Checkpoint inhibitors targeting PD-1/PD-L1, such as pembrolizumab, can be effective in a small population of biomarker-selected patients with metastatic prostate cancer (mPC), as has been demonstrated by small case series. The objective of this study is to help identify which biomarker-selected patients are most likely to benefit from pembrolizumab and estimate their likelihood of response. This is a single-center study in which we analyzed clinical data of 18 patients with mPC who were treated with pembrolizumab for a biomarker-driven indication. We found that 38.9% of patients showed a 50% or greater decline in PSA, all of whom had high microsatellite instability (MSI-H). One patient with MSI-H and high tumor mutation burden (TMB-H) had 100% decline in PSA and remained on pembrolizumab after 47 months. Neither MSI-H nor TMB-H, however, was sufficient for response. These results support biomarker testing for all patients with mPC and use of immunotherapy in select populations.