Emerging systemic treatment for metastatic castration-resistant prostate cancer: a review of recent randomized controlled trials

The landscape of therapy for metastatic castration-resistant prostate cancer (mCRPC) has seen an unprecedented transformation with the emergence of combination therapies. This review summarizes the current findings from randomized controlled trials (RCTs) assessing the oncologic outcomes of mCRPC.In the first-line, treatment-naïve setting, recent RCTs demonstrated the oncologic benefit of adding AKT inhibitors or poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors to abiraterone in terms of radiographical progression-free survival. Although this is a strong surrogate endpoint, these agents have not yet shown overall survival (OS) improvement. In the second- or later-line settings, olaparib improved OS in patients with at least one alteration in BRCA1 , BRCA2 , or ATM gene and lutetium-177-prostate-specific membrane antigen-617 [177-Lu-prostate-specific membrane antigen (PSMA)-617] were superior to repeat androgen receptor signaling inhibitor (ARSI) therapy. In addition, 177-Lu-PSMA-617 had better progression-free survival compared with cabazitaxel but failed to result in an OS benefit. To date, there is no evidence for effective immune checkpoint inhibitor regimens/combinations for mCRPC.According to recent RCTs, several novel agents and/or combinations exhibit promising oncologic outcomes. In the first-line setting, OS benefits compared with currently available regimens are still missing. Results from ongoing/well-designed phase 3 RCTs and real-world data regarding the sequential impact of currently available agents on outcomes of mCRPC patients after ARSI-based combination therapy for metastatic hormone-sensitive prostate cancer are awaited. Such data will improve clinical decision-making in the ever-intensifying treatment era.