Translational prioritization of strategies to overcome poly ADP-ribose polymerase inhibitor resistance in breast cancer based on systematic review of preclinical evidence.

Resistance to poly ADP-ribose polymerase (PARP) inhibitors has emerged as a major obstacle to durable clinical benefit in breast cancer. While multiple preclinical strategies have been proposed, there is a lack of translational frameworks that prioritize interventions based on mechanistic robustness, biomarker relevance, and strength of evidence. We performed a systematic and evidence-informed synthesis of 22 preclinical studies investigating therapeutic approaches to overcome PARP inhibitor resistance. Studies were evaluated across experimental models, mechanistic endpoints, and therapeutic outcomes. Risk of bias was assessed using the SYRCLE and ROBINS-I tools, and the consistency and certainty of evidence were appraised using the GRADE framework to support translational prioritization. Epigenetic targeting via EZH2 inhibition and immune microenvironment modulation through STING pathway activation consistently demonstrated high-quality evidence for tumor suppression, survival benefit, and immunologic activation in BRCA1-mutant models. In contrast, strategies aimed at restoring homologous recombination exhibited strong in vitro synergy but limited in vivo translatability, underscoring pharmacokinetic and model-dependent constraints. This review advances an evidence-based translational prioritization framework to guide the clinical development of combination strategies for PARP inhibitor-resistant breast cancer. We identify critical gaps in biomarker integration, standardized resistance modeling-particularly in BRCA wild-type disease-and dynamic monitoring of resistance evolution, and propose key directions for future preclinical and early-phase clinical research.