Prostate cancer (PCa) is the second leading cause of cancer death in men. Despite initial responses,\nalmost all patients progress to castration-resistant prostate cancer (CRPC). Over the past decade,\nincreased understanding of the mechanisms that drive resistance to castration has led to the development\nof next-generation androgen receptor targeting agents such as abiraterone acetate and\nenzalutamide. Moreover in the last few years, results from large Phase III trials led to the approval\nof an -emitter (radium-223), the bone resorption-targeting drug denosumab and an immunotherapy\n(sipuleucel-T) that showed improvements in terms of overall survival. In the field of metastatic\nCRPC, other novel therapeutics have recently been proven to extend survival via distinct\nmechanisms of action such as the new and more potent classes of androgen inhibitors, ortonel,\nARN-509 and galeterone, the endothelin A receptor antagonist zibotentan, the Src inhibitor dasatinib,\nthe c-MET inhibitor cabozantinib and the immune checkpoint inhibitor ipilimumab. This review\naims to revisit the evolution of androgen receptor targeting therapeutics and to discuss other\nimportant alternative biologic pathways that have given rise to new agents in metastatic prostate\ncancer.
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