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Androgen Receptor Antagonists in Castration-Resistant Prostate Cancer

Rathkopf, Dana MD; Scher, Howard I. MD

doi: 10.1097/PPO.0b013e318282635a

Persistent androgen receptor (AR) signaling despite low levels of serum androgens has been identified as a critical target for drug discovery in castration-resistant prostate cancer (CRPC). As proof of principle that the AR remains relevant in CRPC, 2 AR-targeted agents recently approved by the Food and Drug Administration—abiraterone and enzalutamide—have increased overall survival for patients with CRPC in the setting of prior chemotherapy. This review focuses on the AR and 2 direct antagonists, enzalutamide and ARN-509. These next-generation AR antagonists offer great promise for patients with advanced disease. Relative to conventional antiandrogens such as bicalutamide, they bind to the receptor with higher affinity, prevent nuclear translocation and DNA binding, and induce apoptosis without agonist activity in preclinical models. The success of these AR-targeted agents in the clinic has changed the landscape of therapy for patients with CRPC, and further therapeutic options building on this platform are currently in development.

From the Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center; and Department of Medicine, Weill Cornell Medical College, New York, NY.

Conflicts of interest and sources of funding: Dr. Scher has received compensation from Endo/Orion Pharmaceuticals, Millennium -Takeda, Ortho Biotech Oncology Research and Development, and Sanofi-Aventis and has received research funding from Aragon, Bristol-Myers Squibb, Celegne, Exelixis, Medivation, Ortho Biotech Oncology Research and Development, and Veridex.

Reprints: Howard I. Scher, MD, Genitourinary Oncology Service, Department of Medicine, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065. E-mail:

© 2013 Lippincott Williams & Wilkins, Inc.