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Prostate Cancer Recent Developments in Treatments for Metastatic Castration-resistant Prostate Cancer—A Mechanistic Perspective Guru Sonpavde, MD 1 and E David Crawford, MD 2 1. Oncologist, Comprehensive Cancer Center, Department of Medicine, Section of Medical Oncology, University of Alabama at Birmingham, Birmingham, Alabama, US; 2. Professor of Surgery/Urology/Radiation Oncology, Head of Urologic Oncology, E David Crawford Endowed Chair in Urologic Oncology, University of Colorado, Denver, Colorado, US Abstract Over the past decade, the treatment landscape in metastatic castration-resistant prostate cancer (CRPC) has markedly changed, with the introduction of three new chemotherapeutic agents. The mechanism of CRPC is not fully understood, but it may result from multiple pathways, including a loss or androgen receptor (AR) specificity and increased downstream signalling activity that provide multiple targets for therapeutic agents. For some years, docetaxel was the mainstay of treatment in CRPC, but recently, cabazitaxel (a microtubule inhibitor), sipuleucel-T (a cancer vaccine), and abiraterone acetate (a CYP17 inhibitor) were approved for CRPC treatment. In Phase III clinical trials, these agents have shown significant improvements in survival—over mitoxantrone (for cabazitaxel) and over placebo (for sipuleucel-T and abiraterone acetate)—and were well tolerated. There are also two treatments in late-stage development, MDV3100 (an oral AR antagonist) and radium-223 (an isotope that creates breaks in double-stranded DNA). These have also shown improvements in survival in Phase III trials; their regulatory approval is expected soon. The modes of actions of the existing and new drugs in CRPC are varied, but some are complementary and investigations of different combinations of these medications are much needed; they may enhance efficacy, further extend survival, and improve outcomes in this formerly untreatable disease. Keywords Metastatic castration-resistant prostate cancer, androgen pathway, mechanism of disease, chemotherapy, combination treatments Disclosure: Guru Sonpavde, MD, has been on the speakers bureau for Sanofi-Aventis, Janssen, and Amgen and on advisory boards for Astellas; he has received research support from Celgene, Pfizer, BMS, and Bellicum. E David Crawford, MD, has been on advisory boards for Ferring, Janssen, Dendreon, Medvation, and Astellas. Acknowledgment: Editorial assistance was provided by Angela Chan, Medical Writer at Touch Briefings, and was funded by Janssen. Received: August 8, 2012 Accepted: September 11, 2012 Citation: Oncology & Hematology Review, 2012;8(2):89–93 Correspondence: E David Crawford, MD, University of Colorado, Denver, Mail Stop # F 710, PO Box # 6510, Aurora, CO 80045, US. E: Prostate cancer continues to be a leading cause of cancer-related death worldwide and is the most common malignancy among American men after skin cancer. 1 Based on estimates by the American Cancer Society, approximately 241,740 new cases are expected to be diagnosed and 28,170 men are expected to die from the disease in the US in 2012. Approximately one in six men will be diagnosed with prostate cancer during their lifetime. 1 Although patients with recurrent disease initially respond to androgen deprivation therapy (ADT), most will go on to develop castration-resistant prostate cancer (CRPC) in which the disease becomes refractory to traditional hormone therapies and cancer growth continues despite castrate levels of testosterone. However, this population may still respond to secondary hormonal manipulations and ADT continues to be the gold standard for systemic treatment of men with metastatic disease. 2 While the five-year survival rate for men with advanced prostate cancer has increased from 69 % in the late 1970s to 100 % in the 2000s, 2 there have traditionally been no successful treatments that improved median © TOUCH BRIEFINGS 2012 overall survival in the subset of patients with CRPC. In the last decade, however, since the approval of docetaxel by the US Food and Drug Administration (FDA) for metastatic CRPC in 2004, 3 there has been a substantial evolution in its treatment, as several drugs introduced in quick succession show efficacy in prolonging survival. In particular, greater understanding of the pathogenesis of advanced disease resulted in the development of effective targeted therapies. Biology of the Disease—Dependence on Androgen-mediated Signaling The androgen signaling pathway has recently been found to be critical in both hormone-sensitive prostate cancer and CRPC. 4 Evidence has shown that resistant cancer continues to rely on androgen biosynthesis, its binding to the receptor and consequent uptake in order to progress. 5–7 Figure 1 presents a simplified disease progression pathway illustrating the conversion of cholesterol to androgen and testosterone. Within cells, the hormones are converted to the more potent dihydrotestosterone (DHT) metabolites, which function as intracellular 89