Targeting the androgen receptor in metastatic castration-resistant prostate cancer

Androgen deprivation therapy (ADT) has been the cornerstone of treatment for metastatic prostate cancer. Since the emergence of castration resistance, attempts to define mechanisms of resistance has led the field into a search for nonandrogen receptor (AR)-driven targets. This brought on an era of investigation that began with the use of chemotherapy for prostate cancer. While chemotherapy has been one of the earliest established treatments for men with symptomatic prostate cancer, based on the TAX327 and SWOG 9916 trials, it has only recently been established that the role of chemotherapy may not be limited to microtubule inhibition alone, but also inhibition of AR nuclear translocation [1,2]. The perception that the AR ceases to become a therapeutic target also heralded a generation of agents targeting alternative nonandrogen-dependent pathways that showed promising results in Phase II trials, but failed to provide survival benefit when tested in larger prospective Phase III trials. The landscape of treatment was truly revolutionized when further AR manipulation via the use of androgen biosynthesis inhibitors and novel antiandrogens came into fruition. The traditional concept of testicular androgen suppression was considered insufficient when increased intraprostatic and intratumoral androgens were considered contributors to further testosterone production, which brought about the concept of CYP17 enzyme inhibition that would later give rise to the development and approval of abiraterone acetate in 2011 and 2012 for both postchemotherapy metastatic castration-resistant prostate cancer (CRPC) patients [3], as well as prechemotherapy-naive patients [4], respectively. Similarly, peripheral androgen blockade with novel second-generation enzalutamide provided a unique profile as it was selected from a library of compounds for its AR inhibition of cells overexpressing the AR, which is far more potent than bicalutamide and was approved in 2012 for postchemotherapy metastatic CRPC patients. In addition, the more recently concluded PREVAIL trial has been reported [5] and enzalutamide has been shown to statistically improve overall survival in men who were chemotherapy-naive compared with patients receiving placebo (p < 0.0001). Enzalutamide provided a 30% reduction in risk of death compared with placebo (hazard ratio: 0.70; 95% CI: 0.59–0.83).

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