Enzalutamide Prolongs Overall Survival after Chemotherapy in Prostate Cancer
The once-daily oral androgen-receptor–signaling inhibitor enzalutamide (Xtandi) differs from current antiandrogen therapies by its ability to inhibit nuclear translocation of the androgen receptor, its DNA binding activity, and its coactivator recruitment, in addition to other clinical benefits in the context of prostate cancer. This novel agent is administered without the need for concomitant prednisone, which has been postulated to activate androgen-receptor signaling. In this phase 3, double-blind, placebo-controlled clinical trial, enzalutamide significantly prolonged survival in patients with castration-resistant prostate cancer (CRPC) after standard chemotherapy (Scher HI, et al. N Engl J Med. 2012;367:1187-1197).
A total of 1199 men with CRPC who had received chemotherapy were randomized in a 2:1 ratio to oral enzalutamide 160 mg daily or to placebo. The study primary end point was overall survival (OS). According to the study design, the trial was stopped when 520 deaths occurred, and an interim analysis was conducted; by that point, the OS was not reached with enzalutamide. The median OS was 18.4 months in the group receiving enzalutamide (confidence interval [CI], 18.3-not reached) compared with 13.6 months with placebo (CI, 11.3-15.8).
Enzalutamide was significantly (P <.001) superior to placebo in all of the secondary end points as well. These secondary measures showed that 54% of patients who received enzalutamide had reduced prostate-specific antigen (PSA) levels by more than 50% versus by 2% in the placebo group; the quality-of-life response rate was 43% with enzalutamide versus 18% with placebo; time to PSA progression was 8.3 months versus 3.0 months, respectively; radiographic progression-free survival (PFS) was 8.3 months versus 2.9 months (hazard ratio [HR], 0.40), respectively; and time to first skeletal-related event was 16.7 months versus 13.3 months (HR, 0.69), respectively.
The rates of adverse events (AEs) were similar in the 2 groups, with the exception of higher rates of fatigue, diarrhea, and hot flashes reported with enzalutamide than with placebo. In addition, 5 patients (0.6%) had seizures while taking enzalutamide. Of note, AEs of grade ≥3 occurred 8.4 months earlier with placebo than with enzalutamide—the median time to such events was 4.2 months with placebo and 12.6 months with enzalutamide.
These results confirm that androgen-receptor signaling is a significant target for therapy in men with prostate cancer. Enzalutamide is currently being investigated in clinical trials of men with earlier-stage prostate cancer.