Management of Metastatic Castration-Resistant Prostate Cancer Recent Advances Deborah Mukherji, Andrew Eichholz and Johann S. De Bono Institute of Cancer Research, Sutton, Surrey, UK Abstract Metastatic prostate cancer remains a considerable therapeutic challenge; however, advances in clinical research have resulted in five new treatments in the last 2 years. The immunotherapy sipuleucel-T, the cytotoxic cabazitaxel, the androgen biosynthesis inhibitor abiraterone acetate, the radioisotope al- pharadin and the anti-androgen MDV3100 have all been shown to improve overall survival in randomized phase III studies for patients with metastatic castration-resistant prostate cancer. The therapeutic strategies of targeting androgen-receptor signalling and other key intracellular pathways involved in tumour progression and treatment resistance are yielding promising re- sults. Agents such as the dual vascular endothelial growth factor receptor/ MET inhibitor cabozantinib, the clusterin inhibitor custirsen and the Src inhibitor dasatinib have shown encouraging results in phase II studies. Novel immunotherapeutics such as prostate-specific membrane antigen-directed therapy and the anti-cytotoxic T lymphocyte-associated receptor 4 (CTLA4) antibody ipilimumab are also under investigation. Optimal methods of treat- ment selection, combination and sequencing have yet to be determined. 1. Introduction Prostate cancer is the most common cancer in North American and European men and the sec- ond leading cause of male cancer-related death. [1,2] For patients who relapse following treatment of organ-confined disease and for those who present with metastatic disease, suppression of gonadal androgens remains the first line of therapy. The majority of patients with advanced prostate cancer have disease that is initially sensitive to an- drogen deprivation therapy (ADT); however, re- sponses are not durable and castration-resistant prostate cancer (CRPC) is invariably fatal. In the last 2 years, sipuleucel-T, cabazitaxel, abirater- one acetate, alpharadin and MDV3100 have all been shown to improve survival in randomized phase III studies for patients with CRPC. [3-7] The optimal use and sequencing of these new agents has yet to be determined. Treatment paradigms for advanced prostate cancer are changing rapidly. This comprehensive review covers advances in treatment evaluation and outcome measures, advances in the key therapeutic strategies of tar- geting androgen receptor (AR) signalling, cytotoxic chemotherapy, immunotherapy, targeted therapy and bone-directed therapy. Data for this review were compiled using MEDLINE/PubMed, American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) abstract databases published before March 2012. The search terms included ‘castration resistant LEADING ARTICLE Drugs 2012; 72 (8): 1011-1028 0012-6667/12/0008-1011/$55.55/0 Adis ª 2012 Springer International Publishing AG. All rights reserved.