New treatment options for patients with metastatic castration-resistant prostate cancer.

Chemotherapy for men with metastatic castration-resistant prostate cancer (CRPC) conferred no survival advantage until 2004 when docetaxel was shown to improve survival when compared with mitoxantrone, which was approved for palliation of symptomatic disease in 1996. Since then, clinical trials have concentrated on three main populations of patients with metastatic CRPC: those who are chemotherapy naïve and are asymptomatic or minimally symptomatic, those who need docetaxel therapy, and those who have received docetaxel previously and/or those with symptomatic disease. Over the last year, four Phase III therapeutic trials have met their primary endpoint of improved overall survival: sipuleucel-T in the pre-chemotherapy setting, cabazitaxel and abiraterone in the post-docetaxel setting, and radium-223 for those with symptomatic bone metastases who have received or are not suitable to receive docetaxel. In addition to these therapeutic trials, a Phase III head-to-head trial of denosumab compared to zoledronic acid showed that denosumab was superior to zoledronic acid in delaying or preventing skeletal related events. As a result, the treatment paradigm for metastatic CRPC is changing rapidly. This paper reviews the data from these five completed Phase III trials and places these new agents, as well as those in ongoing Phase III trials, in the context of the old treatment paradigm for metastatic CRPC and discusses some of the challenges ahead for determining optimal timing and sequencing of treatments for metastatic CRPC.