Abiraterone acetate plus prednisone and enzalutamide both have an FDA indication for use in men with mCRPC. For each agent, there is randomized trial data showing a survival benefit for men with mCRPC. Abiraterone Acetate In the placebo-controlled, double-blind, phase III COU-AA-302 study, Ryan et al.120 randomized 1,088 men with mCRPC who had not received prior chemotherapy to receive either abiraterone acetate 1,000mg daily plus prednisone 5mg twice a day or placebo plus prednisone 5mg twice daily. The primary outcomes of the study were radiographic-PFS and OS. Participants randomized to receive abiraterone acetate plus prednisone had statistically significant improvement in radiographic PFS (HR=0.53; p<0.001), as previously reported during interim analyses.121 The final analysis of OS showed a statistically significant increase in patients treated with abiraterone acetate plus prednisone (HR=0.81; 95% CI: 0.70 to 0.93; p=0.0033).120 The most common grades 3 to 4 adverse events were cardiac disorders (8% in the abiraterone acetate group versus 4% in the placebo group), increased alanine aminotransferase (6% versus <1%), and hypertension (5% versus 3%). In the COU-AA-301 trial, de Bono et al. randomly assigned 1,195 patients who had previously received docetaxel in a 2:1 ratio to receive 5mg of prednisone twice daily with either 1,000mg abiraterone acetate or placebo. The primary endpoint was OS. After a median follow-up of 12.8 months, OS was 14.8 months in the abiraterone acetate group compared to 10.9 months in the placebo group (HR=0.65; 95% CI: 0.54 to 0.77; p<0.001). All secondary endpoints, including time to PSA progression, PFS, and PSA response rate favored the abiraterone acetate group. Enzalutamide In the double-blind, phase III PREVAIL study, Beer et al. randomized 1,717 chemotherapy-naïve patients to receive either enzalutamide (at a dose of 160mg) or placebo once daily.122  Co-primary endpoints were radiographic PFS and OS. The results showed that enzalutamide significantly decreased the risk of radiographic progression (HR=0.19; 95% CI: 0.15 to 0.23; p<0.001) and death (29% reduction in the risk of death; HR=0.71; 95% CI: 0.60 to 0.84; p<0.001). Enzalutamide also showed a benefit with respect to all secondary endpoints, including the time until the initiation of chemotherapy (HR=0.35; 95% CI: 0.30 to 0.40; p<0.001) in a group of men with mCRPC and a median follow-up duration for survival of approximately 22 months. Adverse events that occurred in 20% or more of patients receiving enzalutamide at a rate that was at least 2 percentage points higher than that in the placebo group were fatigue, back pain, constipation, and arthralgia. In the phase III, double blind AFFIRM study, Scher et al. stratified 1,199 men with CRPC after chemotherapy in a 2:1 ratio to receive enzalutamide (160mg per day) or placebo. The primary endpoint was OS. At the time of planned interim analysis, the median OS was 18.4 months in the enzalutamide group versus 13.6 months in the placebo group (HR for death in the enzalutamide group=0.63; 95% CI: 0.53 to 0.75; p<0.001). Enzalutamide was superior over placebo with respect to all secondary endpoints, including PSA reduction by 50% or more, soft-tissue response rate, QOL response rate, time to PSA progression, radiographic PFS, and the time to first SRE. More recently, enzalutamide was evaluated in combination with radium-223 in men with bone metastases who were ARPI naive in the PEACE-3 trial.123 Results showed a statistically significant rPFS and OS benefit of 7.3 months for the combination at the interim analysis when used in first line mCRPC. This was associated with 31% decreased risk of death (HR=0.69). The OS was re-iterated at the final OS analysis. This study also re-emphasized the importance of bone protective agents which were ultimately mandated in a study amendment given the high fracture rates seen in both arms.