How PARP Inhibitors Work In Women

In 2014, the first PARP inhibitor to treat certain patients with ovarian cancer was approved by the Food and Drug Administration (FDA). Since then, two more PARP inhibitors have come to market for ovarian cancer, and the types of cancers they can treat have expanded.

These agents block a cellular enzyme called PARP, which helps repair damaged DNA. In cancer treatment, using PARP inhibitors to prevent this process may cause cancer cells to die.

“Typically, what happens is if one pathway doesn’t work, a cell just uses another one,” explains Dr. Shannon Westin, a gynecologic oncologist at The University of Texas MD Anderson Cancer Center in Houston.

“For example, people with BRCA mutations ... have dysfunction of a different DNA-damage repair pathway, which is actually called the homologous recombination pathway. Their homologous recombination pathway doesn’t work. It’s deficient. Their cells really rely on PARP to repair DNA damage. And so if you’ve already got a problem in homologous recombination and then you block PARP, that cell is going to die because it can’t fix its problems.”

The three FDA-approved PARP inhibitors include Lynparza (olaparib), Rubraca (rucaparib) and Zejula (niraparib), all oral medications. If given upfront in the treatment course, patients usually take a PARP inhibitor for two years. However, many women with ovarian cancer face recurrence. In this case, whether a PARP inhibitor is used to re-treat cancer or as maintenance therapy after response to chemotherapy, a patient will be on the medication until the cancer grows or side effects become intolerable.

“One of the common misconceptions, especially when people are coming off chemotherapy, is ... ‘Oh, I’m going to be taking a pill, and it’s going to be easy peasy.’ But these drugs have side effects,” Westin says. Importantly, they can be mitigated with appropriate management.

Toxicities of PARP inhibitors include gastrointestinal issues such as nausea, diarrhea, reflux and feeling full early; headaches and dizziness; and fatigue. They can also affect the bone marrow, Westin says, causing anemia, neutropenia and thrombocytopenia — conditions that affect blood counts.

“I tell patients that we just have to find your sweet spot,” she says. “We’re starting your dose here, but that may not be the best dose for you. We have to manage it and make changes as needed.”

The drugs’ response primarily depends on the tumor; they’re most effective in tumors that have a BRCA gene mutation or another abnormality in a member of the homologous recombination pathway, according to Westin. For patients with no biomarker, there is some efficacy, but combination therapies may work better.

“PARP inhibitors work on their own, but there is not 100% efficacy, and they don’t work forever,” Westin says. “There is a lot of interest around combining PARP inhibitors with other targeted therapies or immunotherapy to try to improve upon the benefit and make it work better for more people.”

Researchers are also examining two other PARP inhibitors, ABT-888 (veliparib) and Talzenna (talazoparib).

In a phase 3 clinical trial that included more than 1,100 women with advanced ovarian cancer, first-line treatment of ABT-888 combined with chemotherapy reduced the risk of disease progression or death. Talzenna, which is FDA approved to treat certain patients with advanced

or metastatic breast cancer, is now being explored in the ovarian cancer space.

“Patients need to talk to their doctor to see if a (PARP inhibitor) is an option for them,” Westin says. “They also must understand that (PARP inhibitors) can’t benefit every single patient that has ovarian cancer, and this is why clinical trials are critical.”