Targeting DNA repair: poly (ADP-ribose) polymerase inhibitors

Ovarian cancer represents a significant challenge in women’s health, with an estimated 21,980 new cases and 14,270 deaths in the United States in the year 2014. Despite excellent response rates to cytotoxic chemotherapy, the majority of patients will relapse within two to three years and extending their remission through consolidation remains a priority. The development of novel treatment agents is therefore imperative. Poly (ADP-ribose) polymerase (PARP) inhibitors are a promising new class of targeted agents currently in clinical trials for ovarian cancer. PARP inhibitors were first studied in patients harboring BRCA1/2 mutations due to the known synthetic lethality of BRCA1/2-associated dysfunctional homologous recombination (HR) DNA repair and PARP inhibitor-associated loss of base excisional repair (BER) and non-homologous end rejoining. However, preclinical and emerging clinical data suggest that PARP inhibitors may benefit a broader patient population. While the initial studies of PARP inhibitors in ovarian cancer are encouraging, there remain many unanswered questions including the ideal timing of administration, whether to give these drugs as monotherapy or in combination with other antineoplastic agents and how to identify the patients most likely to respond. The focus of this review will be on the underlying mechanism of PARP inhibition in cancer, preclinical data, current clinical trials and the future of PARP inhibitors in the treatment of ovarian cancer.