Enzalutamide: the emperor of all anti-androgens

www.amepc.org/tau © Translational Andrology and Urology. All rights reserved. In the last few years, there has been a rekindled interest in the androgen receptor (AR) and AR signaling as valid therapeutic targets in prostate cancer. While the primary goal of therapy for recurrent or advanced prostate cancer has long been to reduce circulating and intratumoral androgen levels, recent laboratory and clinical data have shown that AR signaling remains active (and continues to drive tumor growth) even in the castrationresistant state (1). In addition, while first-generation AR blockers (e.g., flutamide, bicalutamide, nilutamide) have been used clinically with some success, none of these secondary hormonal manipulations have demonstrated an unequivocal survival benefit in men with prostate cancer. These anti-androgens have several shortcomings, including that they are only weak antagonists of the AR and that they may also function as partial AR agonists (especially with prolonged use). Enzalutamide (Xtandi, Medivation Inc. and Astellas Inc), previously known as MDV3100, is a next-generation anti-androgen that has at least 3 separate activities: it functions as a potent and irreversible inhibitor of the AR, it impairs translocation of the AR from the cell cytosol into the nucleus, and it blocks the interaction of the AR with DNA androgen-response elements at the transcription complex. For these reasons, enzalutamide has also been described as an AR signaling inhibitor. In a recent issue of the New England Journal of Medicine, Scher and colleagues (2) report the mature results of the AFFIRM study, a multinational phase III randomized trial of enzalutamide versus placebo in men with metastatic castration-resistant prostate cancer who had developed disease progression despite docetaxel chemotherapy. A total of 1,199 men were randomized (2:1) to receive either oral enzalutamide 160 mg daily (800 patients) or placebo (399 patients). The primary endpoint was overall survival, and the trial was halted early after a planned interim analysis which revealed a significant prolongation of median survival in the enzalutamide arm compared to the placebo arm (18.4 months versus 13.6 months, hazard ratio 0.63, P<0.001). In addition, enzalutamide showed overwhelming evidence of clinical benefit with respect to all pre-planned secondary endpoints, proving superior to placebo in terms of radiographic progression-free survival (8.3 versus 2.9 months, hazard ratio 0.40, P<0.001), PSA response rate (54% versus 2%, P<0.001), time to PSA progression (8.3 versus 3.0 months, hazard ratio 0.25, P<0.001), radiographic response rate (29% versus 4%, P<0.001), and time to first skeletal-related event (16.7 versus 13.3 months, hazard ratio 0.69, P<0.001). In addition, data presented at the 2012 Annual ASCO meeting revealed that enzalutamide produced improvements in several quality-of-life measures including pain palliation, physical wellbeing, functional wellbeing, social wellbeing, and emotional wellbeing (3). Enzalutamide was generally very well tolerated, with the most common adverse events being fatigue (34%), diarrhea (21%), hot flashes (20%), and headache (12%). Notably, about 1% of patients receiving enzalutamide experienced a seizure (compared to 0% in the placebo arm), necessitating discontinuation of the study drug. The results of this trial led to the FDA approval of enzalutamide on August 31, 2012 for the treatment of men with metastatic docetaxel-pretreated castration-resistant prostate cancer. The current study is important because it provides a proof-of-principle that a continued assault on the AR can be a fruitful therapeutic endeavor even in men with castration-resistant prostate cancer who have progressed Research Highlight