Immune checkpoint inhibitors have revolutionised the care of multiple solid organ malignancies, including melanoma, lung and renal cell carcinoma. Unfortunately, the impact of this therapeutic class in metastatic castration-resistant prostate cancer (mCRPC) has been comparatively modest. Pivotal studies of checkpoint inhibitor monotherapy in mCRPC, including CA184-043,1 KEYNOTE-1992 and others,3 have shown modest response rates in the order of 0-10%, with a substantial proportion of patients (~30-50%) experiencing rapid primary disease progression. Combination-based approaches utilizing dual checkpoint blockade have been proposed to improve response, but come with concerns surrounding toxicity. In the CheckMate-650 study, induction ipilimumab and nivolumab followed by maintenance nivolumab was associated with a higher response rate (25% in chemotherapy-naive, 10% in chemotherapy-treated), but nearly half experienced grade 3-4 toxicity, one-third did not complete induction treatment and almost 5% suffered treatment-related death.4 Clearly, there is an urgent need to develop strategies to improve the efficacy and overall tolerance of immunotherapy in mCRPC.