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

Muhammad Latif,1– 3 Sana Mazhar,4,5,* Mussarat Tasleem,6,* Abdulmajeed Alqurashi,7 Muhammad Arfan,8 Zaman Ashraf,3 Muhammad Sohail Zafar9– 11 1Centre for Genetics and Inherited Diseases (CGID), Taibah University, Madinah, 42353, Kingdom of Saudi Arabia; 2Division of Biochemistry and Molecular Biology, Department of Basic Medical Sciences, College of Medicine, Taibah University, Madinah, 42353, Kingdom of Saudi Arabia; 3Department of Chemistry, Rawalpindi Women University, Rawalpindi, 46300, Pakistan; 4Mirpur University of Science and Technology (MUST), Mirpur, Azad Jammu and Kashmir (AJK), 10250, Pakistan; 5Department of Chemistry, School of Natural Sciences (SNS), National University of Sciences and Technology (NUST), H-12, Islamabad, 44000 Pakistan; 6Department of Chemistry and Chemical Engineering, Lahore University of Management Sciences, Lahore, Pakistan; 7Department of Biology, College of Science, Taibah University, Medinah, 42353‎, Kingdom of Saudi Arabia; 8Department of Chemistry, School of Natural Sciences (SNS), National University of Sciences and Technology (NUST), Islamabad, 44000, Pakistan; 9Department of Clinical Sciences, College of Dentistry, Ajman University, Ajman, United Arab Emirates; 10Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates; 11School of Dentistry, Jordan University, Amman, Jordan*These authors contributed equally to this workCorrespondence: Muhammad Latif, Centre for Genetics and Inherited Diseases (CGID), and College of Medicine, Taibah University, Madinah, Kingdom of Saudi Arabia, Email [email protected] Zaman Ashraf, Department of Chemistry, Rawalpindi Women University, Rawalpindi, 46300, Pakistan, Email [email protected]: 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 (IC50 = 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