Understanding Mechanisms of Resistance in Metastatic Castration-resistant Prostate Cancer: The Role of the Androgen Receptor

Context After initiation of androgen deprivation therapy (ADT), most patients progress to castration-resistant prostate cancer (CRPC) within 2 or 3 yr. In the USA, approximately 67 000 men are estimated to have metastatic CRPC. Objective To provide an overview of different mechanisms driving resistance to therapy in metastatic CRPC, with a focus on androgen receptor (AR)–dependent pathways. Evidence acquisition A Medline search via PubMed was performed using the keywords metastatic castration resistant prostate cancer (mCRPC), castration-resistant, CRPC, prostate cancer, androgen resistance, hormone-refractory, hormone-independent, androgen receptor, and androgen receptor axis. Only articles in the English language were included. Abstracts and full-text articles were reviewed and assessed for relevant content. The majority of the articles selected were published between 1993 and 2016. Older studies were included selectively if relevant. Evidence synthesis Numerous resistance mechanisms characterize the development of CRPC. The review focuses on AR-dependent pathways, including mechanisms of resistance to new agents. These include reactivation of AR (via AR amplification, mutations, or splice variants), stress-activated pathways, and aberrant activation of AR. Conclusions Mechanisms of resistance in CRPC are manifold and require multiple combinations of therapeutic approaches to be overcome. An understanding of the mechanisms by which resistance to ADT develops is the basis for identifying future therapeutic targets. Patient summary Castration-resistant prostate cancer is characterized by multiple resistance mechanisms to androgen deprivation treatment and remains an incurable disease. An understanding of the mechanisms underlying this resistance is necessary to identify future therapeutic targets.