A Systematic Review of the Emerging Role of Immune Checkpoint Inhibitors in Metastatic Castration-resistant Prostate Cancer: Will Combination Strategies Improve Efficacy?

The role of immune checkpoint inhibition (ICI) in the treatment of prostate cancer (PC) still remains elusive. It has been proposed that combination of ICI with other molecules increases the efficacy of immunotherapy in PC. To systematically review the literature to assess the potential role of ICI in combination with additional therapies for the management of metastatic castration-resistant PC (mCRPC). A systematic review using Medline and scientific meeting records was carried out in September 2020 according to the Preferred Reporting Items for Systematic Review and Meta-analyses guidelines. Ongoing trials of immunotherapy with standard mCRPC therapeutics were identified via a systematic search on ClinicalTrials.gov. A total of five full-text papers, ten congress abstracts, and 15 trials on ClinicalTrials.gov were identified. Preclinical evidence suggests that combinational approaches might be considered to enhance the efficacy of ICI in PC patients. This led to the design of more than 50 immunotherapy-based clinical trials. The majority of the studies focus on ICI combinations with vaccines, androgen deprivation therapy, chemotherapy, PARP inhibition, radiotherapy, and prostate-specific membrane antigen–guided radioligand therapy. Preliminary analyses reported promising findings for the use of ICI in combination with other anticancer therapies. However, no phase 3 trial has yet reported final results, so no level 1 evidence with long-term outcomes currently supports the combination of ICI with mCRPC therapies. Preclinical and clinical trials have demonstrated that combining immunotherapy with standard mCRPC treatment options has the potential to provide a synergistic effect. Nonetheless, a better understanding of the mechanism and of the optimal treatment approach is still needed. We reviewed the literature on immunotherapy in combination with standard treatments for patients with metastatic castration-resistant prostate cancer (mCRPC). Current evidence supports the hypothesis that immunotherapeutic drugs might be effective in mCRPC if combined with other treatment options. However, results of ongoing trials are still awaited before this novel treatment approach can be implemented in the daily practice. The role of immune checkpoint blockade monotherapy in the treatment of prostate cancer remains elusive. However, recent preclinical studies and first results from clinical trials have demonstrated that combining immunotherapy with standard treatment opti