PARP inhibition in epithelial ovarian cancer: high hopes undergo a reality check.

The treatment strategy of poly(ADP-ribose) polymerase (PARP) inhibition capitalizes on the inherent defect in homologous recombination that occurs in BRCA-deficient tumors by inhibiting the alternative DNA repair pathway involving base excision repair. Although PARP inhibitors were initially considered a potential treatment specifically for tumors with germline BRCA mutations, evidence of frequent somatic deficiency in the BRCA pathway has caused reconsideration of that approach. PARP inhibitors have been shown to have activity in epithelial ovarian, fallopian tube, and primary peritoneal cancer in phase I and II clinical trials. Responses have been seen in both BRCA-deficient and sporadic tumors, and they do not appear to require platinum sensitivity. Although PARP inhibitors are well tolerated as monotherapy, additional study is required to determine their efficacy and toxicity in combination with chemotherapy and other targeted agents. Many hurdles remain along the pathway to drug registration, but the motivation of the community of ovarian cancer patients, researchers, and clinicians to find new treatments may speed the process.