Antiandrogens inhibit the androgen receptor (AR) and play an important role in the treatment of prostate cancer (PC). This review provides a historical perspective on the development and clinical benefit of antiandrogens in the treatment of PC.
We searched PubMed® for clinical trials with the search terms "antiandrogens" and "prostate cancer" combined with drug names for antiandrogens. This article represents a collaboration of clinical investigators who have made critical scientific contributions leading to the approval of antiandrogens for treating patients with PC.
Antiandrogens differ in chemical structure and exert varying efficacy and safety profiles. The unfavorable therapeutic index of steroidal antiandrogens led to their replacement by safer nonsteroidal agents. Flutamide, nilutamide and bicalutamide, designed to target the AR, were developed primarily for use in combination with castration to provide "combined" androgen blockade. Modest clinical benefits were observed with the combination of first-generation antiandrogens and castration vs castration alone. With increased knowledge of the AR structure and its biological functions, a new generation of antiandrogens without agonist activity was designed to provide more potent inhibition of the AR. Randomized clinical trials in patients with metastatic castration-resistant PC exhibited significant survival benefits, which led to the approval, in August 2012, of enzalutamide. Apalutamide was recently approved, while darolutamide is not yet approved in the United States. These next-generation antiandrogens are being actively tested in earlier disease states such as nonmetastatic PC. Evolving knowledge of resistance mechanisms to AR-targeted treatments will stimulate research and drug discovery for additional compounds. Further testing in nonmetastatic castration-resistant PC as well as castration-sensitive disease states will hopefully augment our ability to treat a broader spectrum of PC patients.
Antiandrogens have already provided important benefits for PC treatment. Greater knowledge about the structural and functional biology of the AR in PC will facilitate further discovery and development of further improved antiandrogens with enhanced clinical activity in patients with advanced metastatic disease. Testing of these new agents earlier in the course of a patient's PC may further improve the survival and quality of life of those with current local and/or systemic treatment modalities.
The Journal of urology. 2018 May 03 [Epub ahead of print]
E David Crawford, Paul F Schellhammer, David G McLeod, Judd W Moul, Celestia S Higano, Neal Shore, Louis Denis, Peter Iversen, Mario A Eisenberger, Fernand Labrie
University of Colorado, Denver, Aurora, Colorado. Electronic address: ., Eastern Virginia Medical School, Norfolk, Virginia., Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, Maryland., Duke Cancer Institute, Duke University, Durham, North Carolina., University of Washington, Fred Hutchinson Cancer Research Center, Seattle, Washington., Carolina Urologic Research Center, Myrtle Beach, South Carolina., Europa Uomo, Oncology Centre Antwerp, Antwerp, Belgium., Copenhagen Prostate Cancer Center, University of Copenhagen, Copenhagen, Denmark., The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland., Endoceutics, Quebec City, Canada.