Advances in PARP Inhibition in Improving Outcomes of Breast Cancer, Ovarian Cancer, and Other Solid Tumors: Journey of Discovery, Development, and Clinical Updates of Talazoparib

Abstract: Poly(ADP-ribose) polymerase (PARP) inhibition has emerged as a prominent approach in cancer treatment, leading to the development of several poly(ADP-ribose) polymerase inhibitors (PARPi), which have demonstrated substantial progress in clinical trials and efficacy in the management of ovarian cancer (OC), breast cancer (BC), and solid tumors (STs). These PARPi are approved for several cancers, including BC and OC. Among PARPi, Talazoparib (Talzenna ® ) is a potent therapy for patients with locally advanced or metastatic BC ( mBC ) with germline BRCA mutations ( gBRCAm ) and HER2 -negative status, demonstrating the highest potency (IC 50 = 0.57 nM), which is 4– 10 times lower than that of other PARP inhibitors; olaparib (2.0 nM), rucaparib (1.9 nM), and veliparib (4.7 nM), indicating superior efficacy. This review describes the role of BRCA1/2 in BC and OC, highlighting key discovery milestones and providing an overview of available PARP inhibitors (PARPi) at various stages of development. Additionally, it details the discovery and development of talazoparib, one of the key PARPis, its current clinical status, and therapeutic implications. The latest advancements in talazoparib research, including all related clinical trials (Phase 1– 3) for the treatment of BC, OC, and other solid tumors (STs), are also summarized. A comprehensive analysis of all clinical trials involving talazoparib, whether as monotherapy or in combination with other drugs, elucidates its potential to improve clinical outcomes, address drug resistance, and explore synergistic combinations with other PARPi or novel agents, thereby providing insights into the clinical utility of talazoparib. Keywords: clinical trials, breast cancer, ovarian cancer, third-generation inhibitor, synthetic strategies