Overcoming Resistance to PARP Inhibitors in BRCA-Mutated Cancers: Mechanisms and Therapeutic Strategies

The tumor suppressor genes BRCA1 and BRCA2 are essential for homologous recombination (HR) repair. Mutations in BRCA1/2 compromise HR repair efficacy, resulting in heightened susceptibility of tumor cells to poly (ADP-ribose) polymerase inhibitors (PARPi) via synthetic lethality. To date, several PARPi have been approved for BRCA-mutated and HR-deficient tumors, but acquired resistance and cumulative toxicity continue to limit their long-term clinical benefit. This narrative review offers an updated mechanistic model of PARPi action and categorizes resistance mechanisms by clinical relevance and evidentiary strength. Importantly, we distinguish between standard combination therapies in the PARPi-naïve setting and interventions explicitly tailored for PARPi-exposed or PARPi-resistant disease. Building on this distinction, we propose a biomarker-guided framework that links specific resistance phenotypes to appropriate specimen types, detection assays, and candidate interventions. Through this evidence-based clinical framework, we aim to clarify the current therapeutic landscape, improve data interpretation, and guide prospective trial design.