Enzalutamide in castrate-resistant prostate cancer after chemotherapy

Abstract

Enzalutamide is an androgen receptor-signaling inhibitor that is reported to differ from conventional antiandrogen agents in that it inhibits androgen receptor nuclear translocation, DNA binding, and coactivator recruitment; exhibits increased affinity for the androgen receptor; and induces tumor reduction, rather than slowing growth, in preclinical models. The recently reported AFFIRM study showed that enzalutamide treatment after chemotherapy significantly prolonged overall survival (OS), radiographic progression-free survival (PFS), time to prostate-specific antigen (PSA) progression, and time to skeletal-related events (SREs) in men with castration-resistant prostate cancer. This trial formed the basis for the recent approval of enzalutamide for the treatment of patients with metastatic castrationresistant prostate cancer who have previously received docetaxel. In the double-blind AFFIRM trial, 1,199 patients with castration-resistant prostate cancer who had received at least 1 docetaxel-containing chemotherapy regimen were randomized (2:1) to oral enzalutamide 160 mg once daily (800 patients) or placebo (399 patients). Treatment was continued until radiographic confirmation of disease progression requiring initiation of new systemic antineoplastic treatment. Enzalutamide has been associated with a lowered seizure threshold; thus, patients with a history of or risk factors for seizure or who were taking medications known to decrease seizure threshold were excluded from the trial. All of the patients continued androgen deprivation therapy. Patients were permitted to start or continue corticosteroid treatment during the study. The primary endpoint of the trial was OS. The median age in both groups was 69 years, with 26% of enzalutamide patients and 27% of placebo patients being 75 years of age or older. Similar proportions of enzalutamide and placebo patients had a Gleason score 7 (50% vs 52%, respectively), and ECOG performance status of 0 or 1 (91% vs 92%), a pain score 4 (28% vs 29%), 1 prior chemotherapy regimen (72% vs 74%), bisphosphonate use at baseline (43% in both groups), prior radiation therapy (71% vs 72%), bone disease (92% vs 92%, with 38% in both groups having 20 lesions), soft tissue disease (71% vs 69%), PSA progression at baseline (89% vs 90%), and radiographic progression at baseline (59% in both groups). Median PSA levels at baseline were 108 ng/mL and 128 ng/mL. The median number of prior docetaxel cycles was 8.5 in the enzalutamide group and 8.0 in the placebo group. During the study, 48% of enzalutamide patients and 46% of placebo patients received corticosteroid treatment. At the time of a preplanned interim analysis, median durations of treatment were 8.3 months in the enzalutamide group and 3.0 months in the placebo group. The median duration of follow-up to assess survival outcomes