Patients were eligible if they had histologically or cytologically confirmed adenocarcinoma of the prostate with documented metastases and had PSA progression, radiographic progression, or both in bone or soft tissue, despite receiving LHRH analogue therapy or undergoing orchiectomy, with a serum testosterone level of 1.73 nmol per liter (50 ng per deciliter) or less. Continued androgen-deprivation therapy was required. Previous antiandrogen therapy and concurrent use of glucocorticoids were permitted but not required. Eligible patients had not received cytotoxic chemotherapy, ketoconazole, or abiraterone acetate, had an Eastern Cooperative Oncology Group performance status grade of 0 or 1 (no symptoms or ambulatory but restricted in strenuous activities), and were either asymptomatic (score of 0 to 1) or mildly symptomatic (score of 2 to 3), as measured on the Brief Pain Inventory Short Form question 3 (on which scores range from 0 to 10, with higher scores indicating a greater severity of pain). Patients with visceral disease, including lung or liver metastases, were eligible, as were patients with New York Heart Association class I or II heart failure. Patients with a history of seizure or a condition that could confer a predisposition to seizure were excluded, although patients taking medications associated with lowering the seizure threshold were eligible.
From September 2010 through September 2012, patients were enrolled at 207 sites globally. All patients were randomly assigned to receive either oral enzalutamide (at a dose of 160 mg) or placebo once daily with or without food. Randomization was stratified according to the study site. Treatment continued until the occurrence of unacceptable side effects or confirmed radiographic progression and the initiation of chemotherapy or an investigational agent. Treatment discontinuation because of an increase in the PSA level alone was discouraged.