Response prediction biomarkers and drug combinations of PARP inhibitors in prostate cancer

Abstract

PARP inhibitors are a group of inhibitors targeting poly(ADP-ribose) polymerases (PARP1 or PARP2) involved in DNA repair and transcriptional regulation, which may induce synthetic lethality in BRCAness tumors. Systematic analyzes of genomic sequencing in prostate cancer show that ~10%-19% of patients with primary prostate cancer have inactivated DNA repair genes, with a notably higher proportion of 23%-27% in patients with metastatic castration-resistant prostate cancer (mCRPC). These characteristic genomic alterations confer possible vulnerability to PARP inhibitors in patients with mCRPC who benefit only modestly from other therapies. However, only a small proportion of patients with mCRPC shows sensitivity to PARP inhibitors, and these sensitive patients cannot be fully identified by existing response prediction biomarkers. In this review, we provide an overview of the potential response prediction biomarkers and synergistic combinations studied in the preclinical and clinical stages, which may expand the population of patients with prostate cancer who may benefit from PARP inhibitors.

Racial disparities in prostate cancer: A complex interplay between socioeconomic inequities and genomics

“…However, PARP inhibitor treatment decisions are currently solely driven by mutations in a small panel of homologous recombination repair (HRR) genes. Prior preclinical studies have suggested that SPOP mutation and/or CHD1 loss can result in increased sensitivity to PARP and other DNA damage response inhibitors (such as (ataxia telangiectasia and Rad3-related) ATR inhibitors) [ 68 ]. Retrospective clinical data analysis evaluating performance of PARP inhibitors across racial groups have not been published yet.…”