The Relevance of Continued Medical Castration for Patients With Castration-Resistant Prostate Cancer

Introduction

Prostate cancer is the most common cancer in men in western societies, and accounted for around 14% of all new male cancers and approximately 6% of male cancer-related deaths worldwide in 2008.1 In Europe, prostate cancer accounted for 11.9% of all newly diagnosed cancers in 2008,2 and was the most common cancer in men accounting for 22% of male cancers and 9.3% of male cancer deaths.2

Abstract

Prostate cancer is an androgen-responsive disease with the treatment of advanced prostate cancer involving hormonal therapy. Gonadotropin-releasing hormone (GnRH) analogues are currently the mainstay of treatment, used either as monotherapy or combined with antiandrogens. The GnRH analogues suppress testosterone levels and thus slow proliferation of the tumor cells that depend on testosterone for growth. Androgen deprivation results in the downregulation of androgen receptor (AR) transcriptional activity in the tumor, but the response is transient and tumors eventually progress as castration-resistant prostate cancer (CRPC). Although serum testosterone levels decline dramatically with androgen deprivation, it is clear that CRPC growth remains largely dependent on AR activity. Secondary hormonal therapies, often employed in CRPC patients to further reduce AR-driven transcription, either further deplete androgen synthesis or directly and competitively antagonise the AR. Two new agents, the androgen synthesis inhibitor abiraterone and the AR antagonist MDV3100 have provided the strongest evidence to date that CRPC remains a hormonally driven disease. Although other therapeutic approaches have also been investigated, the continued hormonal dependency of prostate cancer postprogression has ensured that maintenance of the castrate state via continued use of GnRH analogues remains an essential aim in the treatment of CRPC patients who progress on primary hormonal therapy.

Keywords

Androgen-deprivation therapy, androgen receptor, antiandrogens, castration-resistant prostate cancer, gonadotropin releasing hormone analogues, CYP17