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Prostate Cancer Castration-resistant Prostate Cancer— Chemotherapies and Molecular Targets Amit Bahl Consultant Oncologist and Clinical Director, Bristol Haematology and Oncology Centre, University Hospitals, Bristol, UK Abstract Castration-resistant prostate cancer (CRPC) has a poor prognosis: current chemotherapeutic approaches ultimately result in resistance and are associated with survival rates of less than 2 years. However, the last decade has seen an expansion in the number of therapeutic options for CRPC and the regulatory approval of several agents, including the chemotherapy drug cabazitaxel and the targeted agents abiraterone acetate, enzalatumide, and denosumab. Novel targeted agents inhibit androgen receptor-mediated signaling, and nonhormonal targets, including apoptosis, signal transduction pathway inhibitors, angiogenesis, and bone and immune microenvironments. Clinical trials of these agents, however, have demonstrated varied efficacy. Among the drugs in clinical development, custirsen, cabozantinib, and dasatinib are among the most promising. There is a requirement for studies directly comparing agents, and for improved patient selection to identify patients benefitting from a particular therapy. Keywords Castration-resistant prostate cancer, chemotherapy, clusterin, custirsen, targeted therapy Disclosure: Amit Bahl is on the advisory boards and honorarium of Sanofi, Astellas, Takeda, Janssen, Amgen, Pfizer, and Roche. Received: April 18, 2013 Accepted: July 17, 2013 Citation: Oncology & Hematology Review (US), 2013;9(2):90–6 Acknowledgements: Technical editorial assistance was provided by Katrina Mountfort from Touch Medical Media. Correspondence: Amit Bahl, Consultant Oncologist and Clinical Director, Bristol Haematology and Oncology Centre, University Hospitals Bristol, Horfield Rd, Bristol, Avon BS2 8ED, UK. E: Amit.Bahl@UHBristol.nhs.uk Support: The publication of this article was supported by TEVA. The views and opinions expressed are those of the authors and not necessarily those of TEVA. Prostate cancer is the most common noncutaneous malignancy. It is the sixth leading cause of cancer-related death in men worldwide, 1 and the second most common cause of cancer death in US men. 2 In 2012, it was estimated that 241,740 cases would be diagnosed and 28,170 would die of the disease. 3 Prostate cancer responds to androgen-deprivation therapy (ADT). However, most cases become refractory after 1 to 3 years and resume growth despite hormone therapy, leading to the state of castration-resistant prostate cancer (CRPC), for which the prognosis is poor. 4 Many patients enter the disease at an early stage when the only sign of resistance to ADT is a progressive elevation of prostate-specific antigen (PSA). Progression to CRPC occurs via reactivation of androgen receptor (AR) activity, 5 alternative mitogenic growth factor pathways, 6 stress-induced survival genes, 7 and cytoprotective chaperone networks. 8 Following CRPC development, the patient population is likely to continue progression to metastatic disease (mCRCP). During the past decade, a number of new approaches have been developed for the treatment of CRPC, including hormonal agents, cytotoxic chemotherapeutic drugs, targeted therapeutics, and immunotherapy. These developments have led to the regulatory approval of five new therapeutic agents: sipuleucel-T, denosumab, abiraterone acetate, cabazitaxel, and enzalatumide (see Table 1). This article will review recent 90 advances in chemotherapy and discuss the potential molecular targets for new therapeutic approaches. Chemotherapy Historically, prostate cancer was considered refractory to cytotoxic chemotherapy, 9 and chemotherapy options for the treatment of CRPC were limited. Until 2004, only mitoxantrone was approved, providing palliation but no survival benefit. In 2004, docetaxel received approval from the US Food and Drug Administration (FDA) after clinical studies showed that prednisone and docetaxel showed an overall survival (OS) benefit compared with mitoxantrone plus prednisone, as well as a significant improvement of quality of life and pain reduction. 10,11 Docetaxel and prednisone in combination are considered the standard of care for men with CRPC with detectable metastatic disease. 12 However, survival rates remain low: less than 2 years 13,14 and less than a year in metastatic cases. 15 Moreover, a significant proportion of men with CRPC do not respond to docetaxel-based therapy, and all patients will ultimately develop resistance. 16 Mitoxantrone has been the standard treatment following docetaxel failure. 17 New chemotherapeutic agents have recently been evaluated for CRPC. Cabazitaxel was approved by the FDA in 2010 for second-line use in CRPC following docetaxel-based treatment. The © Tou c h M E d ica l ME d ia 2013