Challenges of PARP Inhibitor Selection and HRD Testing in Ovarian Cancer

04/20/18

A continuing medical education session at the Society of Gynecologic Oncology’s 2018 Annual Meeting on Women’s Cancer (March 24-27, 2018; New Orleans, LA) offered insight for optimal selection and administration of poly (ADP-ribose) polymerase (PARP) inhibitors, as well as homologous recombination deficiency (HRD) testing in ovarian cancer.

With many available therapeutic options for treating ovarian cancer, along with many more in the pipeline, the treatment landscape for ovarian cancer can be difficult to navigate. Three individuals attempted to provide some clarity to this challenge: Bradley Monk, MD, FACS, FACOG, professor of gynecologic oncology, University of Arizona; Michael J Birrer, MD, PhD, director, University of Alabama Birmingham Comprehensive Cancer Center; and Ursula A Matulonis, MD, director of gynecologic oncology, Harvard Medical School.

The presenters implored the audience to share their prior knowledge of clinical trials relating to the PARP inhibitors olaparib, rucaparib, and niraparib. The discussion was then directed to when best to use PARP inhibitors in the treatment paradigm, molecular markers for guiding treatment, eligible patients, and inhibitor characteristics to inform treatment decisions.

Genetic alterations are directly related to the homologous recombination repair pathway in up to 50% of epithelial ovarian cancer cases, explained Dr Monk, which is why identifying the germline and somatic mutations involved in homologous recombination DNA repair is a crucial determinant for when to use PARP inhibitors. However, the approved PARP inhibitors are unique and must be assessed individually to ensure optimal utilization. Dr Monk shared a few ongoing and promising trials for PARP inhibitor combinations, including bevacizumab and  inhibitors with immunotherapy as well as triplet therapy with inhibitors, immunotherapy, and bevacizumab.

Dr Birrer then addressed HRD testing in ovarian cancer, stressing the fact while BRCA1/2 are the most common mutations, many other mutations have been uncovered that factor into ensuring patients receive the optimal therapies. A few trials were shared that helped support this argument, including the NOVA trial, in which patients with BRCA mutations responded best with niraparib, though patients with non-BRCA mutations also demonstrated good results.

“All patients with ovarian cancer should undergo genetic testing,” Dr Birrer said, especially now that HRD assays are available.

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Dr Matulonis then addressed the audience with the many challenges associated with PARP inhibitor selection. Physicians must consider clinical trial results, previous regimens patients have been exposed to, dosing schedules, insurance coverage, HRD test results, drug-drug interactions, and which enzymes the inhibitors use to metabolize the drugs. Because PARP inhibitors are still currently considered new treatments, Dr Matulonis explained, drug-drug interactions may not be included in some electronic health records.

Additionally, hypertension and fatigue should be weighed in the decision, she added.—Zachary Bessette