Biomarkers for Programmed Death-1 Inhibition in Prostate Cancer

Prostate cancer is the second leading cause of cancer death in American men. Despite the common nature of this disease, there is a poor understanding of biomarkers that predict responsiveness to immunotherapeutic agents such as the programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors. Herein we describe a case of complete remission with pembrolizumab therapy in a metastatic castrate-resistant prostate cancer patient with a complex germline MSH2 alteration (Boland inversion) in association with a tumor demonstrating high microsatellite instability. Potential utility of high mutational burden assessed by an experimental circulating tumor DNA assay is also shown. The literature concerning biomarkers for PD-1 inhibition is reviewed, including data for various mismatch repair gene deficiencies, microsatellite instability, tumor mutational burden, PD-L1 3' untranslated region mutations, selected POLE mutations, and biallelic CDK12 mutations. Taken together, although prostate cancer is generally believed to be a tumor unresponsive to PD-1 inhibition, careful dissection of tumor biology is able to provide an approach toward predictive biomarkers that has the potential for expanded clinical utility. KEY POINTS: Biomarkers for anti-PD1 and anti-PDL1 therapy are poorly defined in prostate cancer.Recent advances are defining new important classes of responsive patients.