title: Development of Olaparib for BRCA-Deficient Recurrent Epithelial Ovarian Cancer.
abstract: The FDA approval of the PARP inhibitor olaparib for fourth-line therapy of germline BRCA1/2-mutated ovarian cancer represents the first registered indication for this class of drugs in any disease. PARP is a family of proteins involved in the repair of single-strand DNA breaks. High-grade serous ovarian carcinomas with BRCA deficiencies may be particularly vulnerable to both direct and indirect effects of PARP inhibition. This phenotype frequently arises as a consequence of defects in the repair of damaged DNA, rendering cancer cells susceptible to DNA-damaging platinum compounds and targeted therapies affecting homologous recombination repair (HRR). When cells already deficient in HRR are exposed to PARP inhibitors, apoptosis occurs by way of synthetic lethality. In this review, we trace the clinical development of olaparib for women with recurrent epithelial ovarian carcinoma harboring germline BRCA mutations, a biomarker for HRR deficiency present in 15% to 20% of cases. Clinical trials highlighted include not only those pivotal studies that have led to regulatory approval in the United States and in Europe, but also those in which olaparib was studied in novel combinations, including chemotherapy and antiangiogenesis agents.
authors.affiliation: The Division of Gynecologic Oncology, University of California, Irvine Medical Center, Orange, California.
authors.forename: Krishnansu S
authors.initials: KS
authors.lastname: Tewari
authors.affiliation: The Division of Gynecologic Oncology, University of California, Irvine Medical Center, Orange, California.
authors.forename: Ramez N
authors.initials: RN
authors.lastname: Eskander
authors.affiliation: The Division of Gynecologic Oncology, University of Arizona Cancer Center at Dignity Health St. Joseph's Hospital and Medical Center, Phoenix, Arizona. bradley.monk@chw.edu.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Monk
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019313:BRCA1 Protein / Q000172:deficiency*; D024682:BRCA2 Protein / Q000172:deficiency*; D000077216:Carcinoma, Ovarian Epithelial; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D017277:Drug Approval; D005260:Female; D006801:Humans; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D010793:Phthalazines / Q000008:administration & dosage / Q000627:therapeutic use*; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome; D014481:United States
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D024682:BRCA2 Protein; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C531550:olaparib