New Biologic Frontiers in Ovarian Cancer: Olaparib and PARP Inhibition

Introduction Poly (ADP-ribose) polymerase (PARP) inhibition was first introduced as a novel cancer-targeting strategy in 2005, following the publication of preclinical work showing activity in BRCA-mutated tumor cells. Compared with wild-type cells, BRCA1and BRCA2-deficient cells were up to 1000-fold more sensitive to PARP inhibition. In vivo, the growth of BRCA2-deficient tumors was decreased by PARP inhibitors, the first demonstration that inhibition of a DNA repair mechanism could be used to target cancer cells. These studies highlighted the application of synthetic lethality as a potentially effective anticancer therapy and inspired further clinical investigation. PARP inhibitors are now known to work through a variety of mechanisms, in addition to inducing synthetic lethality. PARP inhibition stimulates nonhomologous end joining (NHEJ) selectively in homologous repair-deficient cells. This is achieved via inhibition of DNA-dependent protein kinase substrates, leading to genetic instability, chromosome rearrangement, and cell death. PARP inhibitors have also been shown to trap PARP-1 and PARP-2 on DNA, leading to PARP-DNA complexes. This concept, known as “PARP trapping,” is thought to be responsible for the synergism seen with PARP inhibition and alkylating agents and does not occur with all PARP inhibitors. Since their introduction, PARP inhibitors have been studied in many BRCA-deficient cancers, including ovarian cancer, where they have had notable success. The most extensively studied PARP inhibitor in ovarian cancer is olaparib, an orally available compound with activity against PARP-1 and PARP-2. The recent FDA approval of olaparib in relapsed ovarian cancer brings this drug class to the forefront of new anticancer therapy in this disease. This timely review will discuss the early clinical investigation of olaparib, as well as emerging phase II and III data and future directions in ovarian cancer.