Results of the phase III AFFIRM trial show that enzalutamide significantly prolonged survival of men with metastatic castration-resistant prostate cancer after chemotherapy. The results are published in the New England Journal of Medicine. Men randomized to enzalutamide (MDV3100) had a median overall survival of 18.4 months compared to 13.6 months in the placebo group (P < .001). The median duration of patient follow-up was 14.4 months.

Chemical structure of the antiandrogen enzalutamide (MDV3100)

A significantly higher proportion of men taking enzalutamide had at least a 50% reduction in prostate-specific antigen levels by 50% or more. The quality of life response rate was 43% for the experimental group compared to 18% in the placebo arm (P < .001). Enzalutamide also increased the radiographic progression-free survival from 2.9 months for the placebo to 8.3 months (P < .001). Time to first skeletal-related events was 16.7 months for patients taking enzalutamide compared to 13.3 months for patients receiving placebo (P < .001).

The AFFIRM trial results were first presented at the 2012 Genitourinary Cancers Symposium as a late-breaking abstract. The phase III double-blind trial randomized 1,199 men who had castration-resistant prostate cancer two to one. In the experimental arm, 800 men received 160 mg of enzalutamide per day; the other 399 men received a placebo pill. All men had previously received at most two regimens with docetaxel-based treatment.

Enzalutamide is a second-generation androgen receptor inhibitor that works by competitively blocking the binding of androgens to the androgen receptor. The drug targets the main driver of prostate growth—the multi-step androgen-signaling pathway. “Enzalutamide is distinct from the currently available antiandrogen agents in that it inhibits nuclear translocation of the androgen receptor, DNA binding, and coactivator recruitment,” said Howard I. Scher, MD, of the Memorial Sloan-Kettering Cancer Center in New York, and co-authors.

The adverse events were comparable between the enzalutamide arm and the placebo arm. The enzalutamide arm had lower incidence of toxicity events of grade 3 or higher, 45.3% compared to 53.1% for the placebo group. Patients taking enzalutamide did experience higher rates of fatigue, diarrhea, hot flashes, headaches, and musculoskeletal pain. Five patients (0.6%) in the enzalutamide group experienced a seizure. The authors note that several of the patients had a predisposition for seizures, including two who had brain metastases.

Castration-resistant prostate cancer was previously thought to be hormone-refractory. In their discussion, the authors note that the results of the AFFIRM trial and the recent survival results of abiraterone acetate plus prednisone demonstrate that prostate cancer tumors are not refractory to hormone treatment.

Recently, both cabazitaxel (Jevtana) and abiraterone acetate plus prednisone have been approved by the US Food and Drug Administration (FDA) for men with metastatic hormone refractory prostate cancer who had been treated with docetaxel. Both therapies demonstrated an overall survival benefit. Despite the availability of these agents during the AFFIRM trial for those in the placebo arm, men in the enzalutamide arm had a prolonged survival. “These results validate androgen-receptor signaling as a key therapeutic target throughout the clinical spectrum of prostate cancer, including in men who have received previous chemotherapy,” conclude the authors.

Medivation Inc and Astellas Pharma Inc, the two companies developing enzalutamide, have recently filed a new drug application with the FDA. A decision is expected by the end of this year.