How Do PARP Inhibitors Work For Women With Ovarian Cancer?

There are currently three different types of PARP inhibitors available to women with ovarian cancer. The drugs, which are all taken by mouth, are slightly different, but they all work more or less the same way in that they prevent cancer cells from naturally repairing the DNA that’s been damaged during the course of ovarian cancer treatment.

PARP inhibitors specifically work by blocking a protein that helps cancer cells repair their damaged DNA. “The easiest way to think of it is that, in general, cancer cells are broken,” says Dr. Willmott. “So they’re like someone who’s walking around with a broken leg and needs crutches to help them get around. In other words, they have certain cellular machinery that’s not working like it should. So they’re relying on less perfect forms of repair, like their PARP enzymes, to help them keep walking. PARP inhibitors are like taking away the crutches of someone with a broken leg. And unfortunately, then they can’t walk any longer. But for a cancer cell, that’s a good thing — because we want the cancer cell to die.”

PARP inhibitors are available to almost all women, though women with BRCA gene mutations or who are HRD proficient may benefit the most from these drugs. However, the American Society of Clinical Oncology (ASCO) released new guidelines recommending PARP inhibitors be offered to women, with or without genetic mutations, who are newly diagnosed with stage III or IV ovarian cancer and have improved with chemotherapy.

PARP Inhibitors and Genetic Makeup

One of the key things to know about PARP inhibitors is that your genetic makeup and specific features of your cancer will have a significant impact on how effective these drugs may be. Experts tell SurvivorNet that every woman with ovarian cancer should get a genetic test to determine if they have a mutation called BRCA, because the mutation enables PARP inhibitors to function much more powerfully. Importantly, there is increasing data that even women without BRCA mutations can still derive some benefit from these drugs.

PARP inhibitors interrupt the process of single stranded DNA repair, an essential part of cell replication. Defects in DNA repair ultimately cause cell death. PARP inhibitors work best when there is a second error in DNA repair, such as that caused by a mutation in BRCA. BRCA is a critical player in homologous recombination, a highly effective double stranded DNA repair process. BRCA is not the only important part of homologous recombination, other genes are involved. The label homologous recombination deficient (HRD) indicates a tumor which has one of many possible errors in the double stranded DNA repair process of homologous recombination.

Newly Diagnosed Epithelial Ovarian Cancer

The PARP inhibitor Zejula (niraparib) has been approved by the FDA for all women with newly-diagnosed ovarian cancer irrespective of whether the tumor is HRD. The drug is used after successful treatment with a platinum-based chemotherapy, the mainstay chemotherapy for ovarian cancer.

Due to limited benefit in progression free survival seen in the absence of HRD, gynecologic oncologists differ on whether PARP inhibitors should be universally recommended in the “upfront maintenance setting.” Each patient should be made aware of risks and benefits to PARP inhibitor maintenance and decide with their oncologist what is the best treatment plan for them.

The PARP inhibitor Lynparza (olaparib) is approved for women newly diagnosed with ovarian cancer and with a germline or somatic mutation in BRCA1/2.

Lynparza is also approved in combination with Avastin (bevacizumab) for women with HRD.  Avastin is a blood vessel growth inhibitor, which works by starving the tumor of vital nutrients needed to grow.

Using PARPs to Treat Recurrence

Unfortunately, too often, ovarian cancer comes back.

For women with ovarian cancer who have had a recurrence and responded to platinum-based chemotherapy, Lynparza, Zejula and another PARP inhibitor called Rubraca (rucaparib) are FDA approved for use as a maintenance therapy, regardless of whether a woman has a BRCA mutation or HRD.

For some women who have had prior chemotherapy treatments, Rubraca, Zejula or Lynparza may also be options. These uses are based on factors such as number of prior therapies and BRCA mutation or HRD.

The different PARP inhibitors do have some varying side effects, which oncologists need to evaluate carefully. Some of these considerations are explained here.

Learn more about SurvivorNet's rigorous medical review process.