Next-generation sequencing identifies the presence of protein phosphatase 1D, PPM1D, as a potential biomarker of resistance to PARP inhibition in metastatic castration-resistant prostate cancer.

Abstract

The landscape for the treatment of advanced and metastatic prostate cancer is rapidly changing. For patients with metastatic castration-resistant prostate cancer (mCRPC), next-generation sequencing (NGS) may identify those with Homologous Recombination Deficiency (HRD) who may benefit from Poly ADP [adenosine diphosphate]-ribose polymerase inhibitors (PARP) inhibition therapy. Ongoing questions remain, however, regarding how patients and clinicians can best select therapies to optimize patient outcomes. In this case report, we highlight a patient with rapidly progressive mCRPC with germline BRCA2 for whom olaparib was added with abiraterone and prednisone resulting in a significant but brief response. Using next-generation sequencing of a liquid biopsy, we identified Protein Phosphatase 1D (PPM1D) as a potential resistance mechanism to PARP inhibition. While this alteration has been previously reported in other tumor types, the role of PPM1D and its contribution to PARP inhibitor resistance in mCRPC has not been described; the aim of this report was to highlight the potential role it may play in prostate cancer. With the increasing availability of circulating tumor DNA (ctDNA) to assist clinicians with monitoring patients' responses on therapy, the results from this case study underscore the necessity of exploring optimal timing of liquid and/or repeat tumor biopsies to help longitudinally personalize targeted therapy to improve patient outcomes.