New data, new paradigms for treating prostate cancer patients VI: Novel hormonal therapy approaches
Androgen Receptor Antagonists
Until the 1980s, testosterone suppression for men with advanced prostate cancer was managed surgically, with bilateral orchiectomy, or medically, with diethylstilbestrol, a drug that was associated with a problematic side effect profile. Beginning in the mid-1980s, the U.S. Food and Drug Administration approved the first luteinizing hormone-releasing hormone agonists, which proved effective for suppressing circulating testosterone levels and led to a significant shift away from surgical castration to medical management during the past 25 years. The luteinizing hormone-releasing hormone agonists resulted in a periodic return of noncastrate testosterone levels once the receptor desensitization attenuated and the effect of androgen agonism resumed. Therefore, the introduction of an androgen receptor antagonist (gonadotropin-releasing hormone antagonist) appeared, conceptually at least, to be a preferable alternative. The first such agent, degarelix, has proved to provide rapid testosterone suppression without the initial testosterone surge associated with luteinizing hormone-releasing hormone agonists. Other new agents in early development include a selective and irreversible inhibitor of CYP17, abiraterone, which has shown success in patients with castration-resistant metastatic prostate cancer, and MDV3100, a novel small molecule that acts as an oral nonsteroidal antiandrogen agent. In sum, these latest agents might lead to a paradigm shift in the treatment of patients with advanced prostate cancer; however, additional studies are required to clarify the many questions that remain regarding the optimal use and sequence of these agents.