The biology of castration-resistant prostate cancer

Prostate cancer is one of the most commonly diagnosed cancers and the second leading cause of cancer death in men in the United States. Although there are recently approved therapeutic options for men with advanced and metastatic disease, the unfortunate reality is that advanced prostate cancer is inevitably fatal. Hormonal androgen deprivation therapy (ADT) is the standard of care once a patient has recurrent disease following primary surgical or radiation therapy; however, the benefits from ADT are typically short lived. Recurrent disease that follows ADT treatment is termed castration-resistant prostate cancer (CRPC), which is the most aggressive and lethal form of prostate cancer. The current treatment regime for CRPC consists primarily of chemotherapy with docetaxel, but other agents such as the immunotherapy agent sipuleucel-T, the taxane cabazitaxel, the CYP17 inhibitor abiraterone acetate, and the androgen receptor (AR) antagonist enzalutamide are also Food and Drug Administration (FDA) approved for the treatment of CRPC. Although there are clinical trials testing the potential therapeutic benefits of many other compounds, CRPC remains an incurable disease. Recent advancements in our understanding of the biochemical and genetic pathways critical to CRPC progression have identified many novel potential druggable targets as well as biomarkers of disease progression. This review focuses on the biological aspects of aggressive prostate cancer, biomarkers, therapeutic targets, and future directions for the treatment of CRPC (Fig).