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

Background: Given that some patients with castration-resistant prostate cancer (CRPC) have shown extended responses to the androgen receptor inhibitor enzalutamide, long-term safety of this drug is of interest.

Objective: To evaluate the long-term safety and antitumor activity of enzalutamide in CRPC patients.

Design, Setting, And Participants: This phase 1-2 study evaluated enzalutamide in 140 CRPC patients with and without prior chemotherapy. Initial findings were published in 2010. We report updated results from an additional 17-mo follow-up for antitumor activity and >4 yr for safety.

Intervention: Patients received 30-600mg/d oral enzalutamide. During long-term dosing, all patients were switched first to the maximum tolerated dose of 240mg/d and then to the phase 3 dose of 160mg/d.

Outcome Measurements And Statistical Analysis: Safety was assessed regularly. The Kaplan-Meier method was used to estimate the distributions of time to prostate-specific antigen (PSA) progression and time to radiographic progression.

Results And Limitations: The safety profile of enzalutamide was consistent over time, with little change in the rates of commonly reported adverse events (AEs) or the incidence of grade 3/4 AEs. Fatigue of any grade was the most common dose-dependent AE, experienced by 70% of patients, with 14% of patients reporting grade 3/4 fatigue. The median time to PSA progression was not reached for chemotherapy-naive patients and was 45 wk for postchemotherapy patients; the corresponding median time to radiographic progression was 56 wk and 25 wk.

Conclusions: Enzalutamide showed durable antitumor activity in chemotherapy-naive and postchemotherapy patients, and was well tolerated, even in patients treated for 4 yr.

Patient Summary: Enzalutamide was active against prostate cancer and was well tolerated, even for up to 4 yr of treatment, supporting its potential for long-term use in men with prostate cancer. Fatigue was the most common side effect, occurring at varying degrees of severity in most patients.