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.

The identification of BRCA1 and BRCA2 in the early 1990s as genes that, when mutated, are associated with an increased risk of breast, epithelial ovarian, fallopian tube, primary peritoneal, and other cancers opened a new frontier in managing hereditary cancer risk. The ability to delineate a high-risk subset of patients was of particular benefit to research into epithelial ovarian cancer (EOC), given its poor prognosis, frequent late stage at diagnosis, and relative lack of effective screening techniques. Further study has documented that, depending on the population evaluated, 5% to 15% of EOC cases are hereditary in origin. Mutations in BRCA1/2 or the mismatch repair mutations of Lynch syndrome account for almost all of that risk, although the great majority of EOC cases are sporadic in origin.

Groups at high risk for a disease provide ideal populations for research given their relatively high event rate, which makes studies shorter, smaller, and less expensive to conduct than when the general population is evaluated. These patients also tend to be highly motivated to participate in research, since the results may benefit not only their own treatment but also the care of their family members. In light of the desperate need for improvement in the treatment of EOC, development of poly(ADP-ribose) polymerase (PARP) inhibitors in the treatment of BRCA-deficient cancer has been closely monitored by patients, as well as by clinicians and researchers. The great hope is that lessons learned from the high-risk population will lead to insights into sporadic EOC.

This article will review the trials that have been conducted with PARP inhibitors in EOC, fallopian tube cancer (FTC), and primary peritoneal cancer (PPC). The impact of those results will then be placed in the larger context of PARP inhibitor development.

PARP Inhibitor Trials in Ovarian Cancer

The early history of PARP inhibition has been chronicled thoroughly, including in reviews by Comen et al[1] and Rios et al,[2] and will not be discussed in depth here. The strategy 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. Base excision repair relies on PARP. If that pathway is blocked via PARP inhibition, the loss of both repair mechanisms leads to accumulation of DNA breaks and, ultimately, cell death. The concept of synthetic lethality, originally described in 1946, has gained new life in the setting of these two DNA repair defects, which individually are not lethal but become so when combined.[3]

TABLE 1

Completed Clinical Trials of PARP Inhibitors in Epithelial Ovarian Cancer

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