Long-term Safety and Antitumor Activity in the Phase 1–2 Study of Enzalutamide in Pre- and Post-docetaxel Castration-Resistant Prostate Cancer

The complete study design and methods were published previously [7] . Patients had histologically confirmed prostate cancer, castrate levels of testosterone (<1.7 nmol/l), and increasing PSA levels (minimum of three measurements more than 2 wk apart showing ≥50% increase, with the last value >2 ng/ml). Institutional review board approval and written informed consent from patients were obtained before commencement of any study-related activities. The study was conducted in compliance with the Declaration of Helsinki and its later revisions and all International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice Guidelines. Patients were enrolled from July 2007 to December 2008.

Patients received oral enzalutamide starting at 30 mg/d, with sequential escalations in cohorts of three to six patients to the following dose levels: 60, 150, 240, 360, 480, and 600 mg/d. After confirming dose tolerability, 24 patients were included per dose level (12 chemotherapy-naive and 12 postchemotherapy) at doses ≥60 mg/d, except for 480 and 600 mg/d, for which only postchemotherapy (docetaxel) patients were enrolled.

The study consisted of four periods: single-dose, multiple-dose, long-term dosing, and safety follow-up periods. All patients received a single dose of enzalutamide and were then followed for 6 d (single-dose period). Those not experiencing dose-limiting toxicity (DLT) then entered the multiple-dose period, in which they received the same dose as previously, once daily for 84 d. Patients completing the multiple-dose period entered the long-term dosing period and continued to receive the same dose taken in the multiple-dose period. When patients discontinued treatment for any reason, they entered the 30-d safety follow-up period.

All patients in the long-term dosing period were switched to the 240-mg/d dose in January 2009 after it was determined to be the MTD, and to 160 mg/d in September 2009 after 160 mg/d was determined to be the dose for phase 3 investigation based on the updated risk-benefit analysis [7] . During the long-term dosing period, safety was assessed every 28 d for the first 3 mo and every 12 wk thereafter via a physical examination and evaluation of vital signs, AEs, 12-lead electrocardiogram, and clinical laboratory tests. PSA levels were evaluated every 28 d for the first 3 mo and then every 12 wk thereafter; bone scans and imaging studies (computerized tomography or magnetic resonance imaging) were evaluated every 12 wk. Overall survival was not assessed as a study endpoint.

This report provides an additional 17-mo follow-up for antitumor activity and >4 yr for safety for the initial phase 1–2 trial [7] that evaluated the safety, tolerability, PK, and antitumor activity of enzalutamide in men with CRPC. Our results show that enzalutamide continued to demonstrate durable antitumor activity and a favorable tolerability profile for the men who remained in the study. No new safety signals were detected with extended dosing. The results provide a unique insight into the long-term outcomes with enzalutamide because the follow-up periods exceed that of the completed phase 3 AFFIRM [5] and PREVAIL trials [6] , although these trials enrolled a significantly greater number of patients. It is noteworthy that 31% of the chemotherapy-naive patients remained on enzalutamide therapy for >2 yr and 17% for >4 yr. This contrasts with the 2-yr on-treatment rate of 5% for postchemotherapy patients.

In further support of the durable antitumor activity of enzalutamide, 70% of patients had not experienced PSA progression at 2 yr, and for chemotherapy-naive patients the median time to PSA progression had not been reached and the median time to radiographic progression was more than 1 yr (56 wk). Importantly, patients who were both ketoconazole- and chemotherapy-naive experienced a longer duration of PSA response (median 1.9 yr to PSA progression). These results illustrate the possibility of extended disease control with enzalutamide treatment for a subset of patients, yet to be further characterized with any specific biomarker.

The most common AEs during extended dosing (all grades and grade 3/4) were similar to those previously reported [7] . Fatigue remained the most common dose-dependent AE, reported as any grade by 70% of patients and as grade 3/4 by 14% of patients across the 30–600-mg/d range. Fatigue was also the most common AE in the AFFIRM and PREVAIL trials, phase 3 studies conducted with the approved dose of 160 mg/d. These larger, randomized, double-blind, placebo-controlled studies provide a more thorough evaluation of the safety and tolerability of enzalutamide [5] and [6]. In particular, the rate of fatigue was 34% with enzalutamide and 29% with placebo in AFFIRM, and 36% with enzalutamide and 26% with placebo in PREVAIL.

The safety analyses described here provides evidence that enzalutamide remains well tolerated over extended use. During long-term follow-up, there was no meaningful change in the overall incidence of common AEs or grade 3/4 AEs, and only one of the 19 patients still being treated at the time of the final efficacy analysis in 2010 subsequently discontinued enzalutamide because of an AE. A safety analysis summarizing AEs occurring within 2, 3, or 4 yr after the patient's first dose showed little to no change in frequency of the most common drug-related AEs over time, with few new AEs reported after 2 yr of treatment.

Limitations of the findings reported reflect both the study design, the heterogeneity of this early-phase study population, and the bias inherent in any long-term analysis. First, patients initially received a wide range of doses and were switched to a common dose at several time points during the study. Of particular note is that many patients received enzalutamide at a higher dose (up to 600 mg/d) than the currently approved dose (160 mg/d). Second, patients who remained on treatment at the time of the final analysis had already benefitted from and tolerated enzalutamide for at least 20 mo. Thus, the paucity of new events reported during long-term treatment is within a population of patients who had already demonstrated tolerability and prolonged benefit from enzalutamide. Even though no new safety signal was detected during long-term treatment in this study, clinicians should be mindful of the potential for late-occurring, initially subtle AEs such as bone loss and metabolic syndrome, which have been observed with other hormonal therapies.

Prostate cancer growth is dependent on androgen receptor (AR) signaling. Initial hormonal treatment strategies include depletion of testosterone and inhibition of AR signaling [1] . The response can be dramatic, but virtually all patients progress to a castration-resistant prostate cancer (CRPC) state over time [2] . It is now recognized that tumor growth and progression in the CRPC state remain dependent on AR signaling [3] . Enzalutamide (formerly MDV3100) is an orally administered AR inhibitor that acts on multiple steps in the AR signaling pathway [4] . In phase 3 trials, enzalutamide had overall survival and radiographic progression-free survival benefits in patients with metastatic CRPC both before and after docetaxel treatment [5] and [6].

The first clinical trial of enzalutamide was an open-label, phase 1–2 dose-escalation study (NCT00510718) assessing the safety, pharmacokinetics (PK), and antitumor activity of enzalutamide in CRPC patients, both with and without prior exposure to chemotherapy [7] . The doses tested ranged from 30 to 600 mg/d. The maximum tolerated dose (MTD) of enzalutamide was identified as 240 mg/d. Full evaluation of the antitumor activity and safety data led to selection of 160 mg/d as the dose for evaluation in phase 3 registration studies, and this is now the approved dose. The most common grade 3/4 adverse event (AE) in the phase 1–2 trial was fatigue, which was more common at doses ≥240 mg/d and generally resolved after dose reduction. Antitumor effects, including prostate-specific antigen (PSA) declines, regression of soft-tissue disease, stabilization of bone disease, and conversion from unfavorable to favorable circulating tumor cell counts, were found at all doses studied [7] .

Here we present the results of the final efficacy analysis conducted in September 2010, 17 mo after the initial data cutoff date, and of a long-term safety analysis conducted in September 2013, nearly 4.5 yr after the cutoff date for the initial study report [7] .

The complete study design and methods were published previously [7] . Patients had histologically confirmed prostate cancer, castrate levels of testosterone (<1.7 nmol/l), and increasing PSA levels (minimum of three measurements more than 2 wk apart showing ≥50% increase, with the last value >2 ng/ml). Institutional review board approval and written informed consent from patients were obtained before commencement of any study-related activities. The study was conducted in compliance with the Declaration of Helsinki and its later revisions and all International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice Guidelines. Patients were enrolled from July 2007 to December 2008.

Patients received oral enzalutamide starting at 30 mg/d, with sequential escalations in cohorts of three to six patients to the following dose levels: 60, 150, 240, 360, 480, and 600 mg/d. After confirming dose tolerability, 24 patients were included per dose level (12 chemotherapy-naive and 12 postchemotherapy) at doses ≥60 mg/d, except for 480 and 600 mg/d, for which only postchemotherapy (docetaxel) patients were enrolled.

The study consisted of four periods: single-dose, multiple-dose, long-term dosing, and safety follow-up periods. All patients received a single dose of enzalutamide and were then followed for 6 d (single-dose period). Those not experiencing dose-limiting toxicity (DLT) then entered the multiple-dose period, in which they received the same dose as previously, once daily for 84 d. Patients completing the multiple-dose period entered the long-term dosing period and continued to receive the same dose taken in the multiple-dose period. When patients discontinued treatment for any reason, they entered the 30-d safety follow-up period.

All patients in the long-term dosing period were switched to the 240-mg/d dose in January 2009 after it was determined to be the MTD, and to 160 mg/d in September 2009 after 160 mg/d was determined to be the dose for phase 3 investigation based on the updated risk-benefit analysis [7] . During the long-term dosing period, safety was assessed every 28 d for the first 3 mo and every 12 wk thereafter via a physical examination and evaluation of vital signs, AEs, 12-lead electrocardiogram, and clinical laboratory tests. PSA levels were evaluated every 28 d for the first 3 mo and then every 12 wk thereafter; bone scans and imaging studies (computerized tomography or magnetic resonance imaging) were evaluated every 12 wk. Overall survival was not assessed as a study endpoint.

This report provides an additional 17-mo follow-up for antitumor activity and >4 yr for safety for the initial phase 1–2 trial [7] that evaluated the safety, tolerability, PK, and antitumor activity of enzalutamide in men with CRPC. Our results show that enzalutamide continued to demonstrate durable antitumor activity and a favorable tolerability profile for the men who remained in the study. No new safety signals were detected with extended dosing. The results provide a unique insight into the long-term outcomes with enzalutamide because the follow-up periods exceed that of the completed phase 3 AFFIRM [5] and PREVAIL trials [6] , although these trials enrolled a significantly greater number of patients. It is noteworthy that 31% of the chemotherapy-naive patients remained on enzalutamide therapy for >2 yr and 17% for >4 yr. This contrasts with the 2-yr on-treatment rate of 5% for postchemotherapy patients.

In further support of the durable antitumor activity of enzalutamide, 70% of patients had not experienced PSA progression at 2 yr, and for chemotherapy-naive patients the median time to PSA progression had not been reached and the median time to radiographic progression was more than 1 yr (56 wk). Importantly, patients who were both ketoconazole- and chemotherapy-naive experienced a longer duration of PSA response (median 1.9 yr to PSA progression). These results illustrate the possibility of extended disease control with enzalutamide treatment for a subset of patients, yet to be further characterized with any specific biomarker.

The most common AEs during extended dosing (all grades and grade 3/4) were similar to those previously reported [7] . Fatigue remained the most common dose-dependent AE, reported as any grade by 70% of patients and as grade 3/4 by 14% of patients across the 30–600-mg/d range. Fatigue was also the most common AE in the AFFIRM and PREVAIL trials, phase 3 studies conducted with the approved dose of 160 mg/d. These larger, randomized, double-blind, placebo-controlled studies provide a more thorough evaluation of the safety and tolerability of enzalutamide [5] and [6]. In particular, the rate of fatigue was 34% with enzalutamide and 29% with placebo in AFFIRM, and 36% with enzalutamide and 26% with placebo in PREVAIL.

The safety analyses described here provides evidence that enzalutamide remains well tolerated over extended use. During long-term follow-up, there was no meaningful change in the overall incidence of common AEs or grade 3/4 AEs, and only one of the 19 patients still being treated at the time of the final efficacy analysis in 2010 subsequently discontinued enzalutamide because of an AE. A safety analysis summarizing AEs occurring within 2, 3, or 4 yr after the patient's first dose showed little to no change in frequency of the most common drug-related AEs over time, with few new AEs reported after 2 yr of treatment.

Limitations of the findings reported reflect both the study design, the heterogeneity of this early-phase study population, and the bias inherent in any long-term analysis. First, patients initially received a wide range of doses and were switched to a common dose at several time points during the study. Of particular note is that many patients received enzalutamide at a higher dose (up to 600 mg/d) than the currently approved dose (160 mg/d). Second, patients who remained on treatment at the time of the final analysis had already benefitted from and tolerated enzalutamide for at least 20 mo. Thus, the paucity of new events reported during long-term treatment is within a population of patients who had already demonstrated tolerability and prolonged benefit from enzalutamide. Even though no new safety signal was detected during long-term treatment in this study, clinicians should be mindful of the potential for late-occurring, initially subtle AEs such as bone loss and metabolic syndrome, which have been observed with other hormonal therapies.

Prostate cancer growth is dependent on androgen receptor (AR) signaling. Initial hormonal treatment strategies include depletion of testosterone and inhibition of AR signaling [1] . The response can be dramatic, but virtually all patients progress to a castration-resistant prostate cancer (CRPC) state over time [2] . It is now recognized that tumor growth and progression in the CRPC state remain dependent on AR signaling [3] . Enzalutamide (formerly MDV3100) is an orally administered AR inhibitor that acts on multiple steps in the AR signaling pathway [4] . In phase 3 trials, enzalutamide had overall survival and radiographic progression-free survival benefits in patients with metastatic CRPC both before and after docetaxel treatment [5] and [6].

The first clinical trial of enzalutamide was an open-label, phase 1–2 dose-escalation study (NCT00510718) assessing the safety, pharmacokinetics (PK), and antitumor activity of enzalutamide in CRPC patients, both with and without prior exposure to chemotherapy [7] . The doses tested ranged from 30 to 600 mg/d. The maximum tolerated dose (MTD) of enzalutamide was identified as 240 mg/d. Full evaluation of the antitumor activity and safety data led to selection of 160 mg/d as the dose for evaluation in phase 3 registration studies, and this is now the approved dose. The most common grade 3/4 adverse event (AE) in the phase 1–2 trial was fatigue, which was more common at doses ≥240 mg/d and generally resolved after dose reduction. Antitumor effects, including prostate-specific antigen (PSA) declines, regression of soft-tissue disease, stabilization of bone disease, and conversion from unfavorable to favorable circulating tumor cell counts, were found at all doses studied [7] .

Here we present the results of the final efficacy analysis conducted in September 2010, 17 mo after the initial data cutoff date, and of a long-term safety analysis conducted in September 2013, nearly 4.5 yr after the cutoff date for the initial study report [7] .

The complete study design and methods were published previously [7] . Patients had histologically confirmed prostate cancer, castrate levels of testosterone (<1.7 nmol/l), and increasing PSA levels (minimum of three measurements more than 2 wk apart showing ≥50% increase, with the last value >2 ng/ml). Institutional review board approval and written informed consent from patients were obtained before commencement of any study-related activities. The study was conducted in compliance with the Declaration of Helsinki and its later revisions and all International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice Guidelines. Patients were enrolled from July 2007 to December 2008.

Patients received oral enzalutamide starting at 30 mg/d, with sequential escalations in cohorts of three to six patients to the following dose levels: 60, 150, 240, 360, 480, and 600 mg/d. After confirming dose tolerability, 24 patients were included per dose level (12 chemotherapy-naive and 12 postchemotherapy) at doses ≥60 mg/d, except for 480 and 600 mg/d, for which only postchemotherapy (docetaxel) patients were enrolled.

The study consisted of four periods: single-dose, multiple-dose, long-term dosing, and safety follow-up periods. All patients received a single dose of enzalutamide and were then followed for 6 d (single-dose period). Those not experiencing dose-limiting toxicity (DLT) then entered the multiple-dose period, in which they received the same dose as previously, once daily for 84 d. Patients completing the multiple-dose period entered the long-term dosing period and continued to receive the same dose taken in the multiple-dose period. When patients discontinued treatment for any reason, they entered the 30-d safety follow-up period.

All patients in the long-term dosing period were switched to the 240-mg/d dose in January 2009 after it was determined to be the MTD, and to 160 mg/d in September 2009 after 160 mg/d was determined to be the dose for phase 3 investigation based on the updated risk-benefit analysis [7] . During the long-term dosing period, safety was assessed every 28 d for the first 3 mo and every 12 wk thereafter via a physical examination and evaluation of vital signs, AEs, 12-lead electrocardiogram, and clinical laboratory tests. PSA levels were evaluated every 28 d for the first 3 mo and then every 12 wk thereafter; bone scans and imaging studies (computerized tomography or magnetic resonance imaging) were evaluated every 12 wk. Overall survival was not assessed as a study endpoint.

This report provides an additional 17-mo follow-up for antitumor activity and >4 yr for safety for the initial phase 1–2 trial [7] that evaluated the safety, tolerability, PK, and antitumor activity of enzalutamide in men with CRPC. Our results show that enzalutamide continued to demonstrate durable antitumor activity and a favorable tolerability profile for the men who remained in the study. No new safety signals were detected with extended dosing. The results provide a unique insight into the long-term outcomes with enzalutamide because the follow-up periods exceed that of the completed phase 3 AFFIRM [5] and PREVAIL trials [6] , although these trials enrolled a significantly greater number of patients. It is noteworthy that 31% of the chemotherapy-naive patients remained on enzalutamide therapy for >2 yr and 17% for >4 yr. This contrasts with the 2-yr on-treatment rate of 5% for postchemotherapy patients.

In further support of the durable antitumor activity of enzalutamide, 70% of patients had not experienced PSA progression at 2 yr, and for chemotherapy-naive patients the median time to PSA progression had not been reached and the median time to radiographic progression was more than 1 yr (56 wk). Importantly, patients who were both ketoconazole- and chemotherapy-naive experienced a longer duration of PSA response (median 1.9 yr to PSA progression). These results illustrate the possibility of extended disease control with enzalutamide treatment for a subset of patients, yet to be further characterized with any specific biomarker.

The most common AEs during extended dosing (all grades and grade 3/4) were similar to those previously reported [7] . Fatigue remained the most common dose-dependent AE, reported as any grade by 70% of patients and as grade 3/4 by 14% of patients across the 30–600-mg/d range. Fatigue was also the most common AE in the AFFIRM and PREVAIL trials, phase 3 studies conducted with the approved dose of 160 mg/d. These larger, randomized, double-blind, placebo-controlled studies provide a more thorough evaluation of the safety and tolerability of enzalutamide [5] and [6]. In particular, the rate of fatigue was 34% with enzalutamide and 29% with placebo in AFFIRM, and 36% with enzalutamide and 26% with placebo in PREVAIL.

The safety analyses described here provides evidence that enzalutamide remains well tolerated over extended use. During long-term follow-up, there was no meaningful change in the overall incidence of common AEs or grade 3/4 AEs, and only one of the 19 patients still being treated at the time of the final efficacy analysis in 2010 subsequently discontinued enzalutamide because of an AE. A safety analysis summarizing AEs occurring within 2, 3, or 4 yr after the patient's first dose showed little to no change in frequency of the most common drug-related AEs over time, with few new AEs reported after 2 yr of treatment.

Limitations of the findings reported reflect both the study design, the heterogeneity of this early-phase study population, and the bias inherent in any long-term analysis. First, patients initially received a wide range of doses and were switched to a common dose at several time points during the study. Of particular note is that many patients received enzalutamide at a higher dose (up to 600 mg/d) than the currently approved dose (160 mg/d). Second, patients who remained on treatment at the time of the final analysis had already benefitted from and tolerated enzalutamide for at least 20 mo. Thus, the paucity of new events reported during long-term treatment is within a population of patients who had already demonstrated tolerability and prolonged benefit from enzalutamide. Even though no new safety signal was detected during long-term treatment in this study, clinicians should be mindful of the potential for late-occurring, initially subtle AEs such as bone loss and metabolic syndrome, which have been observed with other hormonal therapies.

Prostate cancer growth is dependent on androgen receptor (AR) signaling. Initial hormonal treatment strategies include depletion of testosterone and inhibition of AR signaling [1] . The response can be dramatic, but virtually all patients progress to a castration-resistant prostate cancer (CRPC) state over time [2] . It is now recognized that tumor growth and progression in the CRPC state remain dependent on AR signaling [3] . Enzalutamide (formerly MDV3100) is an orally administered AR inhibitor that acts on multiple steps in the AR signaling pathway [4] . In phase 3 trials, enzalutamide had overall survival and radiographic progression-free survival benefits in patients with metastatic CRPC both before and after docetaxel treatment [5] and [6].

The first clinical trial of enzalutamide was an open-label, phase 1–2 dose-escalation study (NCT00510718) assessing the safety, pharmacokinetics (PK), and antitumor activity of enzalutamide in CRPC patients, both with and without prior exposure to chemotherapy [7] . The doses tested ranged from 30 to 600 mg/d. The maximum tolerated dose (MTD) of enzalutamide was identified as 240 mg/d. Full evaluation of the antitumor activity and safety data led to selection of 160 mg/d as the dose for evaluation in phase 3 registration studies, and this is now the approved dose. The most common grade 3/4 adverse event (AE) in the phase 1–2 trial was fatigue, which was more common at doses ≥240 mg/d and generally resolved after dose reduction. Antitumor effects, including prostate-specific antigen (PSA) declines, regression of soft-tissue disease, stabilization of bone disease, and conversion from unfavorable to favorable circulating tumor cell counts, were found at all doses studied [7] .

Here we present the results of the final efficacy analysis conducted in September 2010, 17 mo after the initial data cutoff date, and of a long-term safety analysis conducted in September 2013, nearly 4.5 yr after the cutoff date for the initial study report [7] .

The complete study design and methods were published previously [7] . Patients had histologically confirmed prostate cancer, castrate levels of testosterone (<1.7 nmol/l), and increasing PSA levels (minimum of three measurements more than 2 wk apart showing ≥50% increase, with the last value >2 ng/ml). Institutional review board approval and written informed consent from patients were obtained before commencement of any study-related activities. The study was conducted in compliance with the Declaration of Helsinki and its later revisions and all International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice Guidelines. Patients were enrolled from July 2007 to December 2008.

Patients received oral enzalutamide starting at 30 mg/d, with sequential escalations in cohorts of three to six patients to the following dose levels: 60, 150, 240, 360, 480, and 600 mg/d. After confirming dose tolerability, 24 patients were included per dose level (12 chemotherapy-naive and 12 postchemotherapy) at doses ≥60 mg/d, except for 480 and 600 mg/d, for which only postchemotherapy (docetaxel) patients were enrolled.

The study consisted of four periods: single-dose, multiple-dose, long-term dosing, and safety follow-up periods. All patients received a single dose of enzalutamide and were then followed for 6 d (single-dose period). Those not experiencing dose-limiting toxicity (DLT) then entered the multiple-dose period, in which they received the same dose as previously, once daily for 84 d. Patients completing the multiple-dose period entered the long-term dosing period and continued to receive the same dose taken in the multiple-dose period. When patients discontinued treatment for any reason, they entered the 30-d safety follow-up period.

All patients in the long-term dosing period were switched to the 240-mg/d dose in January 2009 after it was determined to be the MTD, and to 160 mg/d in September 2009 after 160 mg/d was determined to be the dose for phase 3 investigation based on the updated risk-benefit analysis [7] . During the long-term dosing period, safety was assessed every 28 d for the first 3 mo and every 12 wk thereafter via a physical examination and evaluation of vital signs, AEs, 12-lead electrocardiogram, and clinical laboratory tests. PSA levels were evaluated every 28 d for the first 3 mo and then every 12 wk thereafter; bone scans and imaging studies (computerized tomography or magnetic resonance imaging) were evaluated every 12 wk. Overall survival was not assessed as a study endpoint.

This report provides an additional 17-mo follow-up for antitumor activity and >4 yr for safety for the initial phase 1–2 trial [7] that evaluated the safety, tolerability, PK, and antitumor activity of enzalutamide in men with CRPC. Our results show that enzalutamide continued to demonstrate durable antitumor activity and a favorable tolerability profile for the men who remained in the study. No new safety signals were detected with extended dosing. The results provide a unique insight into the long-term outcomes with enzalutamide because the follow-up periods exceed that of the completed phase 3 AFFIRM [5] and PREVAIL trials [6] , although these trials enrolled a significantly greater number of patients. It is noteworthy that 31% of the chemotherapy-naive patients remained on enzalutamide therapy for >2 yr and 17% for >4 yr. This contrasts with the 2-yr on-treatment rate of 5% for postchemotherapy patients.

In further support of the durable antitumor activity of enzalutamide, 70% of patients had not experienced PSA progression at 2 yr, and for chemotherapy-naive patients the median time to PSA progression had not been reached and the median time to radiographic progression was more than 1 yr (56 wk). Importantly, patients who were both ketoconazole- and chemotherapy-naive experienced a longer duration of PSA response (median 1.9 yr to PSA progression). These results illustrate the possibility of extended disease control with enzalutamide treatment for a subset of patients, yet to be further characterized with any specific biomarker.

The most common AEs during extended dosing (all grades and grade 3/4) were similar to those previously reported [7] . Fatigue remained the most common dose-dependent AE, reported as any grade by 70% of patients and as grade 3/4 by 14% of patients across the 30–600-mg/d range. Fatigue was also the most common AE in the AFFIRM and PREVAIL trials, phase 3 studies conducted with the approved dose of 160 mg/d. These larger, randomized, double-blind, placebo-controlled studies provide a more thorough evaluation of the safety and tolerability of enzalutamide [5] and [6]. In particular, the rate of fatigue was 34% with enzalutamide and 29% with placebo in AFFIRM, and 36% with enzalutamide and 26% with placebo in PREVAIL.

The safety analyses described here provides evidence that enzalutamide remains well tolerated over extended use. During long-term follow-up, there was no meaningful change in the overall incidence of common AEs or grade 3/4 AEs, and only one of the 19 patients still being treated at the time of the final efficacy analysis in 2010 subsequently discontinued enzalutamide because of an AE. A safety analysis summarizing AEs occurring within 2, 3, or 4 yr after the patient's first dose showed little to no change in frequency of the most common drug-related AEs over time, with few new AEs reported after 2 yr of treatment.

Limitations of the findings reported reflect both the study design, the heterogeneity of this early-phase study population, and the bias inherent in any long-term analysis. First, patients initially received a wide range of doses and were switched to a common dose at several time points during the study. Of particular note is that many patients received enzalutamide at a higher dose (up to 600 mg/d) than the currently approved dose (160 mg/d). Second, patients who remained on treatment at the time of the final analysis had already benefitted from and tolerated enzalutamide for at least 20 mo. Thus, the paucity of new events reported during long-term treatment is within a population of patients who had already demonstrated tolerability and prolonged benefit from enzalutamide. Even though no new safety signal was detected during long-term treatment in this study, clinicians should be mindful of the potential for late-occurring, initially subtle AEs such as bone loss and metabolic syndrome, which have been observed with other hormonal therapies.

Prostate cancer growth is dependent on androgen receptor (AR) signaling. Initial hormonal treatment strategies include depletion of testosterone and inhibition of AR signaling [1] . The response can be dramatic, but virtually all patients progress to a castration-resistant prostate cancer (CRPC) state over time [2] . It is now recognized that tumor growth and progression in the CRPC state remain dependent on AR signaling [3] . Enzalutamide (formerly MDV3100) is an orally administered AR inhibitor that acts on multiple steps in the AR signaling pathway [4] . In phase 3 trials, enzalutamide had overall survival and radiographic progression-free survival benefits in patients with metastatic CRPC both before and after docetaxel treatment [5] and [6].

The first clinical trial of enzalutamide was an open-label, phase 1–2 dose-escalation study (NCT00510718) assessing the safety, pharmacokinetics (PK), and antitumor activity of enzalutamide in CRPC patients, both with and without prior exposure to chemotherapy [7] . The doses tested ranged from 30 to 600 mg/d. The maximum tolerated dose (MTD) of enzalutamide was identified as 240 mg/d. Full evaluation of the antitumor activity and safety data led to selection of 160 mg/d as the dose for evaluation in phase 3 registration studies, and this is now the approved dose. The most common grade 3/4 adverse event (AE) in the phase 1–2 trial was fatigue, which was more common at doses ≥240 mg/d and generally resolved after dose reduction. Antitumor effects, including prostate-specific antigen (PSA) declines, regression of soft-tissue disease, stabilization of bone disease, and conversion from unfavorable to favorable circulating tumor cell counts, were found at all doses studied [7] .

Here we present the results of the final efficacy analysis conducted in September 2010, 17 mo after the initial data cutoff date, and of a long-term safety analysis conducted in September 2013, nearly 4.5 yr after the cutoff date for the initial study report [7] .

The complete study design and methods were published previously [7] . Patients had histologically confirmed prostate cancer, castrate levels of testosterone (<1.7 nmol/l), and increasing PSA levels (minimum of three measurements more than 2 wk apart showing ≥50% increase, with the last value >2 ng/ml). Institutional review board approval and written informed consent from patients were obtained before commencement of any study-related activities. The study was conducted in compliance with the Declaration of Helsinki and its later revisions and all International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice Guidelines. Patients were enrolled from July 2007 to December 2008.

Patients received oral enzalutamide starting at 30 mg/d, with sequential escalations in cohorts of three to six patients to the following dose levels: 60, 150, 240, 360, 480, and 600 mg/d. After confirming dose tolerability, 24 patients were included per dose level (12 chemotherapy-naive and 12 postchemotherapy) at doses ≥60 mg/d, except for 480 and 600 mg/d, for which only postchemotherapy (docetaxel) patients were enrolled.

The study consisted of four periods: single-dose, multiple-dose, long-term dosing, and safety follow-up periods. All patients received a single dose of enzalutamide and were then followed for 6 d (single-dose period). Those not experiencing dose-limiting toxicity (DLT) then entered the multiple-dose period, in which they received the same dose as previously, once daily for 84 d. Patients completing the multiple-dose period entered the long-term dosing period and continued to receive the same dose taken in the multiple-dose period. When patients discontinued treatment for any reason, they entered the 30-d safety follow-up period.

All patients in the long-term dosing period were switched to the 240-mg/d dose in January 2009 after it was determined to be the MTD, and to 160 mg/d in September 2009 after 160 mg/d was determined to be the dose for phase 3 investigation based on the updated risk-benefit analysis [7] . During the long-term dosing period, safety was assessed every 28 d for the first 3 mo and every 12 wk thereafter via a physical examination and evaluation of vital signs, AEs, 12-lead electrocardiogram, and clinical laboratory tests. PSA levels were evaluated every 28 d for the first 3 mo and then every 12 wk thereafter; bone scans and imaging studies (computerized tomography or magnetic resonance imaging) were evaluated every 12 wk. Overall survival was not assessed as a study endpoint.

This report provides an additional 17-mo follow-up for antitumor activity and >4 yr for safety for the initial phase 1–2 trial [7] that evaluated the safety, tolerability, PK, and antitumor activity of enzalutamide in men with CRPC. Our results show that enzalutamide continued to demonstrate durable antitumor activity and a favorable tolerability profile for the men who remained in the study. No new safety signals were detected with extended dosing. The results provide a unique insight into the long-term outcomes with enzalutamide because the follow-up periods exceed that of the completed phase 3 AFFIRM [5] and PREVAIL trials [6] , although these trials enrolled a significantly greater number of patients. It is noteworthy that 31% of the chemotherapy-naive patients remained on enzalutamide therapy for >2 yr and 17% for >4 yr. This contrasts with the 2-yr on-treatment rate of 5% for postchemotherapy patients.

In further support of the durable antitumor activity of enzalutamide, 70% of patients had not experienced PSA progression at 2 yr, and for chemotherapy-naive patients the median time to PSA progression had not been reached and the median time to radiographic progression was more than 1 yr (56 wk). Importantly, patients who were both ketoconazole- and chemotherapy-naive experienced a longer duration of PSA response (median 1.9 yr to PSA progression). These results illustrate the possibility of extended disease control with enzalutamide treatment for a subset of patients, yet to be further characterized with any specific biomarker.

The most common AEs during extended dosing (all grades and grade 3/4) were similar to those previously reported [7] . Fatigue remained the most common dose-dependent AE, reported as any grade by 70% of patients and as grade 3/4 by 14% of patients across the 30–600-mg/d range. Fatigue was also the most common AE in the AFFIRM and PREVAIL trials, phase 3 studies conducted with the approved dose of 160 mg/d. These larger, randomized, double-blind, placebo-controlled studies provide a more thorough evaluation of the safety and tolerability of enzalutamide [5] and [6]. In particular, the rate of fatigue was 34% with enzalutamide and 29% with placebo in AFFIRM, and 36% with enzalutamide and 26% with placebo in PREVAIL.

The safety analyses described here provides evidence that enzalutamide remains well tolerated over extended use. During long-term follow-up, there was no meaningful change in the overall incidence of common AEs or grade 3/4 AEs, and only one of the 19 patients still being treated at the time of the final efficacy analysis in 2010 subsequently discontinued enzalutamide because of an AE. A safety analysis summarizing AEs occurring within 2, 3, or 4 yr after the patient's first dose showed little to no change in frequency of the most common drug-related AEs over time, with few new AEs reported after 2 yr of treatment.

Limitations of the findings reported reflect both the study design, the heterogeneity of this early-phase study population, and the bias inherent in any long-term analysis. First, patients initially received a wide range of doses and were switched to a common dose at several time points during the study. Of particular note is that many patients received enzalutamide at a higher dose (up to 600 mg/d) than the currently approved dose (160 mg/d). Second, patients who remained on treatment at the time of the final analysis had already benefitted from and tolerated enzalutamide for at least 20 mo. Thus, the paucity of new events reported during long-term treatment is within a population of patients who had already demonstrated tolerability and prolonged benefit from enzalutamide. Even though no new safety signal was detected during long-term treatment in this study, clinicians should be mindful of the potential for late-occurring, initially subtle AEs such as bone loss and metabolic syndrome, which have been observed with other hormonal therapies.

Prostate cancer growth is dependent on androgen receptor (AR) signaling. Initial hormonal treatment strategies include depletion of testosterone and inhibition of AR signaling [1] . The response can be dramatic, but virtually all patients progress to a castration-resistant prostate cancer (CRPC) state over time [2] . It is now recognized that tumor growth and progression in the CRPC state remain dependent on AR signaling [3] . Enzalutamide (formerly MDV3100) is an orally administered AR inhibitor that acts on multiple steps in the AR signaling pathway [4] . In phase 3 trials, enzalutamide had overall survival and radiographic progression-free survival benefits in patients with metastatic CRPC both before and after docetaxel treatment [5] and [6].

The first clinical trial of enzalutamide was an open-label, phase 1–2 dose-escalation study (NCT00510718) assessing the safety, pharmacokinetics (PK), and antitumor activity of enzalutamide in CRPC patients, both with and without prior exposure to chemotherapy [7] . The doses tested ranged from 30 to 600 mg/d. The maximum tolerated dose (MTD) of enzalutamide was identified as 240 mg/d. Full evaluation of the antitumor activity and safety data led to selection of 160 mg/d as the dose for evaluation in phase 3 registration studies, and this is now the approved dose. The most common grade 3/4 adverse event (AE) in the phase 1–2 trial was fatigue, which was more common at doses ≥240 mg/d and generally resolved after dose reduction. Antitumor effects, including prostate-specific antigen (PSA) declines, regression of soft-tissue disease, stabilization of bone disease, and conversion from unfavorable to favorable circulating tumor cell counts, were found at all doses studied [7] .

Here we present the results of the final efficacy analysis conducted in September 2010, 17 mo after the initial data cutoff date, and of a long-term safety analysis conducted in September 2013, nearly 4.5 yr after the cutoff date for the initial study report [7] .

The complete study design and methods were published previously [7] . Patients had histologically confirmed prostate cancer, castrate levels of testosterone (<1.7 nmol/l), and increasing PSA levels (minimum of three measurements more than 2 wk apart showing ≥50% increase, with the last value >2 ng/ml). Institutional review board approval and written informed consent from patients were obtained before commencement of any study-related activities. The study was conducted in compliance with the Declaration of Helsinki and its later revisions and all International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice Guidelines. Patients were enrolled from July 2007 to December 2008.

Patients received oral enzalutamide starting at 30 mg/d, with sequential escalations in cohorts of three to six patients to the following dose levels: 60, 150, 240, 360, 480, and 600 mg/d. After confirming dose tolerability, 24 patients were included per dose level (12 chemotherapy-naive and 12 postchemotherapy) at doses ≥60 mg/d, except for 480 and 600 mg/d, for which only postchemotherapy (docetaxel) patients were enrolled.

The study consisted of four periods: single-dose, multiple-dose, long-term dosing, and safety follow-up periods. All patients received a single dose of enzalutamide and were then followed for 6 d (single-dose period). Those not experiencing dose-limiting toxicity (DLT) then entered the multiple-dose period, in which they received the same dose as previously, once daily for 84 d. Patients completing the multiple-dose period entered the long-term dosing period and continued to receive the same dose taken in the multiple-dose period. When patients discontinued treatment for any reason, they entered the 30-d safety follow-up period.

All patients in the long-term dosing period were switched to the 240-mg/d dose in January 2009 after it was determined to be the MTD, and to 160 mg/d in September 2009 after 160 mg/d was determined to be the dose for phase 3 investigation based on the updated risk-benefit analysis [7] . During the long-term dosing period, safety was assessed every 28 d for the first 3 mo and every 12 wk thereafter via a physical examination and evaluation of vital signs, AEs, 12-lead electrocardiogram, and clinical laboratory tests. PSA levels were evaluated every 28 d for the first 3 mo and then every 12 wk thereafter; bone scans and imaging studies (computerized tomography or magnetic resonance imaging) were evaluated every 12 wk. Overall survival was not assessed as a study endpoint.

This report provides an additional 17-mo follow-up for antitumor activity and >4 yr for safety for the initial phase 1–2 trial [7] that evaluated the safety, tolerability, PK, and antitumor activity of enzalutamide in men with CRPC. Our results show that enzalutamide continued to demonstrate durable antitumor activity and a favorable tolerability profile for the men who remained in the study. No new safety signals were detected with extended dosing. The results provide a unique insight into the long-term outcomes with enzalutamide because the follow-up periods exceed that of the completed phase 3 AFFIRM [5] and PREVAIL trials [6] , although these trials enrolled a significantly greater number of patients. It is noteworthy that 31% of the chemotherapy-naive patients remained on enzalutamide therapy for >2 yr and 17% for >4 yr. This contrasts with the 2-yr on-treatment rate of 5% for postchemotherapy patients.

In further support of the durable antitumor activity of enzalutamide, 70% of patients had not experienced PSA progression at 2 yr, and for chemotherapy-naive patients the median time to PSA progression had not been reached and the median time to radiographic progression was more than 1 yr (56 wk). Importantly, patients who were both ketoconazole- and chemotherapy-naive experienced a longer duration of PSA response (median 1.9 yr to PSA progression). These results illustrate the possibility of extended disease control with enzalutamide treatment for a subset of patients, yet to be further characterized with any specific biomarker.

The most common AEs during extended dosing (all grades and grade 3/4) were similar to those previously reported [7] . Fatigue remained the most common dose-dependent AE, reported as any grade by 70% of patients and as grade 3/4 by 14% of patients across the 30–600-mg/d range. Fatigue was also the most common AE in the AFFIRM and PREVAIL trials, phase 3 studies conducted with the approved dose of 160 mg/d. These larger, randomized, double-blind, placebo-controlled studies provide a more thorough evaluation of the safety and tolerability of enzalutamide [5] and [6]. In particular, the rate of fatigue was 34% with enzalutamide and 29% with placebo in AFFIRM, and 36% with enzalutamide and 26% with placebo in PREVAIL.

The safety analyses described here provides evidence that enzalutamide remains well tolerated over extended use. During long-term follow-up, there was no meaningful change in the overall incidence of common AEs or grade 3/4 AEs, and only one of the 19 patients still being treated at the time of the final efficacy analysis in 2010 subsequently discontinued enzalutamide because of an AE. A safety analysis summarizing AEs occurring within 2, 3, or 4 yr after the patient's first dose showed little to no change in frequency of the most common drug-related AEs over time, with few new AEs reported after 2 yr of treatment.

Limitations of the findings reported reflect both the study design, the heterogeneity of this early-phase study population, and the bias inherent in any long-term analysis. First, patients initially received a wide range of doses and were switched to a common dose at several time points during the study. Of particular note is that many patients received enzalutamide at a higher dose (up to 600 mg/d) than the currently approved dose (160 mg/d). Second, patients who remained on treatment at the time of the final analysis had already benefitted from and tolerated enzalutamide for at least 20 mo. Thus, the paucity of new events reported during long-term treatment is within a population of patients who had already demonstrated tolerability and prolonged benefit from enzalutamide. Even though no new safety signal was detected during long-term treatment in this study, clinicians should be mindful of the potential for late-occurring, initially subtle AEs such as bone loss and metabolic syndrome, which have been observed with other hormonal therapies.

Prostate cancer growth is dependent on androgen receptor (AR) signaling. Initial hormonal treatment strategies include depletion of testosterone and inhibition of AR signaling [1] . The response can be dramatic, but virtually all patients progress to a castration-resistant prostate cancer (CRPC) state over time [2] . It is now recognized that tumor growth and progression in the CRPC state remain dependent on AR signaling [3] . Enzalutamide (formerly MDV3100) is an orally administered AR inhibitor that acts on multiple steps in the AR signaling pathway [4] . In phase 3 trials, enzalutamide had overall survival and radiographic progression-free survival benefits in patients with metastatic CRPC both before and after docetaxel treatment [5] and [6].

The first clinical trial of enzalutamide was an open-label, phase 1–2 dose-escalation study (NCT00510718) assessing the safety, pharmacokinetics (PK), and antitumor activity of enzalutamide in CRPC patients, both with and without prior exposure to chemotherapy [7] . The doses tested ranged from 30 to 600 mg/d. The maximum tolerated dose (MTD) of enzalutamide was identified as 240 mg/d. Full evaluation of the antitumor activity and safety data led to selection of 160 mg/d as the dose for evaluation in phase 3 registration studies, and this is now the approved dose. The most common grade 3/4 adverse event (AE) in the phase 1–2 trial was fatigue, which was more common at doses ≥240 mg/d and generally resolved after dose reduction. Antitumor effects, including prostate-specific antigen (PSA) declines, regression of soft-tissue disease, stabilization of bone disease, and conversion from unfavorable to favorable circulating tumor cell counts, were found at all doses studied [7] .

Here we present the results of the final efficacy analysis conducted in September 2010, 17 mo after the initial data cutoff date, and of a long-term safety analysis conducted in September 2013, nearly 4.5 yr after the cutoff date for the initial study report [7] .

The complete study design and methods were published previously [7] . Patients had histologically confirmed prostate cancer, castrate levels of testosterone (<1.7 nmol/l), and increasing PSA levels (minimum of three measurements more than 2 wk apart showing ≥50% increase, with the last value >2 ng/ml). Institutional review board approval and written informed consent from patients were obtained before commencement of any study-related activities. The study was conducted in compliance with the Declaration of Helsinki and its later revisions and all International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice Guidelines. Patients were enrolled from July 2007 to December 2008.

Patients received oral enzalutamide starting at 30 mg/d, with sequential escalations in cohorts of three to six patients to the following dose levels: 60, 150, 240, 360, 480, and 600 mg/d. After confirming dose tolerability, 24 patients were included per dose level (12 chemotherapy-naive and 12 postchemotherapy) at doses ≥60 mg/d, except for 480 and 600 mg/d, for which only postchemotherapy (docetaxel) patients were enrolled.

The study consisted of four periods: single-dose, multiple-dose, long-term dosing, and safety follow-up periods. All patients received a single dose of enzalutamide and were then followed for 6 d (single-dose period). Those not experiencing dose-limiting toxicity (DLT) then entered the multiple-dose period, in which they received the same dose as previously, once daily for 84 d. Patients completing the multiple-dose period entered the long-term dosing period and continued to receive the same dose taken in the multiple-dose period. When patients discontinued treatment for any reason, they entered the 30-d safety follow-up period.

All patients in the long-term dosing period were switched to the 240-mg/d dose in January 2009 after it was determined to be the MTD, and to 160 mg/d in September 2009 after 160 mg/d was determined to be the dose for phase 3 investigation based on the updated risk-benefit analysis [7] . During the long-term dosing period, safety was assessed every 28 d for the first 3 mo and every 12 wk thereafter via a physical examination and evaluation of vital signs, AEs, 12-lead electrocardiogram, and clinical laboratory tests. PSA levels were evaluated every 28 d for the first 3 mo and then every 12 wk thereafter; bone scans and imaging studies (computerized tomography or magnetic resonance imaging) were evaluated every 12 wk. Overall survival was not assessed as a study endpoint.

This report provides an additional 17-mo follow-up for antitumor activity and >4 yr for safety for the initial phase 1–2 trial [7] that evaluated the safety, tolerability, PK, and antitumor activity of enzalutamide in men with CRPC. Our results show that enzalutamide continued to demonstrate durable antitumor activity and a favorable tolerability profile for the men who remained in the study. No new safety signals were detected with extended dosing. The results provide a unique insight into the long-term outcomes with enzalutamide because the follow-up periods exceed that of the completed phase 3 AFFIRM [5] and PREVAIL trials [6] , although these trials enrolled a significantly greater number of patients. It is noteworthy that 31% of the chemotherapy-naive patients remained on enzalutamide therapy for >2 yr and 17% for >4 yr. This contrasts with the 2-yr on-treatment rate of 5% for postchemotherapy patients.

In further support of the durable antitumor activity of enzalutamide, 70% of patients had not experienced PSA progression at 2 yr, and for chemotherapy-naive patients the median time to PSA progression had not been reached and the median time to radiographic progression was more than 1 yr (56 wk). Importantly, patients who were both ketoconazole- and chemotherapy-naive experienced a longer duration of PSA response (median 1.9 yr to PSA progression). These results illustrate the possibility of extended disease control with enzalutamide treatment for a subset of patients, yet to be further characterized with any specific biomarker.

The most common AEs during extended dosing (all grades and grade 3/4) were similar to those previously reported [7] . Fatigue remained the most common dose-dependent AE, reported as any grade by 70% of patients and as grade 3/4 by 14% of patients across the 30–600-mg/d range. Fatigue was also the most common AE in the AFFIRM and PREVAIL trials, phase 3 studies conducted with the approved dose of 160 mg/d. These larger, randomized, double-blind, placebo-controlled studies provide a more thorough evaluation of the safety and tolerability of enzalutamide [5] and [6]. In particular, the rate of fatigue was 34% with enzalutamide and 29% with placebo in AFFIRM, and 36% with enzalutamide and 26% with placebo in PREVAIL.

The safety analyses described here provides evidence that enzalutamide remains well tolerated over extended use. During long-term follow-up, there was no meaningful change in the overall incidence of common AEs or grade 3/4 AEs, and only one of the 19 patients still being treated at the time of the final efficacy analysis in 2010 subsequently discontinued enzalutamide because of an AE. A safety analysis summarizing AEs occurring within 2, 3, or 4 yr after the patient's first dose showed little to no change in frequency of the most common drug-related AEs over time, with few new AEs reported after 2 yr of treatment.

Limitations of the findings reported reflect both the study design, the heterogeneity of this early-phase study population, and the bias inherent in any long-term analysis. First, patients initially received a wide range of doses and were switched to a common dose at several time points during the study. Of particular note is that many patients received enzalutamide at a higher dose (up to 600 mg/d) than the currently approved dose (160 mg/d). Second, patients who remained on treatment at the time of the final analysis had already benefitted from and tolerated enzalutamide for at least 20 mo. Thus, the paucity of new events reported during long-term treatment is within a population of patients who had already demonstrated tolerability and prolonged benefit from enzalutamide. Even though no new safety signal was detected during long-term treatment in this study, clinicians should be mindful of the potential for late-occurring, initially subtle AEs such as bone loss and metabolic syndrome, which have been observed with other hormonal therapies.

Prostate cancer growth is dependent on androgen receptor (AR) signaling. Initial hormonal treatment strategies include depletion of testosterone and inhibition of AR signaling [1] . The response can be dramatic, but virtually all patients progress to a castration-resistant prostate cancer (CRPC) state over time [2] . It is now recognized that tumor growth and progression in the CRPC state remain dependent on AR signaling [3] . Enzalutamide (formerly MDV3100) is an orally administered AR inhibitor that acts on multiple steps in the AR signaling pathway [4] . In phase 3 trials, enzalutamide had overall survival and radiographic progression-free survival benefits in patients with metastatic CRPC both before and after docetaxel treatment [5] and [6].

The first clinical trial of enzalutamide was an open-label, phase 1–2 dose-escalation study (NCT00510718) assessing the safety, pharmacokinetics (PK), and antitumor activity of enzalutamide in CRPC patients, both with and without prior exposure to chemotherapy [7] . The doses tested ranged from 30 to 600 mg/d. The maximum tolerated dose (MTD) of enzalutamide was identified as 240 mg/d. Full evaluation of the antitumor activity and safety data led to selection of 160 mg/d as the dose for evaluation in phase 3 registration studies, and this is now the approved dose. The most common grade 3/4 adverse event (AE) in the phase 1–2 trial was fatigue, which was more common at doses ≥240 mg/d and generally resolved after dose reduction. Antitumor effects, including prostate-specific antigen (PSA) declines, regression of soft-tissue disease, stabilization of bone disease, and conversion from unfavorable to favorable circulating tumor cell counts, were found at all doses studied [7] .

Here we present the results of the final efficacy analysis conducted in September 2010, 17 mo after the initial data cutoff date, and of a long-term safety analysis conducted in September 2013, nearly 4.5 yr after the cutoff date for the initial study report [7] .

The complete study design and methods were published previously [7] . Patients had histologically confirmed prostate cancer, castrate levels of testosterone (<1.7 nmol/l), and increasing PSA levels (minimum of three measurements more than 2 wk apart showing ≥50% increase, with the last value >2 ng/ml). Institutional review board approval and written informed consent from patients were obtained before commencement of any study-related activities. The study was conducted in compliance with the Declaration of Helsinki and its later revisions and all International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice Guidelines. Patients were enrolled from July 2007 to December 2008.

Patients received oral enzalutamide starting at 30 mg/d, with sequential escalations in cohorts of three to six patients to the following dose levels: 60, 150, 240, 360, 480, and 600 mg/d. After confirming dose tolerability, 24 patients were included per dose level (12 chemotherapy-naive and 12 postchemotherapy) at doses ≥60 mg/d, except for 480 and 600 mg/d, for which only postchemotherapy (docetaxel) patients were enrolled.

The study consisted of four periods: single-dose, multiple-dose, long-term dosing, and safety follow-up periods. All patients received a single dose of enzalutamide and were then followed for 6 d (single-dose period). Those not experiencing dose-limiting toxicity (DLT) then entered the multiple-dose period, in which they received the same dose as previously, once daily for 84 d. Patients completing the multiple-dose period entered the long-term dosing period and continued to receive the same dose taken in the multiple-dose period. When patients discontinued treatment for any reason, they entered the 30-d safety follow-up period.

All patients in the long-term dosing period were switched to the 240-mg/d dose in January 2009 after it was determined to be the MTD, and to 160 mg/d in September 2009 after 160 mg/d was determined to be the dose for phase 3 investigation based on the updated risk-benefit analysis [7] . During the long-term dosing period, safety was assessed every 28 d for the first 3 mo and every 12 wk thereafter via a physical examination and evaluation of vital signs, AEs, 12-lead electrocardiogram, and clinical laboratory tests. PSA levels were evaluated every 28 d for the first 3 mo and then every 12 wk thereafter; bone scans and imaging studies (computerized tomography or magnetic resonance imaging) were evaluated every 12 wk. Overall survival was not assessed as a study endpoint.

This report provides an additional 17-mo follow-up for antitumor activity and >4 yr for safety for the initial phase 1–2 trial [7] that evaluated the safety, tolerability, PK, and antitumor activity of enzalutamide in men with CRPC. Our results show that enzalutamide continued to demonstrate durable antitumor activity and a favorable tolerability profile for the men who remained in the study. No new safety signals were detected with extended dosing. The results provide a unique insight into the long-term outcomes with enzalutamide because the follow-up periods exceed that of the completed phase 3 AFFIRM [5] and PREVAIL trials [6] , although these trials enrolled a significantly greater number of patients. It is noteworthy that 31% of the chemotherapy-naive patients remained on enzalutamide therapy for >2 yr and 17% for >4 yr. This contrasts with the 2-yr on-treatment rate of 5% for postchemotherapy patients.

In further support of the durable antitumor activity of enzalutamide, 70% of patients had not experienced PSA progression at 2 yr, and for chemotherapy-naive patients the median time to PSA progression had not been reached and the median time to radiographic progression was more than 1 yr (56 wk). Importantly, patients who were both ketoconazole- and chemotherapy-naive experienced a longer duration of PSA response (median 1.9 yr to PSA progression). These results illustrate the possibility of extended disease control with enzalutamide treatment for a subset of patients, yet to be further characterized with any specific biomarker.

The most common AEs during extended dosing (all grades and grade 3/4) were similar to those previously reported [7] . Fatigue remained the most common dose-dependent AE, reported as any grade by 70% of patients and as grade 3/4 by 14% of patients across the 30–600-mg/d range. Fatigue was also the most common AE in the AFFIRM and PREVAIL trials, phase 3 studies conducted with the approved dose of 160 mg/d. These larger, randomized, double-blind, placebo-controlled studies provide a more thorough evaluation of the safety and tolerability of enzalutamide [5] and [6]. In particular, the rate of fatigue was 34% with enzalutamide and 29% with placebo in AFFIRM, and 36% with enzalutamide and 26% with placebo in PREVAIL.

The safety analyses described here provides evidence that enzalutamide remains well tolerated over extended use. During long-term follow-up, there was no meaningful change in the overall incidence of common AEs or grade 3/4 AEs, and only one of the 19 patients still being treated at the time of the final efficacy analysis in 2010 subsequently discontinued enzalutamide because of an AE. A safety analysis summarizing AEs occurring within 2, 3, or 4 yr after the patient's first dose showed little to no change in frequency of the most common drug-related AEs over time, with few new AEs reported after 2 yr of treatment.

Limitations of the findings reported reflect both the study design, the heterogeneity of this early-phase study population, and the bias inherent in any long-term analysis. First, patients initially received a wide range of doses and were switched to a common dose at several time points during the study. Of particular note is that many patients received enzalutamide at a higher dose (up to 600 mg/d) than the currently approved dose (160 mg/d). Second, patients who remained on treatment at the time of the final analysis had already benefitted from and tolerated enzalutamide for at least 20 mo. Thus, the paucity of new events reported during long-term treatment is within a population of patients who had already demonstrated tolerability and prolonged benefit from enzalutamide. Even though no new safety signal was detected during long-term treatment in this study, clinicians should be mindful of the potential for late-occurring, initially subtle AEs such as bone loss and metabolic syndrome, which have been observed with other hormonal therapies.

Prostate cancer growth is dependent on androgen receptor (AR) signaling. Initial hormonal treatment strategies include depletion of testosterone and inhibition of AR signaling [1] . The response can be dramatic, but virtually all patients progress to a castration-resistant prostate cancer (CRPC) state over time [2] . It is now recognized that tumor growth and progression in the CRPC state remain dependent on AR signaling [3] . Enzalutamide (formerly MDV3100) is an orally administered AR inhibitor that acts on multiple steps in the AR signaling pathway [4] . In phase 3 trials, enzalutamide had overall survival and radiographic progression-free survival benefits in patients with metastatic CRPC both before and after docetaxel treatment [5] and [6].

The first clinical trial of enzalutamide was an open-label, phase 1–2 dose-escalation study (NCT00510718) assessing the safety, pharmacokinetics (PK), and antitumor activity of enzalutamide in CRPC patients, both with and without prior exposure to chemotherapy [7] . The doses tested ranged from 30 to 600 mg/d. The maximum tolerated dose (MTD) of enzalutamide was identified as 240 mg/d. Full evaluation of the antitumor activity and safety data led to selection of 160 mg/d as the dose for evaluation in phase 3 registration studies, and this is now the approved dose. The most common grade 3/4 adverse event (AE) in the phase 1–2 trial was fatigue, which was more common at doses ≥240 mg/d and generally resolved after dose reduction. Antitumor effects, including prostate-specific antigen (PSA) declines, regression of soft-tissue disease, stabilization of bone disease, and conversion from unfavorable to favorable circulating tumor cell counts, were found at all doses studied [7] .

Here we present the results of the final efficacy analysis conducted in September 2010, 17 mo after the initial data cutoff date, and of a long-term safety analysis conducted in September 2013, nearly 4.5 yr after the cutoff date for the initial study report [7] .

The complete study design and methods were published previously [7] . Patients had histologically confirmed prostate cancer, castrate levels of testosterone (<1.7 nmol/l), and increasing PSA levels (minimum of three measurements more than 2 wk apart showing ≥50% increase, with the last value >2 ng/ml). Institutional review board approval and written informed consent from patients were obtained before commencement of any study-related activities. The study was conducted in compliance with the Declaration of Helsinki and its later revisions and all International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice Guidelines. Patients were enrolled from July 2007 to December 2008.

Patients received oral enzalutamide starting at 30 mg/d, with sequential escalations in cohorts of three to six patients to the following dose levels: 60, 150, 240, 360, 480, and 600 mg/d. After confirming dose tolerability, 24 patients were included per dose level (12 chemotherapy-naive and 12 postchemotherapy) at doses ≥60 mg/d, except for 480 and 600 mg/d, for which only postchemotherapy (docetaxel) patients were enrolled.

The study consisted of four periods: single-dose, multiple-dose, long-term dosing, and safety follow-up periods. All patients received a single dose of enzalutamide and were then followed for 6 d (single-dose period). Those not experiencing dose-limiting toxicity (DLT) then entered the multiple-dose period, in which they received the same dose as previously, once daily for 84 d. Patients completing the multiple-dose period entered the long-term dosing period and continued to receive the same dose taken in the multiple-dose period. When patients discontinued treatment for any reason, they entered the 30-d safety follow-up period.

All patients in the long-term dosing period were switched to the 240-mg/d dose in January 2009 after it was determined to be the MTD, and to 160 mg/d in September 2009 after 160 mg/d was determined to be the dose for phase 3 investigation based on the updated risk-benefit analysis [7] . During the long-term dosing period, safety was assessed every 28 d for the first 3 mo and every 12 wk thereafter via a physical examination and evaluation of vital signs, AEs, 12-lead electrocardiogram, and clinical laboratory tests. PSA levels were evaluated every 28 d for the first 3 mo and then every 12 wk thereafter; bone scans and imaging studies (computerized tomography or magnetic resonance imaging) were evaluated every 12 wk. Overall survival was not assessed as a study endpoint.

This report provides an additional 17-mo follow-up for antitumor activity and >4 yr for safety for the initial phase 1–2 trial [7] that evaluated the safety, tolerability, PK, and antitumor activity of enzalutamide in men with CRPC. Our results show that enzalutamide continued to demonstrate durable antitumor activity and a favorable tolerability profile for the men who remained in the study. No new safety signals were detected with extended dosing. The results provide a unique insight into the long-term outcomes with enzalutamide because the follow-up periods exceed that of the completed phase 3 AFFIRM [5] and PREVAIL trials [6] , although these trials enrolled a significantly greater number of patients. It is noteworthy that 31% of the chemotherapy-naive patients remained on enzalutamide therapy for >2 yr and 17% for >4 yr. This contrasts with the 2-yr on-treatment rate of 5% for postchemotherapy patients.

In further support of the durable antitumor activity of enzalutamide, 70% of patients had not experienced PSA progression at 2 yr, and for chemotherapy-naive patients the median time to PSA progression had not been reached and the median time to radiographic progression was more than 1 yr (56 wk). Importantly, patients who were both ketoconazole- and chemotherapy-naive experienced a longer duration of PSA response (median 1.9 yr to PSA progression). These results illustrate the possibility of extended disease control with enzalutamide treatment for a subset of patients, yet to be further characterized with any specific biomarker.

The most common AEs during extended dosing (all grades and grade 3/4) were similar to those previously reported [7] . Fatigue remained the most common dose-dependent AE, reported as any grade by 70% of patients and as grade 3/4 by 14% of patients across the 30–600-mg/d range. Fatigue was also the most common AE in the AFFIRM and PREVAIL trials, phase 3 studies conducted with the approved dose of 160 mg/d. These larger, randomized, double-blind, placebo-controlled studies provide a more thorough evaluation of the safety and tolerability of enzalutamide [5] and [6]. In particular, the rate of fatigue was 34% with enzalutamide and 29% with placebo in AFFIRM, and 36% with enzalutamide and 26% with placebo in PREVAIL.

The safety analyses described here provides evidence that enzalutamide remains well tolerated over extended use. During long-term follow-up, there was no meaningful change in the overall incidence of common AEs or grade 3/4 AEs, and only one of the 19 patients still being treated at the time of the final efficacy analysis in 2010 subsequently discontinued enzalutamide because of an AE. A safety analysis summarizing AEs occurring within 2, 3, or 4 yr after the patient's first dose showed little to no change in frequency of the most common drug-related AEs over time, with few new AEs reported after 2 yr of treatment.

Limitations of the findings reported reflect both the study design, the heterogeneity of this early-phase study population, and the bias inherent in any long-term analysis. First, patients initially received a wide range of doses and were switched to a common dose at several time points during the study. Of particular note is that many patients received enzalutamide at a higher dose (up to 600 mg/d) than the currently approved dose (160 mg/d). Second, patients who remained on treatment at the time of the final analysis had already benefitted from and tolerated enzalutamide for at least 20 mo. Thus, the paucity of new events reported during long-term treatment is within a population of patients who had already demonstrated tolerability and prolonged benefit from enzalutamide. Even though no new safety signal was detected during long-term treatment in this study, clinicians should be mindful of the potential for late-occurring, initially subtle AEs such as bone loss and metabolic syndrome, which have been observed with other hormonal therapies.

Prostate cancer growth is dependent on androgen receptor (AR) signaling. Initial hormonal treatment strategies include depletion of testosterone and inhibition of AR signaling [1] . The response can be dramatic, but virtually all patients progress to a castration-resistant prostate cancer (CRPC) state over time [2] . It is now recognized that tumor growth and progression in the CRPC state remain dependent on AR signaling [3] . Enzalutamide (formerly MDV3100) is an orally administered AR inhibitor that acts on multiple steps in the AR signaling pathway [4] . In phase 3 trials, enzalutamide had overall survival and radiographic progression-free survival benefits in patients with metastatic CRPC both before and after docetaxel treatment [5] and [6].

The first clinical trial of enzalutamide was an open-label, phase 1–2 dose-escalation study (NCT00510718) assessing the safety, pharmacokinetics (PK), and antitumor activity of enzalutamide in CRPC patients, both with and without prior exposure to chemotherapy [7] . The doses tested ranged from 30 to 600 mg/d. The maximum tolerated dose (MTD) of enzalutamide was identified as 240 mg/d. Full evaluation of the antitumor activity and safety data led to selection of 160 mg/d as the dose for evaluation in phase 3 registration studies, and this is now the approved dose. The most common grade 3/4 adverse event (AE) in the phase 1–2 trial was fatigue, which was more common at doses ≥240 mg/d and generally resolved after dose reduction. Antitumor effects, including prostate-specific antigen (PSA) declines, regression of soft-tissue disease, stabilization of bone disease, and conversion from unfavorable to favorable circulating tumor cell counts, were found at all doses studied [7] .

Here we present the results of the final efficacy analysis conducted in September 2010, 17 mo after the initial data cutoff date, and of a long-term safety analysis conducted in September 2013, nearly 4.5 yr after the cutoff date for the initial study report [7] .

The complete study design and methods were published previously [7] . Patients had histologically confirmed prostate cancer, castrate levels of testosterone (<1.7 nmol/l), and increasing PSA levels (minimum of three measurements more than 2 wk apart showing ≥50% increase, with the last value >2 ng/ml). Institutional review board approval and written informed consent from patients were obtained before commencement of any study-related activities. The study was conducted in compliance with the Declaration of Helsinki and its later revisions and all International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice Guidelines. Patients were enrolled from July 2007 to December 2008.

Patients received oral enzalutamide starting at 30 mg/d, with sequential escalations in cohorts of three to six patients to the following dose levels: 60, 150, 240, 360, 480, and 600 mg/d. After confirming dose tolerability, 24 patients were included per dose level (12 chemotherapy-naive and 12 postchemotherapy) at doses ≥60 mg/d, except for 480 and 600 mg/d, for which only postchemotherapy (docetaxel) patients were enrolled.

The study consisted of four periods: single-dose, multiple-dose, long-term dosing, and safety follow-up periods. All patients received a single dose of enzalutamide and were then followed for 6 d (single-dose period). Those not experiencing dose-limiting toxicity (DLT) then entered the multiple-dose period, in which they received the same dose as previously, once daily for 84 d. Patients completing the multiple-dose period entered the long-term dosing period and continued to receive the same dose taken in the multiple-dose period. When patients discontinued treatment for any reason, they entered the 30-d safety follow-up period.

All patients in the long-term dosing period were switched to the 240-mg/d dose in January 2009 after it was determined to be the MTD, and to 160 mg/d in September 2009 after 160 mg/d was determined to be the dose for phase 3 investigation based on the updated risk-benefit analysis [7] . During the long-term dosing period, safety was assessed every 28 d for the first 3 mo and every 12 wk thereafter via a physical examination and evaluation of vital signs, AEs, 12-lead electrocardiogram, and clinical laboratory tests. PSA levels were evaluated every 28 d for the first 3 mo and then every 12 wk thereafter; bone scans and imaging studies (computerized tomography or magnetic resonance imaging) were evaluated every 12 wk. Overall survival was not assessed as a study endpoint.