Beyond poly(ADP-ribose) polymerase inhibition: emerging therapeutic strategies for germline BRCA1/2-mutated and PALB2-mutated breast cancers.

PURPOSE OF REVIEW: Germline or somatic biallelic inactivation of BRCA1, BRCA2 and PALB2 genes define a clinically and biologically distinct subset of breast cancers characterized by homologous recombination deficiency (HRD) and sensitivity to PARP inhibitors. Despite regulatory approvals of olaparib and talazoparib for breast cancers in patients harboring germline BRCA1 and BRCA2 pathogenic/likely pathogenic variants, therapeutic progress in this setting has been limited by therapeutic resistance and treatment-related toxicity. This review studied emerging therapeutic strategies aimed at extending the clinical benefit of PARP inhibition and exploring novel vulnerabilities in HRD-associated breast cancer. RECENT FINDINGS: Resistance to PARP inhibitors can arise through multiple mechanisms, including reversion mutations, restoration of homologous recombination, replication fork stabilization, and upregulation of drug efflux transporters. Importantly, none of these mechanisms has been validated as a clinical biomarker so far. Emerging strategies include next-generation PARP1-selective inhibitors with improved therapeutic windows, rational combinations with CDK4/6 inhibitors, antibody-drug conjugates, immune checkpoint inhibitors, and PI3K/AKT pathway inhibitors. Novel synthetic lethal approaches targeting polymerase theta (POLQ), ATR, WEE1, EZH2, and ATM are also under active investigation, with early clinical evidence of activity in DNA damage response-deficient tumors. SUMMARY: The expanding landscape of therapeutic options in patients with either germline or somatic genetic alterations of BRCA1 and BRCA2, as well as other homologous recombination genes, offers significant opportunities to improve outcomes beyond first-generation PARP inhibition. Translational research to define resistance biomarkers, optimize combination strategies, and validate PALB2 as a fully equivalent therapeutic target remain a priority.