New Molecular Targets in Metastatic Prostate Cancer

Abstract

Prostate cancer (PCa) is the second leading cause of cancer death in men. Despite initial responses, almost all patients progress to castration-resistant prostate cancer (CRPC). Over the past decade, increased understanding of the mechanisms that drive resistance to castration has led to the de-velopment of next-generation androgen receptor targeting agents such as abiraterone acetate and enzalutamide. Moreover in the last few years, results from large Phase III trials led to the approval of an α-emitter (radium-223), the bone resorption-targeting drug denosumab and an immuno-therapy (sipuleucel-T) that showed improvements in terms of overall survival. In the field of me-tastatic CRPC, other novel therapeutics have recently been proven to extend survival via distinct mechanisms of action such as the new and more potent classes of androgen inhibitors, ortonel, ARN-509 and galeterone, the endothelin A receptor antagonist zibotentan, the Src inhibitor dasa-tinib, the c-MET inhibitor cabozantinib and the immune checkpoint inhibitor ipilimumab. This re-view aims to revisit the evolution of androgen receptor targeting therapeutics and to discuss other important alternative biologic pathways that have given rise to new agents in metastatic prostate cancer.