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.