Clinical applications of PARP inhibitors in breast, ovarian, and prostate cancer: current insights and future directions.

Abstract

Poly(ADP-ribose) polymerase (PARP) inhibitors have emerged as an important therapeutic option for patients with homologous recombination repair (HRR)-deficient cancers, especially those with BRCA1/2 mutations. Since the initial US Food Administration approval of olaparib in 2014, PARP inhibitors have shown efficacy across ovarian, breast, and prostate cancers, although differences in trial design and biomarker strategies have resulted in tumor-specific indications. Homologous recombination deficiency (HRD) arises from germline or somatic mutations in HRR genes or from epigenetic inactivation, and it can be assessed through genomic "scars" such as loss of heterozygosity and mutational signatures. Although BRCA1/2 alterations confer the strongest sensitivity to PARP inhibitors, non-BRCA HRR gene mutations demonstrate heterogeneous responses, highlighting the need for more precise HRD assessment, including the role of biallelic vs monoallelic inactivation. Despite initial success, both primary and acquired resistance-through reversion mutations, replication fork stabilization, and therapy-induced clonal hematopoiesis-limit the durability of the response to PARP inhibition. Ongoing studies are evaluating rational combinations targeting complementary DNA damage response pathways (ATR/CHK1/WEE1, PI3K/AKT) and integrating immunotherapy or hormonal agents to extend benefit. Moving forward, harmonizing HRD testing across tumor types, accounting for germline, somatic, and liquid biopsy-derived alterations, and refining patient selection will be essential to maximize therapeutic efficacy and safely expand PARP inhibitor use beyond canonical BRCA-mutated cancers.