Second-Generation Antiandrogens: From Discovery to Standard of Care in Castration Resistant Prostate Cancer

Abstract

Prostate cancer is the most commonly diagnosed cancer affecting men in the United States. The prostate is a hormone-dependent gland in which androgen hormones testosterone and dihydrotestosterone bind to and activate the androgen receptor, initiating nuclear translocation of androgen receptor and a subsequent signaling cascade. Due to the androgen dependency of the prostate, androgen deprivation therapies have emerged as first line treatment for aggressive prostate cancer. Such therapies are effective until the point at which prostate cancer, through a variety of mechanisms including but not limited to generation of ligand-independent androgen receptor splice variants, or intratumoral androgen production, overcome hormone deprivation. These cancers are androgen ablation resistant, clinically termed castration resistant prostate cancer (CRPC) and remain incurable. First-generation antiandrogens established androgen receptor blockade as a therapeutic strategy, but these therapies do not completely block androgen receptor activity. Efficacy and potency have been improved by the development of second-generation antiandrogen therapies, which remain the standard of care for patients with CRPC. Four second-generation anti-androgens are currently approved by the Food and Drug Administration (FDA); abiraterone acetate, enzalutamide, and recently approved apalutamide and darolutamide. This review is intended to provide a thorough overview of FDA approved second-generation antiandrogen discovery, treatment application, strategies for combination therapy to overcome resistance, and an insight for the potential future approaches for therapeutic inhibition of androgen receptor.

Keywords: CRPC; abiraterone acetate; antiandrogens; apalutamide; darolutamide; enzalutamide; prostate cancer; second-generation antiandrogens.

Figure 1

Diagram of androgen production and subsequent signaling through the androgen receptor. Testosterone (T) is produced in the testes and adrenal glands. Testosterone is then converted to its most common and active metabolite, dihydrotestosterone (DHT) by 5α-reductase. Androgens, usually DHT, bind to the androgen receptor (AR), dissociating chaperone proteins, members of the heat shock protein family HSP27 and HSP70. Ligand-bound AR molecules homodimerize and translocate to the nucleus where they bind to androgen response elements (ARE), and act as transcription factors to signal downstream targets. Second-generation antiandrogens are illustrated at their points of pathway disruption; Abiraterone acetate prevents androgen biosynthesis, and Enzalutamide, Apalutamide and Darolutamide prevent AR translocation to the nucleus.