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Study Overview
Objective. To evaluate the efficacy of enzalutamide compared with standard first-line testosterone suppression in men with newly diagnosed metastatic, castrate-sensitive prostate cancer.
Design. Multinational, open-label, randomized phase 3 trial.
Setting and participants. 1125 men were randomly assigned to receive enzalutamide (563 patients) or standard care (562 patients) from March 2014 through March 2017. Eligible patients had a histologic diagnosis of prostate adenocarcinoma with metastases documented by conventional imaging with computed tomography (CT) and/or technetium-99 bone scan. Prior use of adjuvant testosterone suppression was allowed for up to 2 years, provided this had been completed at least 12 months prior to enrollment.
Intervention. Patients were randomized in a 1:1 fashion to receive enzalutamide 160 mg daily or nonsteroidal antiandrogen therapy with bicalutamide, nilutamide, or flutamide. All patients received testosterone suppression with goserelin, leuprolide, or degarelix. Therapy was continued until disease progression or intolerable adverse effects occurred. In November 2014 the protocol was amended to allow for early administration of docetaxel 75 mg/m2 every 3 weeks for 6 cycles and androgen suppression. Patients were stratified according to having received docetaxel prior to randomization. This amendment was based on evidence of improved survival noted with this combination, and the decision to add docetaxel was up to the treating physician. The randomization was further stratified by disease volume, the use of bone-modifying agents, and comorbidity scores. High-volume disease was defined as the presence of visceral metastases or at least 4 bone lesions, with at least 1 being in the appendicular skeleton.
Main outcome measures. The primary endpoint was overall survival (OS). The secondary endpoints were prostate-specific antigen (PSA) progression-free survival (PFS), clinical PFS, death from any cause, or the last known follow-up PSA. PSA progression was defined as an increase in PSA level from the nadir value by ≥ 25% and by ≥ 2 ng/mL.
Main results. The baseline characteristics were well balanced between the treatment arms. High-volume disease was present in 52% of patients. Early docetaxel was planned in 45% of patients; however, 22 patients in whom docetaxel treatment was planned did not receive it. All 6 cycles of docetaxel were given to 159 patients in the enzalutamide group and 181 patients in the standard-care group. After a median follow-up of 34 months, there were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group, with a hazard ratio (HR) for death of 0.67 (95% confidence interval [CI], 0.52-0.86; P = 0.002). Early docetaxel treatment, volume of disease, and use of bone-modifying agents did not affect this outcome. At 3 years, the OS was 80% in the enzalutamide group and 72% in the standard-care group. The rate of PSA-determined PFS was higher in the enzalutamide group compared with the standard group (3-year event-free survival, 67% and 37%, respectively), with a HR of 0.39 (95% CI, 0.33-0.47; P < 0.001). There were fewer clinical PFS events in the enzalutamide group (167 events vs 320 events), with a HR of 0.40 (95% CI, 0.33-0.49; P < 0.001). Analysis of the stratified subgroups showed the effect on OS was diminished in those with use of bone-modifying agents, those with high-volume disease, and those who received early docetaxel. The clinical PFS benefit was maintained across all subgroups, albeit with a smaller effect in those with high-volume disease and in those with early docetaxel treatment.
Treatment discontinuation for reasons other than progressive disease occurred in 12% of those in the enzalutamide group and 19% of those in the standard-care group. Overall, the adverse events were consistent with the known safety profiles of the treatment regimen. Seizures occurred in 7 patients on enzalutamide and no patients in the standard-care group. Fatigue was more common with enzalutamide.
Conclusion. Enzalutamide treatment was associated with significantly longer PFS and OS compared with standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression.
Commentary
The current study shows that the addition of enzalutamide to standard androgen deprivation therapy (ADT) improves OS and PFS in men with newly diagnosed metastatic, hormone-sensitive prostate cancer. Until recently, antiandrogen therapy had been the standard of care for these men; however, with the advent of novel antiandrogen agents, outcomes in men with metastatic prostate cancer in both the androgen-sensitive and castrate-resistant settings have steadily improved.1-5 In the castrate-resistant setting, enzalutamide has previously been shown to improve survival in chemotherapy-naïve patients and those previously exposed to docetaxel chemotherapy.5-7 Similarly, in the hormone-sensitive setting the combination of ADT with either abiraterone or chemotherapy has been shown to improve outcomes. In the phase 3 LATITUDE and STAMPEDE trials, the combination of abiraterone plus prednisone and ADT resulted in a 30% and 37% improvement in OS, respectively.1,2 Six cycles of docetaxel in combination with ADT also resulted in a 37% increase in OS in those with high-volume metastatic disease.3
The current study adds to the growing body of literature suggesting that combination therapy in the upfront, hormone-sensitive setting improves outcomes. In the CHAARTED trial, the combination of docetaxel and ADT improved survival in men with high-volume disease, but it did not seem to benefit those with lower-volume disease.3 However, the current data suggests a survival advantage with enzalutamide with low-volume disease as well. The use of docetaxel was similar between the 2 groups, and this suggests that the benefits of enzalutamide cannot be attributed to early integration of docetaxel. It is important to note that the subgroup analysis of those who received early docetaxel showed that these patients did not experience the same survival benefit as those who did not receive docetaxel. However, this trial was not powered for this analysis, and thus it should be interpreted with caution. PFS benefit was maintained across those who received and did not receive early docetaxel. Also worth noting is the increased docetaxel-related toxicity in the combination docetaxel and enzalutamide arm of this study. The neurological toxicity of enzalutamide was again noted, with 7 seizure events documented in this study.
Because this report on the ENZAMET study is an interim analysis, it will be important to follow these outcomes as the data set matures to ensure these effects are maintained over time. Additionally, it will be important to see what implications the addition of enzalutamide have on quality of life measures, as these data have not yet been published.
Applications for Clinical Practice
The ENZAMET study provides evidence that in men with metastatic, hormone-sensitive prostate cancer receiving ADT, the addition of enzalutamide improves PFS and OS. In men who received early docetaxel, enzalutamide was associated with increased toxicity. Additionally, while PFS was improved in men who received enzalutamide and docetaxel, OS was not improved. The neurologic toxicities of enzalutamide should be considered, particularly in those with a prior history of seizure disorders. Based on these data, enzalutamide in combination with ADT represents a reasonable treatment option in men with metastatic, hormone-sensitive prostate cancer.
—Daniel Isaac, DO, MS
1. Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377:352-360.
2. James ND, de Bono JS, Spears MR, et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017;377:338-351.
3. Kytriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol. 2018;36:1080-1087.
4. Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naïve men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomized, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16:152-160.
5. Beer TM, Armstrong AJ, Rathkopf D, et al. Enzalutamide in men with chemotherapy-naïve metastatic castration-resistant prostate cancer: extended analysis of the phase 3 PREVAIL study. Eur Urol. 2017;71:151-154.
6. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197.
7. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with non-metastatic castration resistant prostate cancer. N Engl J Med. 2018;378:2465-2474.
Study Overview
Objective. To evaluate the efficacy of enzalutamide compared with standard first-line testosterone suppression in men with newly diagnosed metastatic, castrate-sensitive prostate cancer.
Design. Multinational, open-label, randomized phase 3 trial.
Setting and participants. 1125 men were randomly assigned to receive enzalutamide (563 patients) or standard care (562 patients) from March 2014 through March 2017. Eligible patients had a histologic diagnosis of prostate adenocarcinoma with metastases documented by conventional imaging with computed tomography (CT) and/or technetium-99 bone scan. Prior use of adjuvant testosterone suppression was allowed for up to 2 years, provided this had been completed at least 12 months prior to enrollment.
Intervention. Patients were randomized in a 1:1 fashion to receive enzalutamide 160 mg daily or nonsteroidal antiandrogen therapy with bicalutamide, nilutamide, or flutamide. All patients received testosterone suppression with goserelin, leuprolide, or degarelix. Therapy was continued until disease progression or intolerable adverse effects occurred. In November 2014 the protocol was amended to allow for early administration of docetaxel 75 mg/m2 every 3 weeks for 6 cycles and androgen suppression. Patients were stratified according to having received docetaxel prior to randomization. This amendment was based on evidence of improved survival noted with this combination, and the decision to add docetaxel was up to the treating physician. The randomization was further stratified by disease volume, the use of bone-modifying agents, and comorbidity scores. High-volume disease was defined as the presence of visceral metastases or at least 4 bone lesions, with at least 1 being in the appendicular skeleton.
Main outcome measures. The primary endpoint was overall survival (OS). The secondary endpoints were prostate-specific antigen (PSA) progression-free survival (PFS), clinical PFS, death from any cause, or the last known follow-up PSA. PSA progression was defined as an increase in PSA level from the nadir value by ≥ 25% and by ≥ 2 ng/mL.
Main results. The baseline characteristics were well balanced between the treatment arms. High-volume disease was present in 52% of patients. Early docetaxel was planned in 45% of patients; however, 22 patients in whom docetaxel treatment was planned did not receive it. All 6 cycles of docetaxel were given to 159 patients in the enzalutamide group and 181 patients in the standard-care group. After a median follow-up of 34 months, there were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group, with a hazard ratio (HR) for death of 0.67 (95% confidence interval [CI], 0.52-0.86; P = 0.002). Early docetaxel treatment, volume of disease, and use of bone-modifying agents did not affect this outcome. At 3 years, the OS was 80% in the enzalutamide group and 72% in the standard-care group. The rate of PSA-determined PFS was higher in the enzalutamide group compared with the standard group (3-year event-free survival, 67% and 37%, respectively), with a HR of 0.39 (95% CI, 0.33-0.47; P < 0.001). There were fewer clinical PFS events in the enzalutamide group (167 events vs 320 events), with a HR of 0.40 (95% CI, 0.33-0.49; P < 0.001). Analysis of the stratified subgroups showed the effect on OS was diminished in those with use of bone-modifying agents, those with high-volume disease, and those who received early docetaxel. The clinical PFS benefit was maintained across all subgroups, albeit with a smaller effect in those with high-volume disease and in those with early docetaxel treatment.
Treatment discontinuation for reasons other than progressive disease occurred in 12% of those in the enzalutamide group and 19% of those in the standard-care group. Overall, the adverse events were consistent with the known safety profiles of the treatment regimen. Seizures occurred in 7 patients on enzalutamide and no patients in the standard-care group. Fatigue was more common with enzalutamide.
Conclusion. Enzalutamide treatment was associated with significantly longer PFS and OS compared with standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression.
Commentary
The current study shows that the addition of enzalutamide to standard androgen deprivation therapy (ADT) improves OS and PFS in men with newly diagnosed metastatic, hormone-sensitive prostate cancer. Until recently, antiandrogen therapy had been the standard of care for these men; however, with the advent of novel antiandrogen agents, outcomes in men with metastatic prostate cancer in both the androgen-sensitive and castrate-resistant settings have steadily improved.1-5 In the castrate-resistant setting, enzalutamide has previously been shown to improve survival in chemotherapy-naïve patients and those previously exposed to docetaxel chemotherapy.5-7 Similarly, in the hormone-sensitive setting the combination of ADT with either abiraterone or chemotherapy has been shown to improve outcomes. In the phase 3 LATITUDE and STAMPEDE trials, the combination of abiraterone plus prednisone and ADT resulted in a 30% and 37% improvement in OS, respectively.1,2 Six cycles of docetaxel in combination with ADT also resulted in a 37% increase in OS in those with high-volume metastatic disease.3
The current study adds to the growing body of literature suggesting that combination therapy in the upfront, hormone-sensitive setting improves outcomes. In the CHAARTED trial, the combination of docetaxel and ADT improved survival in men with high-volume disease, but it did not seem to benefit those with lower-volume disease.3 However, the current data suggests a survival advantage with enzalutamide with low-volume disease as well. The use of docetaxel was similar between the 2 groups, and this suggests that the benefits of enzalutamide cannot be attributed to early integration of docetaxel. It is important to note that the subgroup analysis of those who received early docetaxel showed that these patients did not experience the same survival benefit as those who did not receive docetaxel. However, this trial was not powered for this analysis, and thus it should be interpreted with caution. PFS benefit was maintained across those who received and did not receive early docetaxel. Also worth noting is the increased docetaxel-related toxicity in the combination docetaxel and enzalutamide arm of this study. The neurological toxicity of enzalutamide was again noted, with 7 seizure events documented in this study.
Because this report on the ENZAMET study is an interim analysis, it will be important to follow these outcomes as the data set matures to ensure these effects are maintained over time. Additionally, it will be important to see what implications the addition of enzalutamide have on quality of life measures, as these data have not yet been published.
Applications for Clinical Practice
The ENZAMET study provides evidence that in men with metastatic, hormone-sensitive prostate cancer receiving ADT, the addition of enzalutamide improves PFS and OS. In men who received early docetaxel, enzalutamide was associated with increased toxicity. Additionally, while PFS was improved in men who received enzalutamide and docetaxel, OS was not improved. The neurologic toxicities of enzalutamide should be considered, particularly in those with a prior history of seizure disorders. Based on these data, enzalutamide in combination with ADT represents a reasonable treatment option in men with metastatic, hormone-sensitive prostate cancer.
—Daniel Isaac, DO, MS
Study Overview
Objective. To evaluate the efficacy of enzalutamide compared with standard first-line testosterone suppression in men with newly diagnosed metastatic, castrate-sensitive prostate cancer.
Design. Multinational, open-label, randomized phase 3 trial.
Setting and participants. 1125 men were randomly assigned to receive enzalutamide (563 patients) or standard care (562 patients) from March 2014 through March 2017. Eligible patients had a histologic diagnosis of prostate adenocarcinoma with metastases documented by conventional imaging with computed tomography (CT) and/or technetium-99 bone scan. Prior use of adjuvant testosterone suppression was allowed for up to 2 years, provided this had been completed at least 12 months prior to enrollment.
Intervention. Patients were randomized in a 1:1 fashion to receive enzalutamide 160 mg daily or nonsteroidal antiandrogen therapy with bicalutamide, nilutamide, or flutamide. All patients received testosterone suppression with goserelin, leuprolide, or degarelix. Therapy was continued until disease progression or intolerable adverse effects occurred. In November 2014 the protocol was amended to allow for early administration of docetaxel 75 mg/m2 every 3 weeks for 6 cycles and androgen suppression. Patients were stratified according to having received docetaxel prior to randomization. This amendment was based on evidence of improved survival noted with this combination, and the decision to add docetaxel was up to the treating physician. The randomization was further stratified by disease volume, the use of bone-modifying agents, and comorbidity scores. High-volume disease was defined as the presence of visceral metastases or at least 4 bone lesions, with at least 1 being in the appendicular skeleton.
Main outcome measures. The primary endpoint was overall survival (OS). The secondary endpoints were prostate-specific antigen (PSA) progression-free survival (PFS), clinical PFS, death from any cause, or the last known follow-up PSA. PSA progression was defined as an increase in PSA level from the nadir value by ≥ 25% and by ≥ 2 ng/mL.
Main results. The baseline characteristics were well balanced between the treatment arms. High-volume disease was present in 52% of patients. Early docetaxel was planned in 45% of patients; however, 22 patients in whom docetaxel treatment was planned did not receive it. All 6 cycles of docetaxel were given to 159 patients in the enzalutamide group and 181 patients in the standard-care group. After a median follow-up of 34 months, there were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group, with a hazard ratio (HR) for death of 0.67 (95% confidence interval [CI], 0.52-0.86; P = 0.002). Early docetaxel treatment, volume of disease, and use of bone-modifying agents did not affect this outcome. At 3 years, the OS was 80% in the enzalutamide group and 72% in the standard-care group. The rate of PSA-determined PFS was higher in the enzalutamide group compared with the standard group (3-year event-free survival, 67% and 37%, respectively), with a HR of 0.39 (95% CI, 0.33-0.47; P < 0.001). There were fewer clinical PFS events in the enzalutamide group (167 events vs 320 events), with a HR of 0.40 (95% CI, 0.33-0.49; P < 0.001). Analysis of the stratified subgroups showed the effect on OS was diminished in those with use of bone-modifying agents, those with high-volume disease, and those who received early docetaxel. The clinical PFS benefit was maintained across all subgroups, albeit with a smaller effect in those with high-volume disease and in those with early docetaxel treatment.
Treatment discontinuation for reasons other than progressive disease occurred in 12% of those in the enzalutamide group and 19% of those in the standard-care group. Overall, the adverse events were consistent with the known safety profiles of the treatment regimen. Seizures occurred in 7 patients on enzalutamide and no patients in the standard-care group. Fatigue was more common with enzalutamide.
Conclusion. Enzalutamide treatment was associated with significantly longer PFS and OS compared with standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression.
Commentary
The current study shows that the addition of enzalutamide to standard androgen deprivation therapy (ADT) improves OS and PFS in men with newly diagnosed metastatic, hormone-sensitive prostate cancer. Until recently, antiandrogen therapy had been the standard of care for these men; however, with the advent of novel antiandrogen agents, outcomes in men with metastatic prostate cancer in both the androgen-sensitive and castrate-resistant settings have steadily improved.1-5 In the castrate-resistant setting, enzalutamide has previously been shown to improve survival in chemotherapy-naïve patients and those previously exposed to docetaxel chemotherapy.5-7 Similarly, in the hormone-sensitive setting the combination of ADT with either abiraterone or chemotherapy has been shown to improve outcomes. In the phase 3 LATITUDE and STAMPEDE trials, the combination of abiraterone plus prednisone and ADT resulted in a 30% and 37% improvement in OS, respectively.1,2 Six cycles of docetaxel in combination with ADT also resulted in a 37% increase in OS in those with high-volume metastatic disease.3
The current study adds to the growing body of literature suggesting that combination therapy in the upfront, hormone-sensitive setting improves outcomes. In the CHAARTED trial, the combination of docetaxel and ADT improved survival in men with high-volume disease, but it did not seem to benefit those with lower-volume disease.3 However, the current data suggests a survival advantage with enzalutamide with low-volume disease as well. The use of docetaxel was similar between the 2 groups, and this suggests that the benefits of enzalutamide cannot be attributed to early integration of docetaxel. It is important to note that the subgroup analysis of those who received early docetaxel showed that these patients did not experience the same survival benefit as those who did not receive docetaxel. However, this trial was not powered for this analysis, and thus it should be interpreted with caution. PFS benefit was maintained across those who received and did not receive early docetaxel. Also worth noting is the increased docetaxel-related toxicity in the combination docetaxel and enzalutamide arm of this study. The neurological toxicity of enzalutamide was again noted, with 7 seizure events documented in this study.
Because this report on the ENZAMET study is an interim analysis, it will be important to follow these outcomes as the data set matures to ensure these effects are maintained over time. Additionally, it will be important to see what implications the addition of enzalutamide have on quality of life measures, as these data have not yet been published.
Applications for Clinical Practice
The ENZAMET study provides evidence that in men with metastatic, hormone-sensitive prostate cancer receiving ADT, the addition of enzalutamide improves PFS and OS. In men who received early docetaxel, enzalutamide was associated with increased toxicity. Additionally, while PFS was improved in men who received enzalutamide and docetaxel, OS was not improved. The neurologic toxicities of enzalutamide should be considered, particularly in those with a prior history of seizure disorders. Based on these data, enzalutamide in combination with ADT represents a reasonable treatment option in men with metastatic, hormone-sensitive prostate cancer.
—Daniel Isaac, DO, MS
1. Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377:352-360.
2. James ND, de Bono JS, Spears MR, et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017;377:338-351.
3. Kytriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol. 2018;36:1080-1087.
4. Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naïve men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomized, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16:152-160.
5. Beer TM, Armstrong AJ, Rathkopf D, et al. Enzalutamide in men with chemotherapy-naïve metastatic castration-resistant prostate cancer: extended analysis of the phase 3 PREVAIL study. Eur Urol. 2017;71:151-154.
6. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197.
7. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with non-metastatic castration resistant prostate cancer. N Engl J Med. 2018;378:2465-2474.
1. Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377:352-360.
2. James ND, de Bono JS, Spears MR, et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017;377:338-351.
3. Kytriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol. 2018;36:1080-1087.
4. Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naïve men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomized, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16:152-160.
5. Beer TM, Armstrong AJ, Rathkopf D, et al. Enzalutamide in men with chemotherapy-naïve metastatic castration-resistant prostate cancer: extended analysis of the phase 3 PREVAIL study. Eur Urol. 2017;71:151-154.
6. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197.
7. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with non-metastatic castration resistant prostate cancer. N Engl J Med. 2018;378:2465-2474.