# PARP inhibitors in gastric cancer: unlocking precision oncology

## TL;DR

This paper reviews how PARP inhibitors might be used in gastric cancer by targeting tumors with homologous recombination repair deficiencies and explores biomarkers and combination therapies to improve treatment outcomes.

## Contribution

The paper provides a comprehensive review of biomarkers and clinical strategies for using PARP inhibitors in gastric cancer with homologous recombination repair deficiencies.

## Key findings

- PARP inhibitors show synthetic lethality with homologous recombination repair deficiencies in preclinical models.
- Current biomarkers like genomic instability scores and RAD51 foci formation are being evaluated for patient selection.
- Combining PARP inhibitors with other therapies may enhance efficacy and overcome resistance.

## Abstract

Gastric cancer (GC) demonstrates frequent alterations in homologous recombination repair (HRR) genes, and preclinical studies have demonstrated a clear synthetic lethality between HRR deficiency (HRD) and PARPi. While such preclinical synthetic lethality has translated into clinical benefits of PARPi in patients with HRD breast, ovarian, pancreatic, or prostate cancer, the therapeutic role of PARPi in GC remains unclear due to molecular heterogeneity and lack of validated biomarkers for patient selection. This review summarizes the mechanistic foundation for PARPi sensitivity in HRR-deficient GC tumors and evaluates emerging biomarkers, including genomic instability scores, RAD51 foci formation, mutational signatures, and candidate genes such as BRCA1/2, PALB2, and BARD1. We highlight key clinical trials and ongoing research aimed at refining patient selection, optimizing combination strategies, and identifying predictive biomarkers. Improving biomarkers to identify bona fide HRD is essential to optimizing PARPi as a valuable treatment option for patients with GC. We outline a pathway for biomarker-guided adoption of PARPi in GC management. Early-phase clinical trials of PARPi monotherapy in GC have yielded limited efficacy, likely due to variable HRD status and other mechanisms of primary resistance. Combining PARPi with chemotherapy, immune checkpoint inhibitors, or anti-angiogenic agents offers strategies to potentially increase the tumor susceptibility to PARPi and overcome resistance.