ClinicalApplicationofPARPInhibitorsin BreastCancer:CurrentEvidence, Biomarkers,Resistance,andFuture

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Poly(ADP-ribose) polymerase (PARP) inhibitors have established a precision-treatment paradigm in breast cancer by exploiting synthetic lethality in tumors with defective homologousrecombination repair. Olaparib and talazoparib improve progression-free survival and patientreported outcomes compared with single-agent chemotherapy in germline BRCA1/2-mutated, HER2-negative advanced breast cancer, while one year of adjuvant olaparib provides sustained invasive disease-free, distant disease-free, and overall-survival benefits in patients with germline BRCA1/2-mutated, HER2-negative high-risk early disease. Six-year follow-up of OlympiA confirms that the benefit persists after treatment completion, supporting early germline testing when the result may alter systemic therapy. Nevertheless, BRCA1/2 mutation is not a uniform predictor of response, and the clinical value of PARP inhibition depends on mutation origin, functional homologous-recombination deficiency, previous platinum exposure, disease setting, and competing treatment options. Phase II evidence supports substantial activity in germline PALB2mutated and somatic BRCA1/2-mutated metastatic breast cancer, whereas isolated ATM or CHEK2 mutations have not reliably predicted benefit. Attempts to extend PARP inhibition to unselected triple-negative disease or to intensify platinum-containing chemotherapy have produced mixed or negative randomized results. Resistance arises through BRCA reversion, restoration of homologous recombination, replication-fork protection, altered PARP1 function, and drug efflux. Hematologic toxicity, fatigue, gastrointestinal symptoms, renal function, drug interactions, reproductive risk, and the rare possibility of myelodysplastic syndrome or acute myeloid leukemia require structured monitoring. This review summarizes the biological rationale, pivotal clinical trials, biomarker selection, treatment sequencing, resistance mechanisms, safety management, and emerging combinations of PARP inhibitors in breast cancer. Their future value will depend on functional biomarker development and rational integration with platinum agents, immunotherapy, targeted therapy, and antibody–drug conjugates rather than indiscriminate expansion beyond biologicallysensitivedisease.

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