Targeting the androgen receptor signalling axis in castration-resistant prostate cancer (CRPC)

What's known on the subject? and What does the study add? Castration resistance has been appreciated for decades, and several mechanisms theorising on this effect have been proposed. A rich pipeline of novel agents, including abiraterone and MDV3100, have provided proof of principle that novel agents targeting the AR signalling pathway with superior selectivity and activity than predecessors have yielded significant clinical benefit for patients with metastatic castration-resistant prostate cancer. Our review provides an update in the development of several novel agents targeting the AR signalling pathway now in clinical testing, as well as review novel therapies in development with distinct mechanisms of action showing promising preclinical activity. Despite undergoing local therapy with curative intent, 20-30% of patients with prostate cancer will ultimately development metastatic disease, leading to morbidity and mortality. Androgen-deprivation therapy (ADT) for men with metastatic prostate cancer results in transient clinical benefit, but ultimately, cancers progress despite castrate levels of serum testosterone, a clinical state classically referred to as 'hormone refractory' disease. In this review, we examine mechanisms of resistance to ADT that have redefined our understanding of the more appropriately termed 'castration resistant' disease, and have paved the way for a new generation of therapeutics targeting the androgen signalling axis in advanced prostate cancer.