OBJECTIVE: We performed a systematic review of the literature to assess the 
efficacy and the safety of second-line agents targeting metastatic 
castration-resistant prostate cancer (mCRPC) that has progressed after 
docetaxel. Pooled-analysis was also performed, to assess the effectiveness of 
agents targeting the androgen axis via identical mechanisms of action 
(abiraterone acetate, orteronel).
MATERIALS AND METHODS: We included phase III randomized controlled trials that 
enrolled patients with mCRPC progressing during or after first-line docetaxel 
treatment. Trials were identified by electronic database searching. The primary 
outcome of the review was overall survival. Secondary outcomes were radiographic 
progression-free survival (rPFS) and severe adverse effects (grade 3 or higher).
RESULTS: Ten articles met the inclusion criteria for the review. These articles 
reported the results of five clinical trials, enrolling in total 5047 patients. 
The experimental interventions tested in these studies were enzalutamide, 
ipilimumab, abiraterone acetate, orteronel and cabazitaxel. Compared to control 
cohorts (active drug-treated or placebo-treated), the significant overall 
survival advantages achieved were 4.8 months for enzalutamide (hazard ratio for 
death vs. placebo: 0.63; 95% CI 0.53 to 0.75, P < 0.0001), 4.6 months for 
abiraterone (hazard ratio for death vs. placebo: 0.66, 95% CI 0.58 to 0.75, P < 
0.0001) and 2.4 months for cabazitaxel (hazard ratio for death vs. 
mitoxantrone-prednisone: 0.70, 95% CI 0.59 to 0.83, p < 0.0001). Pooled analysis 
of androgen synthesis inhibitors orteronel and abiraterone resulted in 
significantly increased overall and progression-free survival for anti-androgen 
agents, compared to placebo (hazard ratio for death: 0.76, 95% CI 0.67 to 0.87, 
P < 0.0001; hazard ratio for radiographic progression: 0.7, 95% CI 0.63 to 0.77, 
P < 0.00001). Androgen synthesis inhibitors induced significant increases in 
risk ratios for adverse effects linked to elevated mineralocorticoid secretion, 
compared to placebo (risk ratio for hypokalemia: 5.75, 95% CI 2.08 to 15.90; P = 
0.0008; risk-ratio for hypertension: 2.29, 95% CI 1.02 to 5.17; P = 0.05).
CONCLUSIONS: In docetaxel-pretreated patients enzalutamide, 
abiraterone-prednisone and cabazitaxel-prednisone can improve overall survival 
of patients, compared to placebo or to best of care at the time of study 
(mitoxantrone-prednisone). Agents targeting the androgen axis (enzalutamide, 
abiraterone, orteronel) significantly prolonged rPFS, compared to placebo. 
Further investigation is warranted to evaluate the benefit of combination or 
sequential administration of these agents. Large-scale studies are also 
necessary to evaluate the impact of relevant toxic effects observed in a limited 
number of patients (e.g., enzalutamide-induced seizures, orteronel-induced 
pancreatitis, and others).