DNA Damage Response Inhibitor and Anti-PD-L1 Therapy for Prostate Cancer: Development of Predictive Biomarkers

Abstract

Despite significant benefit for other cancer subtypes, immune checkpoint therapy (ICT) has not yet been shown to significantly improve outcomes for men with castrationresistant prostate cancer (CRPC). Previous studies have shown that DNA damage response (DDR) deficiency, via genetic alteration and/or pharmacologic induction using DDR inhibitors (DDRi), may improve ICT response in prostate cancer and potentially oither solid tumors, in part due to the induction of innate immune activation and regulation of the tumor cell– and/or immune cell–expressed B7 immune checkpoint protein PD-L1, which can be targeted by anti-PD-L1 agents. With this information and orientation, development of PD-L1 expression as a potential predictive biomarker for clinical response to ICT therapy has received widespread attention. However, the complex heterogeneous expression patterns of tumor cell–expressed PD-L1 and its related posttranslational modification in tumors substantially complicate detection and interpretation of PD-L1 in clinical samples using IHC and currently available PD-L1 antibodies. We discuss the potential roles of PD-L1 in prostate cancer and potential approaches to more accurately detect its expression in clinical tumor samples. Additional understanding of PD-L1 functions and development of improved methods to detect PD-L1 as a predictive biomarker for prostate cancer immunotherapy will likely benefit patients with advanced prostate cancer.