E David Crawford1, Paul F Schellhammer2, David G McLeod3, Judd W Moul4, Celestia S Higano5, Neal Shore6, Louis Denis7, Peter Iversen8, Mario A Eisenberger9, Fernand Labrie10. 1. University of Colorado-Denver, Aurora, Colorado. Electronic address: edc@edavidcrawford.com. 2. Eastern Virginia Medical School, Norfolk, Virginia. 3. Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda. 4. Duke Cancer Institute, Duke University, Durham, North Carolina. 5. Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington. 6. Carolina Urologic Research Center, Myrtle Beach, South Carolina. 7. Europa Uomo, Oncology Centre Antwerp, Antwerp, Belgium. 8. Copenhagen Prostate Cancer Center, University of Copenhagen, Copenhagen, Denmark. 9. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland. 10. Endoceutics, Quebec City, Quebec, Canada.
Abstract
PURPOSE: Antiandrogens inhibit the androgen receptor and have an important role in the treatment of prostate cancer. This review provides a historical perspective on the development and clinical benefit of antiandrogens in the treatment of prostate cancer. MATERIALS AND METHODS: 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 prostate cancer. RESULTS: Antiandrogens differ in chemical structure and exert varying efficacy and safety profiles. The unfavorable therapeutic index of steroidal antiandrogens led to replacement by safer nonsteroidal agents. Flutamide, nilutamide and bicalutamide, which were designed to target the androgen receptor, 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 androgen receptor structure and its biological functions a new generation of antiandrogens without agonist activity was designed to provide more potent inhibition of the androgen receptor. Randomized clinical trials in patients with metastatic, castration resistant prostate cancer showed significant survival benefits, which led to the approval of enzalutamide in August 2012. 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 prostate cancer. Evolving knowledge of resistance mechanisms to androgen receptor targeted treatments will stimulate research and drug discovery for additional compounds. Further testing in nonmetastatic castration resistant prostate cancer as well as castration sensitive disease states will hopefully augment our ability to treat a broader spectrum of patients with prostate cancer. CONCLUSIONS: Antiandrogens have already provided important benefits for prostate cancer treatment. Greater knowledge about the structural and functional biology of the androgen receptor in prostate cancer will facilitate further discovery and development of further improved antiandrogens with enhanced clinical activity in patients with advanced metastatic disease. Testing these new agents earlier in the course of prostate cancer may further improve the survival and quality of life of patients with current local and/or systemic treatment modalities.
PURPOSE: Antiandrogens inhibit the androgen receptor and have an important role in the treatment of prostate cancer. This review provides a historical perspective on the development and clinical benefit of antiandrogens in the treatment of prostate cancer. MATERIALS AND METHODS: 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 prostate cancer. RESULTS: Antiandrogens differ in chemical structure and exert varying efficacy and safety profiles. The unfavorable therapeutic index of steroidal antiandrogens led to replacement by safer nonsteroidal agents. Flutamide, nilutamide and bicalutamide, which were designed to target the androgen receptor, 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 androgen receptor structure and its biological functions a new generation of antiandrogens without agonist activity was designed to provide more potent inhibition of the androgen receptor. Randomized clinical trials in patients with metastatic, castration resistant prostate cancer showed significant survival benefits, which led to the approval of enzalutamide in August 2012. 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 prostate cancer. Evolving knowledge of resistance mechanisms to androgen receptor targeted treatments will stimulate research and drug discovery for additional compounds. Further testing in nonmetastatic castration resistant prostate cancer as well as castration sensitive disease states will hopefully augment our ability to treat a broader spectrum of patients with prostate cancer. CONCLUSIONS: Antiandrogens have already provided important benefits for prostate cancer treatment. Greater knowledge about the structural and functional biology of the androgen receptor in prostate cancer will facilitate further discovery and development of further improved antiandrogens with enhanced clinical activity in patients with advanced metastatic disease. Testing these new agents earlier in the course of prostate cancer may further improve the survival and quality of life of patients with current local and/or systemic treatment modalities.
Authors: Kornelia J Skowron; Kenneth Booker; Changfeng Cheng; Simone Creed; Brian P David; Phillip R Lazzara; Amy Lian; Zamia Siddiqui; Thomas E Speltz; Terry W Moore Journal: Mol Cell Endocrinol Date: 2019-06-01 Impact factor: 4.102
Authors: Fernando Cotait Maluf; Felipe Moraes Toledo Pereira; Adriano Gonçalves Silva; Aldo Lourenço Abbade Dettino; Ana Paula Garcia Cardoso; André Seeke Sasse; Andrey Soares; Ariel Galapo Kann; Daniel Herchenhorn; Denis Leonardo Fontes Jardim; Diego Emilio Lopera Cortés; Fábio Roberto Kater; Igor A Protzner Morbeck; João Francisco Navarro Reolon; José Augusto Rinck; Juan Jose Zarbá; Juan Pablo Sade; Karine Martins da Trindade; Leonardo Atem G A Costa; Lucas V Dos Santos; Manuel Caitano Maia; Mariana Bruno Siqueira; Silke Gillessen Journal: JCO Glob Oncol Date: 2021-04