received definitive radiation therapy, and 1 patient received primary AD. Of the 14 patients who received radiation, 13 experienced biochemical recurrence, fulfilling the contemporary Phoenix criteria. ⁶ Median time from primary treatment to biochemical recurrence was 3.3 years (range, 0.5-14.6 years).

Figure 2 Consort Diagram. The Diagram Displays the Rationale for the Selection of the 62 Patients From the Clinical Trial for this Exploratory Analysis Abbreviations: AD = androgen deprivation; IAD = intermittent androgen deprivation; PSA = prostate-specific antigen; T = testosterone.

At study entry, the median age was 66.2 years (range, 51.2-81.1 years), with median baseline pre-study PSA and T levels of 3.9 ng/mL (range, 0.46-152.4 ng/mL) and 350 ng/dL (range, 140-640 ng/dL), respectively ( Table 1 ). There were 52 patients who achieved a PSA nadir of < 0.1 ng/mL during the first treatment cycle, whereas the remaining 10 patients had a median PSA nadir of 0.2 ng/mL (range, 0.1-0.4 ng/mL). During the first off-treatment interval, the median time of recovery to first T > 50 ng/dL was 3.1 months (range, 0-5.1 months). The median time to PSA rise was 4.5 months (range, 0.9-92.3 months), and the median time to PSA rise after first T > 50 ng/dL was 1.0 month (range, −0.9 to 88.5 months). The median duration of the first off-treatment interval was 9.5 months (range, 3.4 to more than 47.5 months). At the time of this report, 5 patients were still in their first off-treatment interval because they had not yet reached the PSA threshold for initiating the second cycle of IAD, and 3 of these patients still had an undetectable PSA; for these patients, the times to CRPC and PCM were censored at the date of the last clinic visit. The median PSAdt during the first off-treatment period starting from the first PSA rise was 1.2 months (range, 0-8.3 months).

Of 62 patients, 40 are alive (23 remain on IAD, 11 have CRPC, and 6 are off study), and 22 have died. Of the 22 patients who died, 13 (59%) died of progressive CRPC and 9 (41%) died of other causes. There were 39 patients who came off study at some point after completing the first full cycle: 29 patients owing to progression to CRPC and 10 for other reasons. After the first full cycle, median time to CRPC was 4.0 years (range, 0.5-8.6 years), and median time to death was 6.6 years (range, 2.9-13.0 years). Median times from primary treatment to CRPC and to death were 9.7 years (range, 4.0-21.0 years) and 12.8 years (range, 5.5-21.6 years), respectively.

Results of the Cox proportional hazard models are presented in Table 2 . There is moderate evidence that time to PSA rise and time to PSA rise after T > 50 ng/dL were each associated with time to CRPC after controlling for age at study entry and Gleason category (P = .02 and .05, respectively). Each 30-day increase in the time to PSA rise was associated with a 21% decrease in the risk of CRPC (95% CI, 3%-36%). If a patient had a time to PSA rise of ≥ 60 days after their first T > 50 ng/dL, this was associated with a 71% decrease in the risk of CRPC (95% CI 92% decrease to 2% increase). A sensitivity analysis found that the association was similar for patients who had a time to PSA rise of ≥ 30 days after their first T > 50 ng/dL (57% decrease; 95% CI, 85% decrease to 28% increase) and for patients who had a time to PSA rise of ≥ 90 days after their first T > 50 ng/dL (69% decrease; 95% CI, 93% decrease to 37% increase). Associations between time to T > 50 ng/mL and PSAdt and time to CRPC are consistent with clinically important prognostic markers (each 30-day increase in time to T > 50 ng/dL is associated with a 32% decrease in the risk of CRPC, and each 30-day increase in PSAdt is associated with a 39% decrease in the risk of CRPC); however, this study had insufficient power to conclude statistical significance. No time intervals were associated with PCM. Figure 3 shows Kaplan-Meier survival curves predicted from the Cox models for time to CRPC and time to PCM for each time interval of interest.

Figure 3 Kaplan-Meier Curves. The Curves Show Time to Castration-Resistant Prostate Cancer (Left Panels) and Prostate Cancer Mortality (Right Panels) Predicted by 4 Time Intervals (Panel Rows) Above (Gray) and Below (Black) the Marker Median Values or, for Time From T > 50 ng/dL to PSA Rise, < 60 Days (Gray) versus ≥ 60 Days (Black) Abbreviations: PSA = prostate-specific antigen; T = testosterone.

Discussion

Recent randomized phase III trial data support the concept that IAD is not inferior in terms of survival compared with CAD for men with biochemically recurrent disease after definitive or salvage radiation. ¹ Patients on IAD have a net improved quality of life with fewer hot flashes, reduced sexual adverse effects, and long-term preservation of bone mineral density.^{1, 7, 8, 9, and 10}Given the significant heterogeneity in long-term response to IAD, prognostic markers that distinguish those with indolent versus aggressive disease would be useful. Patients with early PSA rise could be considered for novel clinical trial designs, given that this study's data indicate that they have a worse prognosis if they simply continue on intermittent ADT. Those patients with late PSA rise might require less therapy and be apt to experience mortality from other causes, rather than prostate cancer. Therefore, early identification of these patients not only may stratify risk groups but also could affect future treatment.

Previously, the present authors found that the duration of the first off-treatment interval is prognostic for both time to CRPC and death in this patient population. ³ Drawbacks to using the duration of the first off-treatment interval as a prognostic factor are that it requires waiting for the off-treatment interval to end and it does not take into account the biologic relationship between T and PSA. Knowing that changes in PSA levels over time have been found to be an important prognostic factor in other prostate cancer disease states,^{11, 12, 13, 14, 15, and 16}and hoping to find earlier indicators of prognosis than the duration of the first off-treatment interval, the present authors sought to evaluate the kinetics and relationships of PSA and T rise during the first off-treatment period.

The present analysis found that there is a significant association between a longer time to PSA rise during the first off-treatment interval and a longer time to CRPC. This is not surprising, given the prior results that defined the duration of the first off-treatment interval as prognostic for both CRPC and death. However, the time to PSA rise occurs at an earlier time point and can be used to inform subsequent treatment decisions. This analysis also found that those with a longer time (eg, ≥ 60 days) to PSA rise after first T > 50 ng/dL experience a longer time to CRPC. This is an important finding, because it confirms that a delay in PSA rise with a noncastrate T level is “good” and that a longer time from first T > 50 ng/dL to PSA rise has improved outcomes.

Although it is intuitive that a greater interval between T and PSA rise would lead to improved quality of life and long-term outcomes, this is the first study in which the concept has been confirmed. However, the explanation for this relationship is unclear. A simple explanation is that patients with a smaller overall tumor burden require greater overall stimulation from T to produce enough PSA to reach the threshold to start the next IAD cycle. Another more biologically relevant explanation relies on the known intratumoral production of androgens.^{17 and 18}It is possible that those tumors that respond very quickly to T with a rise in PSA are tumors that are already producing androgens, requiring very little exogenous T stimulation to produce and increase PSA, and hence are closer to the clinical definition of CRPC. Conversely, those tumors that are making little to no androgens rely more on testicular sources of T before the neoplastic cells are stimulated and PSA begins to rise.

Numerous studies have reported that PSAdt values after primary treatment,^{11, 12, 19, and 20}biochemical recurrence,^{13, 15, and 21}and in the castration-resistant^{22 and 23}and metastatic disease states^{16 and 24}are associated with poorer prognosis. Although an increased PSAdt is associated with a clinically important reduction in time to CRPC or PCM in the present data, these relationships did not meet statistical significance, owing to inadequate patient numbers. One challenge in this analysis is that PSAdt may not be accurate when calculated at very low PSA values. Additionally, PSAdt is usually calculated to indirectly measure tumor growth at steady-state androgen levels. It may be challenging to determine the effect of PSAdt in a setting in which T levels are actively rising.

A number of factors may have contributed to the lack of prognostic significance in some of the present evaluations. The patient population size was likely insufficient to find a marker of marginal or moderate significance. Furthermore, the long duration of time and heterogeneity in the course of subsequent treatments after the development of CRPC, as well as the small number of patients who had PCM (n = 13), limited the statistical power to test for prognostic time intervals for PCM. Finally, studying prognostic time intervals during IAD is challenging, because some patients progress during the first treatment cycle of AD whereas others may remain chronically castrate in the off-treatment period after only 1 treatment cycle of AD.

Owing to issues surrounding the morbidity and cost of continuous androgen deprivation (CAD), multiple randomized studies of intermittent androgen deprivation (IAD) versus CAD have been performed.^{1 and 2}Overall survival and time to castration resistance have been similar, but there is evidence of less toxicity for those treated with IAD. Recently, a large trial of IAD versus CAD for men who underwent radiation for prostate cancer found no difference in overall survival, with more prostate cancer–related deaths for those receiving IAD yet more non–prostate cancer–associated deaths for those receiving CAD. ¹ These findings suggest that IAD should be a standard of care for men treated with androgen deprivation (AD) in this setting.

There are few markers prognostic for progression to castration-resistant prostate cancer (CRPC) or prostate cancer mortality (PCM). This is particularly true for men undergoing IAD. The present authors have previously found that, when a predetermined prostate-specific antigen (PSA) threshold is used in a prospective trial of IAD, the duration from the end of AD to reaching that threshold (defining the first off-treatment interval) is prognostic for time to CRPC and death. ³ However, this prognostic time interval requires follow-up for long periods until the PSA threshold is met and AD is resumed for a second treatment cycle. An earlier biologic and prognostic marker would be useful both in the clinic and to stratify risk for future clinical trials. For this reason, this study evaluated times to testosterone (T) and PSA rises, times between these events, and PSA doubling time (PSAdt) during the first off-treatment interval of IAD as potential prognostic time intervals for time to CRPC and PCM in men with nonmetastatic castration-sensitive prostate cancer in this prospective trial of IAD.

Results

Between June 1996 and September 2006, 100 patients were accrued to the IAD trial. Of those, 62 were eligible for this exploratory analysis ( Figure 2 ). Characteristics of the eligible patients are presented in Table 1 . At diagnosis, the median age was 61.2 years (range, 48.3-74.8 years), with a median PSA of 9.7 ng/mL (range, 3.9-130.5 ng/mL). The median Gleason score was 3 + 4 (range, 6-9). The treatment choices were as follows: 47 patients underwent radical prostatectomy, 14 received definitive radiation therapy, and 1 patient received primary AD. Of the 14 patients who received radiation, 13 experienced biochemical recurrence, fulfilling the contemporary Phoenix criteria. ⁶ Median time from primary treatment to biochemical recurrence was 3.3 years (range, 0.5-14.6 years).

Figure 2 Consort Diagram. The Diagram Displays the Rationale for the Selection of the 62 Patients From the Clinical Trial for this Exploratory Analysis Abbreviations: AD = androgen deprivation; IAD = intermittent androgen deprivation; PSA = prostate-specific antigen; T = testosterone.

At study entry, the median age was 66.2 years (range, 51.2-81.1 years), with median baseline pre-study PSA and T levels of 3.9 ng/mL (range, 0.46-152.4 ng/mL) and 350 ng/dL (range, 140-640 ng/dL), respectively ( Table 1 ). There were 52 patients who achieved a PSA nadir of < 0.1 ng/mL during the first treatment cycle, whereas the remaining 10 patients had a median PSA nadir of 0.2 ng/mL (range, 0.1-0.4 ng/mL). During the first off-treatment interval, the median time of recovery to first T > 50 ng/dL was 3.1 months (range, 0-5.1 months). The median time to PSA rise was 4.5 months (range, 0.9-92.3 months), and the median time to PSA rise after first T > 50 ng/dL was 1.0 month (range, −0.9 to 88.5 months). The median duration of the first off-treatment interval was 9.5 months (range, 3.4 to more than 47.5 months). At the time of this report, 5 patients were still in their first off-treatment interval because they had not yet reached the PSA threshold for initiating the second cycle of IAD, and 3 of these patients still had an undetectable PSA; for these patients, the times to CRPC and PCM were censored at the date of the last clinic visit. The median PSAdt during the first off-treatment period starting from the first PSA rise was 1.2 months (range, 0-8.3 months).

Of 62 patients, 40 are alive (23 remain on IAD, 11 have CRPC, and 6 are off study), and 22 have died. Of the 22 patients who died, 13 (59%) died of progressive CRPC and 9 (41%) died of other causes. There were 39 patients who came off study at some point after completing the first full cycle: 29 patients owing to progression to CRPC and 10 for other reasons. After the first full cycle, median time to CRPC was 4.0 years (range, 0.5-8.6 years), and median time to death was 6.6 years (range, 2.9-13.0 years). Median times from primary treatment to CRPC and to death were 9.7 years (range, 4.0-21.0 years) and 12.8 years (range, 5.5-21.6 years), respectively.

Results of the Cox proportional hazard models are presented in Table 2 . There is moderate evidence that time to PSA rise and time to PSA rise after T > 50 ng/dL were each associated with time to CRPC after controlling for age at study entry and Gleason category (P = .02 and .05, respectively). Each 30-day increase in the time to PSA rise was associated with a 21% decrease in the risk of CRPC (95% CI, 3%-36%). If a patient had a time to PSA rise of ≥ 60 days after their first T > 50 ng/dL, this was associated with a 71% decrease in the risk of CRPC (95% CI 92% decrease to 2% increase). A sensitivity analysis found that the association was similar for patients who had a time to PSA rise of ≥ 30 days after their first T > 50 ng/dL (57% decrease; 95% CI, 85% decrease to 28% increase) and for patients who had a time to PSA rise of ≥ 90 days after their first T > 50 ng/dL (69% decrease; 95% CI, 93% decrease to 37% increase). Associations between time to T > 50 ng/mL and PSAdt and time to CRPC are consistent with clinically important prognostic markers (each 30-day increase in time to T > 50 ng/dL is associated with a 32% decrease in the risk of CRPC, and each 30-day increase in PSAdt is associated with a 39% decrease in the risk of CRPC); however, this study had insufficient power to conclude statistical significance. No time intervals were associated with PCM. Figure 3 shows Kaplan-Meier survival curves predicted from the Cox models for time to CRPC and time to PCM for each time interval of interest.

Figure 3 Kaplan-Meier Curves. The Curves Show Time to Castration-Resistant Prostate Cancer (Left Panels) and Prostate Cancer Mortality (Right Panels) Predicted by 4 Time Intervals (Panel Rows) Above (Gray) and Below (Black) the Marker Median Values or, for Time From T > 50 ng/dL to PSA Rise, < 60 Days (Gray) versus ≥ 60 Days (Black) Abbreviations: PSA = prostate-specific antigen; T = testosterone.

Discussion

Recent randomized phase III trial data support the concept that IAD is not inferior in terms of survival compared with CAD for men with biochemically recurrent disease after definitive or salvage radiation. ¹ Patients on IAD have a net improved quality of life with fewer hot flashes, reduced sexual adverse effects, and long-term preservation of bone mineral density.^{1, 7, 8, 9, and 10}Given the significant heterogeneity in long-term response to IAD, prognostic markers that distinguish those with indolent versus aggressive disease would be useful. Patients with early PSA rise could be considered for novel clinical trial designs, given that this study's data indicate that they have a worse prognosis if they simply continue on intermittent ADT. Those patients with late PSA rise might require less therapy and be apt to experience mortality from other causes, rather than prostate cancer. Therefore, early identification of these patients not only may stratify risk groups but also could affect future treatment.

Previously, the present authors found that the duration of the first off-treatment interval is prognostic for both time to CRPC and death in this patient population. ³ Drawbacks to using the duration of the first off-treatment interval as a prognostic factor are that it requires waiting for the off-treatment interval to end and it does not take into account the biologic relationship between T and PSA. Knowing that changes in PSA levels over time have been found to be an important prognostic factor in other prostate cancer disease states,^{11, 12, 13, 14, 15, and 16}and hoping to find earlier indicators of prognosis than the duration of the first off-treatment interval, the present authors sought to evaluate the kinetics and relationships of PSA and T rise during the first off-treatment period.

The present analysis found that there is a significant association between a longer time to PSA rise during the first off-treatment interval and a longer time to CRPC. This is not surprising, given the prior results that defined the duration of the first off-treatment interval as prognostic for both CRPC and death. However, the time to PSA rise occurs at an earlier time point and can be used to inform subsequent treatment decisions. This analysis also found that those with a longer time (eg, ≥ 60 days) to PSA rise after first T > 50 ng/dL experience a longer time to CRPC. This is an important finding, because it confirms that a delay in PSA rise with a noncastrate T level is “good” and that a longer time from first T > 50 ng/dL to PSA rise has improved outcomes.

Although it is intuitive that a greater interval between T and PSA rise would lead to improved quality of life and long-term outcomes, this is the first study in which the concept has been confirmed. However, the explanation for this relationship is unclear. A simple explanation is that patients with a smaller overall tumor burden require greater overall stimulation from T to produce enough PSA to reach the threshold to start the next IAD cycle. Another more biologically relevant explanation relies on the known intratumoral production of androgens.^{17 and 18}It is possible that those tumors that respond very quickly to T with a rise in PSA are tumors that are already producing androgens, requiring very little exogenous T stimulation to produce and increase PSA, and hence are closer to the clinical definition of CRPC. Conversely, those tumors that are making little to no androgens rely more on testicular sources of T before the neoplastic cells are stimulated and PSA begins to rise.

Numerous studies have reported that PSAdt values after primary treatment,^{11, 12, 19, and 20}biochemical recurrence,^{13, 15, and 21}and in the castration-resistant^{22 and 23}and metastatic disease states^{16 and 24}are associated with poorer prognosis. Although an increased PSAdt is associated with a clinically important reduction in time to CRPC or PCM in the present data, these relationships did not meet statistical significance, owing to inadequate patient numbers. One challenge in this analysis is that PSAdt may not be accurate when calculated at very low PSA values. Additionally, PSAdt is usually calculated to indirectly measure tumor growth at steady-state androgen levels. It may be challenging to determine the effect of PSAdt in a setting in which T levels are actively rising.

A number of factors may have contributed to the lack of prognostic significance in some of the present evaluations. The patient population size was likely insufficient to find a marker of marginal or moderate significance. Furthermore, the long duration of time and heterogeneity in the course of subsequent treatments after the development of CRPC, as well as the small number of patients who had PCM (n = 13), limited the statistical power to test for prognostic time intervals for PCM. Finally, studying prognostic time intervals during IAD is challenging, because some patients progress during the first treatment cycle of AD whereas others may remain chronically castrate in the off-treatment period after only 1 treatment cycle of AD.