Enhanced Efficacy with Enzalutamide. Enzalutamide has greater androgen receptor (AR) binding affinity and a greater negative impact on AR nuclear import than bicalutamide with Dihydrotestosterone (DHT) as a control. In addition with enzalutamide there is no AR binding with the DNA and coactivatior recruitment. A Phase I/II study of enzalutamide demonstrated safety and suggested efficacy in both chemotherapy-naïve and chemotherapy-treated castration-resistant prostate cancer (CRPC) patients, the vast majority of whom had metastatic disease [8]. Two phase III studies were then launched in metastatic CRPC (mCRPC). One study enrolled chemotherapy-naïve patients; the other enrolled patients who had progressive disease on docetaxel. AFFIRM enrolled 1199 patients with progressive mCRPC on docetaxel and randomized them 2:1 to enzalutamide 160 mg/day (n=800) or placebo (n=399). The overall survival favored patients randomized to the enzalutamide arm 18.4 to 13.6 months. This 4.8 months improvement in survival represented a 37% risk reduction in death (hazard ratio 0.63; 95% CI: 0.53 to 0.75; P<0.001) the largest relative and absolute improvement in overall survival in an appropriately powered phase III study in prostate cancer. Median TTP based on radiographic findings was 8.3 vs. 2.9 months; HR: 0.40; P<0.001). ( Figure 2) Modest increases in fatigue, hot flashes, diarrhea, musculoskeletal pain, and headaches reported in the enzalutamide group, but this was possibly related to the substantially longer monitoring time for patients on this treatment compared to the placebo group. Therefore, there were no significant concerns about the side effect profile of enzalutamide compared to placebo [5].