OBJECTIVES: Docetaxel (D) + prednisone (P), mitoxantrone (MTX), estramustine (E) and sipuleucel-T (S) are authorized in the US for castrate-resistant prostate cancer (CRPC) treatment. New agents such as abiraterone and zibotentan are being investigated. This systematic review aims to assess current clinical evidence of treating metastatic CRPC (mCRPC). METHODS: MEDLINE, Embase, and Cochrane were searched to March 22, 2010, as were abstracts from ASCO, ASCO GU, AUA, ESMO, and EAU (2006 – March 2010). RCTs and observational studies (English) were included. Endpoints extracted include overall survival (OS), progression-free survival (PFS), prostate-specific antigen (PSA) response, and adverse events (AEs). RESULTS: A total of 171 studies (331 publications) were included: prechemotherapy patients (71 RCTs, 15 observational), postchemotherapy patients (6 RCTs, 71 observational), and mixed populations (8 RCTs). D, P, and E were most commonly investigated. In postchemotherapy RCTs, D + P + custirsen (14.7 mos) and cabazitaxel + P (15 mos) exhibited a relatively high OS compared to other regimens. Regimens with D and MTX showed longer PFS versus other regimens. D regimens were associated with a high PSA response (40%). In postchemotherapy observational studies, D + bevacizumab showed a relatively high OS (17.5 mos) and PFS (8.9 mos). In prechemotherapy RCTs, S (26 mos) and D + P (27 mos) showed a high OS. D + P showed a favorable PFS (11 mos), as did E + etoposide (15 mos). Overall, PRO, bone pain, and skeletal-related events were rarely reported in these studies. Nausea, anemia, diarrhea, neutropenia, and thrombocytopenia were common across trials. Grade 3/4 AEs were frequently reported with D-based regimens. CONCLUSIONS: mCRPC remains a clinical challenge. D was frequently investigated. D improved survival but produced significant AEs. New treatments for D-refractory patients are needed.