Efficacy of Enzalutamide Following Abiraterone Acetate in Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer Patients

In this retrospective study, we examined the antitumour activity of enzalutamide after abiraterone in mCRPC patients. We found that the efficacy of enzalutamide was comparable in docetaxel-experienced and docetaxel-naive patients in terms of confirmed PSA response rates (22% vs 26%;p = 0.8), median time to radiologic/clinical progression (4.6 mo vs 6.6 mo;p = 0.6), and median OS (10.6 mo vs 8.6 mo;p = 0.2). These findings are somewhat surprising because we had anticipated that enzalutamide would be less efficacious in more heavily pretreated patients, that is, those who had also received prior docetaxel. The differences in baseline age and LDH between the cohorts, which were biased against the docetaxel-naive group, may have had an impact on our results, although age and LDH have not been shown differentially to affect the benefit of enzalutamide[10] and [11].

Population-based studies have shown that only a third of mCRPC patients receive docetaxel [12] . However, results from the recently presented Androgen Ablation Therapy with or Without Chemotherapy in Treating Patients with Metastatic Prostate Cancer (CHAARTED) trial [13] are likely to lead to an increase in docetaxel use in patients with high-risk metastatic castration-sensitive disease. Our results, which indicate that earlier treatment with docetaxel does not have a large impact on the activity of enzalutamide after abiraterone, may therefore be of increasing relevance to the management of patients with metastatic prostate cancer.

The findings of this study point to a common mechanism of resistance to enzalutamide in docetaxel-experienced and -naive patients. Resistance mechanisms to enzalutamide include induction of AR splice variants [14] , an activating point mutation in the AR (F876L)[15] and [16], upregulation of the stress-activated chaperone protein clusterin [17] , enhanced protein kinase C/Twist1 signalling [18] , and activation of the glucocorticoid receptor [19] . These factors do not overlap with known mechanisms of docetaxel resistance [20] , although it has been postulated that cross-resistance may develop between docetaxel, enzalutamide, and abiraterone because all of these agents are known to modulate AR nuclear translocation [21] . The similar efficacy of enzalutamide regardless of prior docetaxel use in our study suggests that cross-resistance between abiraterone and enzalutamide emerges independently of docetaxel.

The PSA response rate to enzalutamide in our cohort was 23%, median time to progression was 5.3 mo, and median OS was 10.6 mo. These results are broadly in keeping with earlier studies that reported PSA response rates of 13–29%, median PFS of 2.9–4.0 mo, and median OS of 7.3–7.5 mo in mCRPC patients treated with enzalutamide after abiraterone[4], [5], [6], [7], [8], and [9]. In our chemotherapy-naive cohort, PSA declines ≥50% and ≥30% were seen in 23% and 35% of patients, respectively. These findings are also comparable with the only prior study to include chemotherapy-naive patients [9] , which reported PSA declines ≥30% in 40% of patients. Collectively, these data indicate that enzalutamide has relatively modest activity when used after abiraterone. Abiraterone is also reported to have limited efficacy after prior treatment with enzalutamide[22] and [23]. This lends weight to the possibility of a common mechanism of resistance between enzalutamide and abiraterone. In support of this, a recent report linked detection of the AR-V7 splice variant with primary and acquired resistance to both enzalutamide and abiraterone [24] .

Despite its limited overall activity, enzalutamide did confer longer-term benefit for a subset of patients in our study with 21% of patients remaining on treatment for at least 6 mo. However, predicting which patients will benefit from treatment with enzalutamide remains a major challenge. We could not find any clinicopathologic factors that predicted a PSA decline ≥50% on enzalutamide. Although prior PSA decline ≥50% on abiraterone has been linked to subsequent response to enzalutamide[8] and [9], we and other investigators[4] and [5]have not corroborated these findings. Gleason score has also been implicated as a predictor for enzalutamide response following abiraterone [4] ; however, we did not find this to be the case. Similarly, although coadministration of corticosteroids was found to be associated with inferior survival parameters in a post hoc analysis of the Safety and Efficacy Study of MDV3100 in the Patients with Castration-resistant Prostate Cancer Who Have Been Previously Treated with Docetaxel-based Chemotherapy (AFFIRM) trial [25] , we did not observe lower PSA response rates in patients receiving corticosteroids at the initiation of enzalutamide. Participation in clinical trials has also been linked to improved outcomes with systemic therapy in mCRPC patients [26] . However, this was not relevant to our study because no patients received enzalutamide in the context of a clinical trial.

The absence of predictive clinicopathologic factors for enzalutamide efficacy illustrates the need for further translational studies to identify novel predictive biomarkers. Pretreatment measurement of serum androgens [27] and enumeration of circulating tumour cells (CTCs)[28], [29], and [30]are avenues of interest, having been identified as prognostic factors in mCRPC patients receiving systemic therapy. Correlating outcomes on enzalutamide with genomic aberrations (eg,ARamplification,ARmutations, andTMPRSS2-ERGrearrangement) detectable in tumour biopsies, CTCs, and/or circulating tumour DNA would also be of significant interest.

We acknowledge that this study has several limitations. The limited cohort size means our data must be interpreted with due caution and require validation in larger, prospective series. Other limitations of this study include its retrospective design, its restriction to a single province in Canada, and the relatively short follow-up period. We also could not assess radiologic response to treatment because imaging was not consistently performed, and postenzalutamide treatment may have confounded assessment of OS.

The therapeutic armamentarium for metastatic castration-resistant prostate cancer (mCRPC) has rapidly expanded in recent years with several novel agents demonstrating a benefit on overall survival (OS) [1] . Among these agents are the novel androgen receptor (AR)-targeted therapies abiraterone acetate (abiraterone) and enzalutamide that inhibit CYP17 and AR, respectively. Both abiraterone and enzalutamide are increasingly being used in chemotherapy-naive mCRPC patients on the basis of positive data from the COU-AA-302 (abiraterone) and PREVAIL (enzalutamide) phase 3 studies[2] and [3]. Despite their efficacy, however, many questions regarding the use of abiraterone and enzalutamide remain unanswered including the optimal sequencing of treatment. Several prior studies have reported on outcomes in mCRPC patients treated with enzalutamide after abiraterone[4], [5], [6], [7], [8], and [9]. All but one of these studies [9] were restricted to patients previously treated with docetaxel, and currently little is known about the activity of enzalutamide following abiraterone in docetaxel-naive mCRPC patients. The aim of this study was to examine the activity of enzalutamide after abiraterone in mCRPC patients not previously treated with docetaxel chemotherapy and to compare outcomes with docetaxel-experienced patients.

In this retrospective study, we examined the antitumour activity of enzalutamide after abiraterone in mCRPC patients. We found that the efficacy of enzalutamide was comparable in docetaxel-experienced and docetaxel-naive patients in terms of confirmed PSA response rates (22% vs 26%;p = 0.8), median time to radiologic/clinical progression (4.6 mo vs 6.6 mo;p = 0.6), and median OS (10.6 mo vs 8.6 mo;p = 0.2). These findings are somewhat surprising because we had anticipated that enzalutamide would be less efficacious in more heavily pretreated patients, that is, those who had also received prior docetaxel. The differences in baseline age and LDH between the cohorts, which were biased against the docetaxel-naive group, may have had an impact on our results, although age and LDH have not been shown differentially to affect the benefit of enzalutamide[10] and [11].

Population-based studies have shown that only a third of mCRPC patients receive docetaxel [12] . However, results from the recently presented Androgen Ablation Therapy with or Without Chemotherapy in Treating Patients with Metastatic Prostate Cancer (CHAARTED) trial [13] are likely to lead to an increase in docetaxel use in patients with high-risk metastatic castration-sensitive disease. Our results, which indicate that earlier treatment with docetaxel does not have a large impact on the activity of enzalutamide after abiraterone, may therefore be of increasing relevance to the management of patients with metastatic prostate cancer.

The findings of this study point to a common mechanism of resistance to enzalutamide in docetaxel-experienced and -naive patients. Resistance mechanisms to enzalutamide include induction of AR splice variants [14] , an activating point mutation in the AR (F876L)[15] and [16], upregulation of the stress-activated chaperone protein clusterin [17] , enhanced protein kinase C/Twist1 signalling [18] , and activation of the glucocorticoid receptor [19] . These factors do not overlap with known mechanisms of docetaxel resistance [20] , although it has been postulated that cross-resistance may develop between docetaxel, enzalutamide, and abiraterone because all of these agents are known to modulate AR nuclear translocation [21] . The similar efficacy of enzalutamide regardless of prior docetaxel use in our study suggests that cross-resistance between abiraterone and enzalutamide emerges independently of docetaxel.

The PSA response rate to enzalutamide in our cohort was 23%, median time to progression was 5.3 mo, and median OS was 10.6 mo. These results are broadly in keeping with earlier studies that reported PSA response rates of 13–29%, median PFS of 2.9–4.0 mo, and median OS of 7.3–7.5 mo in mCRPC patients treated with enzalutamide after abiraterone[4], [5], [6], [7], [8], and [9]. In our chemotherapy-naive cohort, PSA declines ≥50% and ≥30% were seen in 23% and 35% of patients, respectively. These findings are also comparable with the only prior study to include chemotherapy-naive patients [9] , which reported PSA declines ≥30% in 40% of patients. Collectively, these data indicate that enzalutamide has relatively modest activity when used after abiraterone. Abiraterone is also reported to have limited efficacy after prior treatment with enzalutamide[22] and [23]. This lends weight to the possibility of a common mechanism of resistance between enzalutamide and abiraterone. In support of this, a recent report linked detection of the AR-V7 splice variant with primary and acquired resistance to both enzalutamide and abiraterone [24] .

Despite its limited overall activity, enzalutamide did confer longer-term benefit for a subset of patients in our study with 21% of patients remaining on treatment for at least 6 mo. However, predicting which patients will benefit from treatment with enzalutamide remains a major challenge. We could not find any clinicopathologic factors that predicted a PSA decline ≥50% on enzalutamide. Although prior PSA decline ≥50% on abiraterone has been linked to subsequent response to enzalutamide[8] and [9], we and other investigators[4] and [5]have not corroborated these findings. Gleason score has also been implicated as a predictor for enzalutamide response following abiraterone [4] ; however, we did not find this to be the case. Similarly, although coadministration of corticosteroids was found to be associated with inferior survival parameters in a post hoc analysis of the Safety and Efficacy Study of MDV3100 in the Patients with Castration-resistant Prostate Cancer Who Have Been Previously Treated with Docetaxel-based Chemotherapy (AFFIRM) trial [25] , we did not observe lower PSA response rates in patients receiving corticosteroids at the initiation of enzalutamide. Participation in clinical trials has also been linked to improved outcomes with systemic therapy in mCRPC patients [26] . However, this was not relevant to our study because no patients received enzalutamide in the context of a clinical trial.

The absence of predictive clinicopathologic factors for enzalutamide efficacy illustrates the need for further translational studies to identify novel predictive biomarkers. Pretreatment measurement of serum androgens [27] and enumeration of circulating tumour cells (CTCs)[28], [29], and [30]are avenues of interest, having been identified as prognostic factors in mCRPC patients receiving systemic therapy. Correlating outcomes on enzalutamide with genomic aberrations (eg,ARamplification,ARmutations, andTMPRSS2-ERGrearrangement) detectable in tumour biopsies, CTCs, and/or circulating tumour DNA would also be of significant interest.

We acknowledge that this study has several limitations. The limited cohort size means our data must be interpreted with due caution and require validation in larger, prospective series. Other limitations of this study include its retrospective design, its restriction to a single province in Canada, and the relatively short follow-up period. We also could not assess radiologic response to treatment because imaging was not consistently performed, and postenzalutamide treatment may have confounded assessment of OS.

The therapeutic armamentarium for metastatic castration-resistant prostate cancer (mCRPC) has rapidly expanded in recent years with several novel agents demonstrating a benefit on overall survival (OS) [1] . Among these agents are the novel androgen receptor (AR)-targeted therapies abiraterone acetate (abiraterone) and enzalutamide that inhibit CYP17 and AR, respectively. Both abiraterone and enzalutamide are increasingly being used in chemotherapy-naive mCRPC patients on the basis of positive data from the COU-AA-302 (abiraterone) and PREVAIL (enzalutamide) phase 3 studies[2] and [3]. Despite their efficacy, however, many questions regarding the use of abiraterone and enzalutamide remain unanswered including the optimal sequencing of treatment. Several prior studies have reported on outcomes in mCRPC patients treated with enzalutamide after abiraterone[4], [5], [6], [7], [8], and [9]. All but one of these studies [9] were restricted to patients previously treated with docetaxel, and currently little is known about the activity of enzalutamide following abiraterone in docetaxel-naive mCRPC patients. The aim of this study was to examine the activity of enzalutamide after abiraterone in mCRPC patients not previously treated with docetaxel chemotherapy and to compare outcomes with docetaxel-experienced patients.

In this retrospective study, we examined the antitumour activity of enzalutamide after abiraterone in mCRPC patients. We found that the efficacy of enzalutamide was comparable in docetaxel-experienced and docetaxel-naive patients in terms of confirmed PSA response rates (22% vs 26%;p = 0.8), median time to radiologic/clinical progression (4.6 mo vs 6.6 mo;p = 0.6), and median OS (10.6 mo vs 8.6 mo;p = 0.2). These findings are somewhat surprising because we had anticipated that enzalutamide would be less efficacious in more heavily pretreated patients, that is, those who had also received prior docetaxel. The differences in baseline age and LDH between the cohorts, which were biased against the docetaxel-naive group, may have had an impact on our results, although age and LDH have not been shown differentially to affect the benefit of enzalutamide[10] and [11].

Population-based studies have shown that only a third of mCRPC patients receive docetaxel [12] . However, results from the recently presented Androgen Ablation Therapy with or Without Chemotherapy in Treating Patients with Metastatic Prostate Cancer (CHAARTED) trial [13] are likely to lead to an increase in docetaxel use in patients with high-risk metastatic castration-sensitive disease. Our results, which indicate that earlier treatment with docetaxel does not have a large impact on the activity of enzalutamide after abiraterone, may therefore be of increasing relevance to the management of patients with metastatic prostate cancer.

The findings of this study point to a common mechanism of resistance to enzalutamide in docetaxel-experienced and -naive patients. Resistance mechanisms to enzalutamide include induction of AR splice variants [14] , an activating point mutation in the AR (F876L)[15] and [16], upregulation of the stress-activated chaperone protein clusterin [17] , enhanced protein kinase C/Twist1 signalling [18] , and activation of the glucocorticoid receptor [19] . These factors do not overlap with known mechanisms of docetaxel resistance [20] , although it has been postulated that cross-resistance may develop between docetaxel, enzalutamide, and abiraterone because all of these agents are known to modulate AR nuclear translocation [21] . The similar efficacy of enzalutamide regardless of prior docetaxel use in our study suggests that cross-resistance between abiraterone and enzalutamide emerges independently of docetaxel.

The PSA response rate to enzalutamide in our cohort was 23%, median time to progression was 5.3 mo, and median OS was 10.6 mo. These results are broadly in keeping with earlier studies that reported PSA response rates of 13–29%, median PFS of 2.9–4.0 mo, and median OS of 7.3–7.5 mo in mCRPC patients treated with enzalutamide after abiraterone[4], [5], [6], [7], [8], and [9]. In our chemotherapy-naive cohort, PSA declines ≥50% and ≥30% were seen in 23% and 35% of patients, respectively. These findings are also comparable with the only prior study to include chemotherapy-naive patients [9] , which reported PSA declines ≥30% in 40% of patients. Collectively, these data indicate that enzalutamide has relatively modest activity when used after abiraterone. Abiraterone is also reported to have limited efficacy after prior treatment with enzalutamide[22] and [23]. This lends weight to the possibility of a common mechanism of resistance between enzalutamide and abiraterone. In support of this, a recent report linked detection of the AR-V7 splice variant with primary and acquired resistance to both enzalutamide and abiraterone [24] .

Despite its limited overall activity, enzalutamide did confer longer-term benefit for a subset of patients in our study with 21% of patients remaining on treatment for at least 6 mo. However, predicting which patients will benefit from treatment with enzalutamide remains a major challenge. We could not find any clinicopathologic factors that predicted a PSA decline ≥50% on enzalutamide. Although prior PSA decline ≥50% on abiraterone has been linked to subsequent response to enzalutamide[8] and [9], we and other investigators[4] and [5]have not corroborated these findings. Gleason score has also been implicated as a predictor for enzalutamide response following abiraterone [4] ; however, we did not find this to be the case. Similarly, although coadministration of corticosteroids was found to be associated with inferior survival parameters in a post hoc analysis of the Safety and Efficacy Study of MDV3100 in the Patients with Castration-resistant Prostate Cancer Who Have Been Previously Treated with Docetaxel-based Chemotherapy (AFFIRM) trial [25] , we did not observe lower PSA response rates in patients receiving corticosteroids at the initiation of enzalutamide. Participation in clinical trials has also been linked to improved outcomes with systemic therapy in mCRPC patients [26] . However, this was not relevant to our study because no patients received enzalutamide in the context of a clinical trial.

The absence of predictive clinicopathologic factors for enzalutamide efficacy illustrates the need for further translational studies to identify novel predictive biomarkers. Pretreatment measurement of serum androgens [27] and enumeration of circulating tumour cells (CTCs)[28], [29], and [30]are avenues of interest, having been identified as prognostic factors in mCRPC patients receiving systemic therapy. Correlating outcomes on enzalutamide with genomic aberrations (eg,ARamplification,ARmutations, andTMPRSS2-ERGrearrangement) detectable in tumour biopsies, CTCs, and/or circulating tumour DNA would also be of significant interest.

We acknowledge that this study has several limitations. The limited cohort size means our data must be interpreted with due caution and require validation in larger, prospective series. Other limitations of this study include its retrospective design, its restriction to a single province in Canada, and the relatively short follow-up period. We also could not assess radiologic response to treatment because imaging was not consistently performed, and postenzalutamide treatment may have confounded assessment of OS.

The therapeutic armamentarium for metastatic castration-resistant prostate cancer (mCRPC) has rapidly expanded in recent years with several novel agents demonstrating a benefit on overall survival (OS) [1] . Among these agents are the novel androgen receptor (AR)-targeted therapies abiraterone acetate (abiraterone) and enzalutamide that inhibit CYP17 and AR, respectively. Both abiraterone and enzalutamide are increasingly being used in chemotherapy-naive mCRPC patients on the basis of positive data from the COU-AA-302 (abiraterone) and PREVAIL (enzalutamide) phase 3 studies[2] and [3]. Despite their efficacy, however, many questions regarding the use of abiraterone and enzalutamide remain unanswered including the optimal sequencing of treatment. Several prior studies have reported on outcomes in mCRPC patients treated with enzalutamide after abiraterone[4], [5], [6], [7], [8], and [9]. All but one of these studies [9] were restricted to patients previously treated with docetaxel, and currently little is known about the activity of enzalutamide following abiraterone in docetaxel-naive mCRPC patients. The aim of this study was to examine the activity of enzalutamide after abiraterone in mCRPC patients not previously treated with docetaxel chemotherapy and to compare outcomes with docetaxel-experienced patients.

In this retrospective study, we examined the antitumour activity of enzalutamide after abiraterone in mCRPC patients. We found that the efficacy of enzalutamide was comparable in docetaxel-experienced and docetaxel-naive patients in terms of confirmed PSA response rates (22% vs 26%;p = 0.8), median time to radiologic/clinical progression (4.6 mo vs 6.6 mo;p = 0.6), and median OS (10.6 mo vs 8.6 mo;p = 0.2). These findings are somewhat surprising because we had anticipated that enzalutamide would be less efficacious in more heavily pretreated patients, that is, those who had also received prior docetaxel. The differences in baseline age and LDH between the cohorts, which were biased against the docetaxel-naive group, may have had an impact on our results, although age and LDH have not been shown differentially to affect the benefit of enzalutamide[10] and [11].

Population-based studies have shown that only a third of mCRPC patients receive docetaxel [12] . However, results from the recently presented Androgen Ablation Therapy with or Without Chemotherapy in Treating Patients with Metastatic Prostate Cancer (CHAARTED) trial [13] are likely to lead to an increase in docetaxel use in patients with high-risk metastatic castration-sensitive disease. Our results, which indicate that earlier treatment with docetaxel does not have a large impact on the activity of enzalutamide after abiraterone, may therefore be of increasing relevance to the management of patients with metastatic prostate cancer.

The findings of this study point to a common mechanism of resistance to enzalutamide in docetaxel-experienced and -naive patients. Resistance mechanisms to enzalutamide include induction of AR splice variants [14] , an activating point mutation in the AR (F876L)[15] and [16], upregulation of the stress-activated chaperone protein clusterin [17] , enhanced protein kinase C/Twist1 signalling [18] , and activation of the glucocorticoid receptor [19] . These factors do not overlap with known mechanisms of docetaxel resistance [20] , although it has been postulated that cross-resistance may develop between docetaxel, enzalutamide, and abiraterone because all of these agents are known to modulate AR nuclear translocation [21] . The similar efficacy of enzalutamide regardless of prior docetaxel use in our study suggests that cross-resistance between abiraterone and enzalutamide emerges independently of docetaxel.

The PSA response rate to enzalutamide in our cohort was 23%, median time to progression was 5.3 mo, and median OS was 10.6 mo. These results are broadly in keeping with earlier studies that reported PSA response rates of 13–29%, median PFS of 2.9–4.0 mo, and median OS of 7.3–7.5 mo in mCRPC patients treated with enzalutamide after abiraterone[4], [5], [6], [7], [8], and [9]. In our chemotherapy-naive cohort, PSA declines ≥50% and ≥30% were seen in 23% and 35% of patients, respectively. These findings are also comparable with the only prior study to include chemotherapy-naive patients [9] , which reported PSA declines ≥30% in 40% of patients. Collectively, these data indicate that enzalutamide has relatively modest activity when used after abiraterone. Abiraterone is also reported to have limited efficacy after prior treatment with enzalutamide[22] and [23]. This lends weight to the possibility of a common mechanism of resistance between enzalutamide and abiraterone. In support of this, a recent report linked detection of the AR-V7 splice variant with primary and acquired resistance to both enzalutamide and abiraterone [24] .

Despite its limited overall activity, enzalutamide did confer longer-term benefit for a subset of patients in our study with 21% of patients remaining on treatment for at least 6 mo. However, predicting which patients will benefit from treatment with enzalutamide remains a major challenge. We could not find any clinicopathologic factors that predicted a PSA decline ≥50% on enzalutamide. Although prior PSA decline ≥50% on abiraterone has been linked to subsequent response to enzalutamide[8] and [9], we and other investigators[4] and [5]have not corroborated these findings. Gleason score has also been implicated as a predictor for enzalutamide response following abiraterone [4] ; however, we did not find this to be the case. Similarly, although coadministration of corticosteroids was found to be associated with inferior survival parameters in a post hoc analysis of the Safety and Efficacy Study of MDV3100 in the Patients with Castration-resistant Prostate Cancer Who Have Been Previously Treated with Docetaxel-based Chemotherapy (AFFIRM) trial [25] , we did not observe lower PSA response rates in patients receiving corticosteroids at the initiation of enzalutamide. Participation in clinical trials has also been linked to improved outcomes with systemic therapy in mCRPC patients [26] . However, this was not relevant to our study because no patients received enzalutamide in the context of a clinical trial.

The absence of predictive clinicopathologic factors for enzalutamide efficacy illustrates the need for further translational studies to identify novel predictive biomarkers. Pretreatment measurement of serum androgens [27] and enumeration of circulating tumour cells (CTCs)[28], [29], and [30]are avenues of interest, having been identified as prognostic factors in mCRPC patients receiving systemic therapy. Correlating outcomes on enzalutamide with genomic aberrations (eg,ARamplification,ARmutations, andTMPRSS2-ERGrearrangement) detectable in tumour biopsies, CTCs, and/or circulating tumour DNA would also be of significant interest.

We acknowledge that this study has several limitations. The limited cohort size means our data must be interpreted with due caution and require validation in larger, prospective series. Other limitations of this study include its retrospective design, its restriction to a single province in Canada, and the relatively short follow-up period. We also could not assess radiologic response to treatment because imaging was not consistently performed, and postenzalutamide treatment may have confounded assessment of OS.

The therapeutic armamentarium for metastatic castration-resistant prostate cancer (mCRPC) has rapidly expanded in recent years with several novel agents demonstrating a benefit on overall survival (OS) [1] . Among these agents are the novel androgen receptor (AR)-targeted therapies abiraterone acetate (abiraterone) and enzalutamide that inhibit CYP17 and AR, respectively. Both abiraterone and enzalutamide are increasingly being used in chemotherapy-naive mCRPC patients on the basis of positive data from the COU-AA-302 (abiraterone) and PREVAIL (enzalutamide) phase 3 studies[2] and [3]. Despite their efficacy, however, many questions regarding the use of abiraterone and enzalutamide remain unanswered including the optimal sequencing of treatment. Several prior studies have reported on outcomes in mCRPC patients treated with enzalutamide after abiraterone[4], [5], [6], [7], [8], and [9]. All but one of these studies [9] were restricted to patients previously treated with docetaxel, and currently little is known about the activity of enzalutamide following abiraterone in docetaxel-naive mCRPC patients. The aim of this study was to examine the activity of enzalutamide after abiraterone in mCRPC patients not previously treated with docetaxel chemotherapy and to compare outcomes with docetaxel-experienced patients.

In this retrospective study, we examined the antitumour activity of enzalutamide after abiraterone in mCRPC patients. We found that the efficacy of enzalutamide was comparable in docetaxel-experienced and docetaxel-naive patients in terms of confirmed PSA response rates (22% vs 26%;p = 0.8), median time to radiologic/clinical progression (4.6 mo vs 6.6 mo;p = 0.6), and median OS (10.6 mo vs 8.6 mo;p = 0.2). These findings are somewhat surprising because we had anticipated that enzalutamide would be less efficacious in more heavily pretreated patients, that is, those who had also received prior docetaxel. The differences in baseline age and LDH between the cohorts, which were biased against the docetaxel-naive group, may have had an impact on our results, although age and LDH have not been shown differentially to affect the benefit of enzalutamide[10] and [11].

Population-based studies have shown that only a third of mCRPC patients receive docetaxel [12] . However, results from the recently presented Androgen Ablation Therapy with or Without Chemotherapy in Treating Patients with Metastatic Prostate Cancer (CHAARTED) trial [13] are likely to lead to an increase in docetaxel use in patients with high-risk metastatic castration-sensitive disease. Our results, which indicate that earlier treatment with docetaxel does not have a large impact on the activity of enzalutamide after abiraterone, may therefore be of increasing relevance to the management of patients with metastatic prostate cancer.

The findings of this study point to a common mechanism of resistance to enzalutamide in docetaxel-experienced and -naive patients. Resistance mechanisms to enzalutamide include induction of AR splice variants [14] , an activating point mutation in the AR (F876L)[15] and [16], upregulation of the stress-activated chaperone protein clusterin [17] , enhanced protein kinase C/Twist1 signalling [18] , and activation of the glucocorticoid receptor [19] . These factors do not overlap with known mechanisms of docetaxel resistance [20] , although it has been postulated that cross-resistance may develop between docetaxel, enzalutamide, and abiraterone because all of these agents are known to modulate AR nuclear translocation [21] . The similar efficacy of enzalutamide regardless of prior docetaxel use in our study suggests that cross-resistance between abiraterone and enzalutamide emerges independently of docetaxel.

The PSA response rate to enzalutamide in our cohort was 23%, median time to progression was 5.3 mo, and median OS was 10.6 mo. These results are broadly in keeping with earlier studies that reported PSA response rates of 13–29%, median PFS of 2.9–4.0 mo, and median OS of 7.3–7.5 mo in mCRPC patients treated with enzalutamide after abiraterone[4], [5], [6], [7], [8], and [9]. In our chemotherapy-naive cohort, PSA declines ≥50% and ≥30% were seen in 23% and 35% of patients, respectively. These findings are also comparable with the only prior study to include chemotherapy-naive patients [9] , which reported PSA declines ≥30% in 40% of patients. Collectively, these data indicate that enzalutamide has relatively modest activity when used after abiraterone. Abiraterone is also reported to have limited efficacy after prior treatment with enzalutamide[22] and [23]. This lends weight to the possibility of a common mechanism of resistance between enzalutamide and abiraterone. In support of this, a recent report linked detection of the AR-V7 splice variant with primary and acquired resistance to both enzalutamide and abiraterone [24] .

Despite its limited overall activity, enzalutamide did confer longer-term benefit for a subset of patients in our study with 21% of patients remaining on treatment for at least 6 mo. However, predicting which patients will benefit from treatment with enzalutamide remains a major challenge. We could not find any clinicopathologic factors that predicted a PSA decline ≥50% on enzalutamide. Although prior PSA decline ≥50% on abiraterone has been linked to subsequent response to enzalutamide[8] and [9], we and other investigators[4] and [5]have not corroborated these findings. Gleason score has also been implicated as a predictor for enzalutamide response following abiraterone [4] ; however, we did not find this to be the case. Similarly, although coadministration of corticosteroids was found to be associated with inferior survival parameters in a post hoc analysis of the Safety and Efficacy Study of MDV3100 in the Patients with Castration-resistant Prostate Cancer Who Have Been Previously Treated with Docetaxel-based Chemotherapy (AFFIRM) trial [25] , we did not observe lower PSA response rates in patients receiving corticosteroids at the initiation of enzalutamide. Participation in clinical trials has also been linked to improved outcomes with systemic therapy in mCRPC patients [26] . However, this was not relevant to our study because no patients received enzalutamide in the context of a clinical trial.

The absence of predictive clinicopathologic factors for enzalutamide efficacy illustrates the need for further translational studies to identify novel predictive biomarkers. Pretreatment measurement of serum androgens [27] and enumeration of circulating tumour cells (CTCs)[28], [29], and [30]are avenues of interest, having been identified as prognostic factors in mCRPC patients receiving systemic therapy. Correlating outcomes on enzalutamide with genomic aberrations (eg,ARamplification,ARmutations, andTMPRSS2-ERGrearrangement) detectable in tumour biopsies, CTCs, and/or circulating tumour DNA would also be of significant interest.

We acknowledge that this study has several limitations. The limited cohort size means our data must be interpreted with due caution and require validation in larger, prospective series. Other limitations of this study include its retrospective design, its restriction to a single province in Canada, and the relatively short follow-up period. We also could not assess radiologic response to treatment because imaging was not consistently performed, and postenzalutamide treatment may have confounded assessment of OS.

The therapeutic armamentarium for metastatic castration-resistant prostate cancer (mCRPC) has rapidly expanded in recent years with several novel agents demonstrating a benefit on overall survival (OS) [1] . Among these agents are the novel androgen receptor (AR)-targeted therapies abiraterone acetate (abiraterone) and enzalutamide that inhibit CYP17 and AR, respectively. Both abiraterone and enzalutamide are increasingly being used in chemotherapy-naive mCRPC patients on the basis of positive data from the COU-AA-302 (abiraterone) and PREVAIL (enzalutamide) phase 3 studies[2] and [3]. Despite their efficacy, however, many questions regarding the use of abiraterone and enzalutamide remain unanswered including the optimal sequencing of treatment. Several prior studies have reported on outcomes in mCRPC patients treated with enzalutamide after abiraterone[4], [5], [6], [7], [8], and [9]. All but one of these studies [9] were restricted to patients previously treated with docetaxel, and currently little is known about the activity of enzalutamide following abiraterone in docetaxel-naive mCRPC patients. The aim of this study was to examine the activity of enzalutamide after abiraterone in mCRPC patients not previously treated with docetaxel chemotherapy and to compare outcomes with docetaxel-experienced patients.

In this retrospective study, we examined the antitumour activity of enzalutamide after abiraterone in mCRPC patients. We found that the efficacy of enzalutamide was comparable in docetaxel-experienced and docetaxel-naive patients in terms of confirmed PSA response rates (22% vs 26%;p = 0.8), median time to radiologic/clinical progression (4.6 mo vs 6.6 mo;p = 0.6), and median OS (10.6 mo vs 8.6 mo;p = 0.2). These findings are somewhat surprising because we had anticipated that enzalutamide would be less efficacious in more heavily pretreated patients, that is, those who had also received prior docetaxel. The differences in baseline age and LDH between the cohorts, which were biased against the docetaxel-naive group, may have had an impact on our results, although age and LDH have not been shown differentially to affect the benefit of enzalutamide[10] and [11].

Population-based studies have shown that only a third of mCRPC patients receive docetaxel [12] . However, results from the recently presented Androgen Ablation Therapy with or Without Chemotherapy in Treating Patients with Metastatic Prostate Cancer (CHAARTED) trial [13] are likely to lead to an increase in docetaxel use in patients with high-risk metastatic castration-sensitive disease. Our results, which indicate that earlier treatment with docetaxel does not have a large impact on the activity of enzalutamide after abiraterone, may therefore be of increasing relevance to the management of patients with metastatic prostate cancer.

The findings of this study point to a common mechanism of resistance to enzalutamide in docetaxel-experienced and -naive patients. Resistance mechanisms to enzalutamide include induction of AR splice variants [14] , an activating point mutation in the AR (F876L)[15] and [16], upregulation of the stress-activated chaperone protein clusterin [17] , enhanced protein kinase C/Twist1 signalling [18] , and activation of the glucocorticoid receptor [19] . These factors do not overlap with known mechanisms of docetaxel resistance [20] , although it has been postulated that cross-resistance may develop between docetaxel, enzalutamide, and abiraterone because all of these agents are known to modulate AR nuclear translocation [21] . The similar efficacy of enzalutamide regardless of prior docetaxel use in our study suggests that cross-resistance between abiraterone and enzalutamide emerges independently of docetaxel.

The PSA response rate to enzalutamide in our cohort was 23%, median time to progression was 5.3 mo, and median OS was 10.6 mo. These results are broadly in keeping with earlier studies that reported PSA response rates of 13–29%, median PFS of 2.9–4.0 mo, and median OS of 7.3–7.5 mo in mCRPC patients treated with enzalutamide after abiraterone[4], [5], [6], [7], [8], and [9]. In our chemotherapy-naive cohort, PSA declines ≥50% and ≥30% were seen in 23% and 35% of patients, respectively. These findings are also comparable with the only prior study to include chemotherapy-naive patients [9] , which reported PSA declines ≥30% in 40% of patients. Collectively, these data indicate that enzalutamide has relatively modest activity when used after abiraterone. Abiraterone is also reported to have limited efficacy after prior treatment with enzalutamide[22] and [23]. This lends weight to the possibility of a common mechanism of resistance between enzalutamide and abiraterone. In support of this, a recent report linked detection of the AR-V7 splice variant with primary and acquired resistance to both enzalutamide and abiraterone [24] .

Despite its limited overall activity, enzalutamide did confer longer-term benefit for a subset of patients in our study with 21% of patients remaining on treatment for at least 6 mo. However, predicting which patients will benefit from treatment with enzalutamide remains a major challenge. We could not find any clinicopathologic factors that predicted a PSA decline ≥50% on enzalutamide. Although prior PSA decline ≥50% on abiraterone has been linked to subsequent response to enzalutamide[8] and [9], we and other investigators[4] and [5]have not corroborated these findings. Gleason score has also been implicated as a predictor for enzalutamide response following abiraterone [4] ; however, we did not find this to be the case. Similarly, although coadministration of corticosteroids was found to be associated with inferior survival parameters in a post hoc analysis of the Safety and Efficacy Study of MDV3100 in the Patients with Castration-resistant Prostate Cancer Who Have Been Previously Treated with Docetaxel-based Chemotherapy (AFFIRM) trial [25] , we did not observe lower PSA response rates in patients receiving corticosteroids at the initiation of enzalutamide. Participation in clinical trials has also been linked to improved outcomes with systemic therapy in mCRPC patients [26] . However, this was not relevant to our study because no patients received enzalutamide in the context of a clinical trial.

The absence of predictive clinicopathologic factors for enzalutamide efficacy illustrates the need for further translational studies to identify novel predictive biomarkers. Pretreatment measurement of serum androgens [27] and enumeration of circulating tumour cells (CTCs)[28], [29], and [30]are avenues of interest, having been identified as prognostic factors in mCRPC patients receiving systemic therapy. Correlating outcomes on enzalutamide with genomic aberrations (eg,ARamplification,ARmutations, andTMPRSS2-ERGrearrangement) detectable in tumour biopsies, CTCs, and/or circulating tumour DNA would also be of significant interest.

We acknowledge that this study has several limitations. The limited cohort size means our data must be interpreted with due caution and require validation in larger, prospective series. Other limitations of this study include its retrospective design, its restriction to a single province in Canada, and the relatively short follow-up period. We also could not assess radiologic response to treatment because imaging was not consistently performed, and postenzalutamide treatment may have confounded assessment of OS.

The therapeutic armamentarium for metastatic castration-resistant prostate cancer (mCRPC) has rapidly expanded in recent years with several novel agents demonstrating a benefit on overall survival (OS) [1] . Among these agents are the novel androgen receptor (AR)-targeted therapies abiraterone acetate (abiraterone) and enzalutamide that inhibit CYP17 and AR, respectively. Both abiraterone and enzalutamide are increasingly being used in chemotherapy-naive mCRPC patients on the basis of positive data from the COU-AA-302 (abiraterone) and PREVAIL (enzalutamide) phase 3 studies[2] and [3]. Despite their efficacy, however, many questions regarding the use of abiraterone and enzalutamide remain unanswered including the optimal sequencing of treatment. Several prior studies have reported on outcomes in mCRPC patients treated with enzalutamide after abiraterone[4], [5], [6], [7], [8], and [9]. All but one of these studies [9] were restricted to patients previously treated with docetaxel, and currently little is known about the activity of enzalutamide following abiraterone in docetaxel-naive mCRPC patients. The aim of this study was to examine the activity of enzalutamide after abiraterone in mCRPC patients not previously treated with docetaxel chemotherapy and to compare outcomes with docetaxel-experienced patients.

In this retrospective study, we examined the antitumour activity of enzalutamide after abiraterone in mCRPC patients. We found that the efficacy of enzalutamide was comparable in docetaxel-experienced and docetaxel-naive patients in terms of confirmed PSA response rates (22% vs 26%;p = 0.8), median time to radiologic/clinical progression (4.6 mo vs 6.6 mo;p = 0.6), and median OS (10.6 mo vs 8.6 mo;p = 0.2). These findings are somewhat surprising because we had anticipated that enzalutamide would be less efficacious in more heavily pretreated patients, that is, those who had also received prior docetaxel. The differences in baseline age and LDH between the cohorts, which were biased against the docetaxel-naive group, may have had an impact on our results, although age and LDH have not been shown differentially to affect the benefit of enzalutamide[10] and [11].

Population-based studies have shown that only a third of mCRPC patients receive docetaxel [12] . However, results from the recently presented Androgen Ablation Therapy with or Without Chemotherapy in Treating Patients with Metastatic Prostate Cancer (CHAARTED) trial [13] are likely to lead to an increase in docetaxel use in patients with high-risk metastatic castration-sensitive disease. Our results, which indicate that earlier treatment with docetaxel does not have a large impact on the activity of enzalutamide after abiraterone, may therefore be of increasing relevance to the management of patients with metastatic prostate cancer.

The findings of this study point to a common mechanism of resistance to enzalutamide in docetaxel-experienced and -naive patients. Resistance mechanisms to enzalutamide include induction of AR splice variants [14] , an activating point mutation in the AR (F876L)[15] and [16], upregulation of the stress-activated chaperone protein clusterin [17] , enhanced protein kinase C/Twist1 signalling [18] , and activation of the glucocorticoid receptor [19] . These factors do not overlap with known mechanisms of docetaxel resistance [20] , although it has been postulated that cross-resistance may develop between docetaxel, enzalutamide, and abiraterone because all of these agents are known to modulate AR nuclear translocation [21] . The similar efficacy of enzalutamide regardless of prior docetaxel use in our study suggests that cross-resistance between abiraterone and enzalutamide emerges independently of docetaxel.

The PSA response rate to enzalutamide in our cohort was 23%, median time to progression was 5.3 mo, and median OS was 10.6 mo. These results are broadly in keeping with earlier studies that reported PSA response rates of 13–29%, median PFS of 2.9–4.0 mo, and median OS of 7.3–7.5 mo in mCRPC patients treated with enzalutamide after abiraterone[4], [5], [6], [7], [8], and [9]. In our chemotherapy-naive cohort, PSA declines ≥50% and ≥30% were seen in 23% and 35% of patients, respectively. These findings are also comparable with the only prior study to include chemotherapy-naive patients [9] , which reported PSA declines ≥30% in 40% of patients. Collectively, these data indicate that enzalutamide has relatively modest activity when used after abiraterone. Abiraterone is also reported to have limited efficacy after prior treatment with enzalutamide[22] and [23]. This lends weight to the possibility of a common mechanism of resistance between enzalutamide and abiraterone. In support of this, a recent report linked detection of the AR-V7 splice variant with primary and acquired resistance to both enzalutamide and abiraterone [24] .

Despite its limited overall activity, enzalutamide did confer longer-term benefit for a subset of patients in our study with 21% of patients remaining on treatment for at least 6 mo. However, predicting which patients will benefit from treatment with enzalutamide remains a major challenge. We could not find any clinicopathologic factors that predicted a PSA decline ≥50% on enzalutamide. Although prior PSA decline ≥50% on abiraterone has been linked to subsequent response to enzalutamide[8] and [9], we and other investigators[4] and [5]have not corroborated these findings. Gleason score has also been implicated as a predictor for enzalutamide response following abiraterone [4] ; however, we did not find this to be the case. Similarly, although coadministration of corticosteroids was found to be associated with inferior survival parameters in a post hoc analysis of the Safety and Efficacy Study of MDV3100 in the Patients with Castration-resistant Prostate Cancer Who Have Been Previously Treated with Docetaxel-based Chemotherapy (AFFIRM) trial [25] , we did not observe lower PSA response rates in patients receiving corticosteroids at the initiation of enzalutamide. Participation in clinical trials has also been linked to improved outcomes with systemic therapy in mCRPC patients [26] . However, this was not relevant to our study because no patients received enzalutamide in the context of a clinical trial.

The absence of predictive clinicopathologic factors for enzalutamide efficacy illustrates the need for further translational studies to identify novel predictive biomarkers. Pretreatment measurement of serum androgens [27] and enumeration of circulating tumour cells (CTCs)[28], [29], and [30]are avenues of interest, having been identified as prognostic factors in mCRPC patients receiving systemic therapy. Correlating outcomes on enzalutamide with genomic aberrations (eg,ARamplification,ARmutations, andTMPRSS2-ERGrearrangement) detectable in tumour biopsies, CTCs, and/or circulating tumour DNA would also be of significant interest.

We acknowledge that this study has several limitations. The limited cohort size means our data must be interpreted with due caution and require validation in larger, prospective series. Other limitations of this study include its retrospective design, its restriction to a single province in Canada, and the relatively short follow-up period. We also could not assess radiologic response to treatment because imaging was not consistently performed, and postenzalutamide treatment may have confounded assessment of OS.

The therapeutic armamentarium for metastatic castration-resistant prostate cancer (mCRPC) has rapidly expanded in recent years with several novel agents demonstrating a benefit on overall survival (OS) [1] . Among these agents are the novel androgen receptor (AR)-targeted therapies abiraterone acetate (abiraterone) and enzalutamide that inhibit CYP17 and AR, respectively. Both abiraterone and enzalutamide are increasingly being used in chemotherapy-naive mCRPC patients on the basis of positive data from the COU-AA-302 (abiraterone) and PREVAIL (enzalutamide) phase 3 studies[2] and [3]. Despite their efficacy, however, many questions regarding the use of abiraterone and enzalutamide remain unanswered including the optimal sequencing of treatment. Several prior studies have reported on outcomes in mCRPC patients treated with enzalutamide after abiraterone[4], [5], [6], [7], [8], and [9]. All but one of these studies [9] were restricted to patients previously treated with docetaxel, and currently little is known about the activity of enzalutamide following abiraterone in docetaxel-naive mCRPC patients. The aim of this study was to examine the activity of enzalutamide after abiraterone in mCRPC patients not previously treated with docetaxel chemotherapy and to compare outcomes with docetaxel-experienced patients.