BRCA mutations, homologous recombination deficiency, and PARP inhibitor resistance in ovarian cancer

Ovarian cancer remains one of the most lethal gynecologic malignancies worldwide, largely due to late-stage diagnosis and the eventual development of therapeutic resistance. A major breakthrough in its management has been the identification of defects in homologous recombination repair, particularly those involving BRCA1 and BRCA2 mutations. These discoveries have led to the clinical adoption of poly (ADP-ribose) polymerase (PARP) inhibitors, which exploit synthetic lethality in tumors harboring homologous recombination deficiency. Despite significant improvements in progression-free survival, resistance to PARP inhibitors has emerged as a major clinical challenge. This review explores the molecular basis of BRCA mutations and homologous recombination deficiency in ovarian cancer, the mechanisms of action of PARP inhibitors, and the evolving landscape of resistance mechanisms. It also discusses emerging therapeutic strategies aimed at overcoming resistance and improving patient outcomes.