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PARP Inhibitor Therapy Improves Outcomes for Ovarian Cancer Patients Who Have BRCA Wild-Type Tumors

Web Exclusives - Ovarian Cancer

Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer–related death and the fifth leading cause of cancer-related death in US women.1 Most women who are diagnosed with EOC undergo surgical tumor removal followed by chemotherapy.1 However, since chemotherapy often produces unpleasant toxic side effects throughout the body, the search is ongoing for alternative therapies such as poly (ADP ribose) polymerase (PARP) inhibitors that specifically target tumor cells and exploit tumor cells’ particular weaknesses.1

Although it is not fully understood how the PARP protein functions in a tumor cell, its general role was discovered after investigators found that BRCA gene–mutated tumor cells (commonly associated with breast cancer, but also seen in ovarian cancer) are unable to repair their own DNA damage. This repair defect was deduced from the response of BRCA tumor cells to platinum-based chemotherapy, which damages the tumor cell by inappropriately crosslinking the cell’s DNA strands. Repair of crosslinked DNA damage relies upon a specific type of repair mechanism known as homologous repair, which happens to be absent in the BRCA tumor cell. Platinum-based chemotherapy exploits this absence by introducing the type of damage that a BRCA tumor cell cannot repair, and this leads to the cell’s demise.1

However, other types of DNA damage can occur in a cell, which is where PARP enters the picture. PARP actually refers to a family of proteins (eg, PARP1, PARP2, etc) that repair DNA. PARP1 was first found to be essential for the type of DNA repair known as base excision repair.1 Drugs known as PARP inhibitors that block PARP proteins from repairing DNA prevent base excision repair, which leads to worsening DNA damage that then relies on homologous repair, which is deficient in a BRCA-mutant cell.1 This description of the PARP protein repair role is but a generalized one and many theories exist about how exactly PARP proteins work to repair cellular DNA.1

Nonetheless, the discovery of PARP’s overall repair role has resulted in the development of several PARP inhibitors, most of which have, in trials, demonstrated an ability to inhibit 2 types of PARP proteins, PARP1 and PARP2.1 In clinical trials, women with BRCA EOC who had already been treated with chemotherapy received PARP inhibitors, which produced encouraging responses and improved survival periods over placebo controls.1 These promising results have naturally led investigators to wonder about the use of PARP inhibitors in those women with non-BRCA ovarian cancer, that is, women with what is known as BRCA wild-type EOC.

While laboratory in vitro studies of PARP inhibitors in BRCA wild-type cells produced less impressive results than they had in BRCA cells,2 clinical studies have shown that PARP inhibitors do have some effect in patients with BRCA wild-type tumors, although the effect is less robust than in BRCA EOC patients.3,4 Through the course of these studies, it has been found that tumor cells may have other mutations that disable DNA damage repair, and investigators have been able to categorize BRCA wild-type tumors by the extent of their DNA homologous repair inability.3 What is more, investigators have proposed that BRCA wild-type tumors’ weaker response to PARP inhibitors be met with increased doses of a PARP inhibitor.2 Not only may PARP inhibitor doses need to be adjusted depending on the type of BRCA and homologous repair tumors that are present, but it also appears that for those patients with BRCA wild-type tumors, there may be a smaller window of time in which to get the most effect from PARP inhibitor therapy.4,5

References

  1. Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D’Andrea AD. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov. 2015;5(11):1137-1154.
  2. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917-921.
  3. da Cunha Colombo Bonadio RR, Fogace RN, Miranda VC, Diz MDPE. Homologous recombination deficiency in ovarian cancer: a review of its epidemiology and management. Clinics (Sao Paulo). 2018;73(suppl 1):e450s.
  4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Ovarian cancer including fallopian tube cancer and primary peritoneal cancer. Version 2.2019. NCCN.org.
  5. Moore KN, Secord AA, Geller MA, et al. Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019;20(5):636-648.
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Last modified: December 12, 2019