PARP Inhibitors — Why There Is So Much Hope

The relatively new class of ovarian cancer drugs called PARP inhibitors, which so far includes olaparib, rucaparib, and niraparib, is giving women—especially those with specific tumor makeups—an exciting sense of hope.

The Food and Drug Administration has approved niraparib (brand name Zejula) for almost all women, regardless of whether they have the BRCA mutation, as part of an initial course of treatment, or what’s called front-line treatment. The American Society of Clinical Oncology (ASCO) guidelines recommend 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.

“For the first time in the history of this field, and certainly for the first time for me, we’re actually using the ‘C’ word,” says Dr. Michael Birrer, senior scientist of the O’Neal Comprehensive Cancer Center at University of Alabama at Birmingham. “We’re actually thinking maybe we’ve cured some of these patients—that’s how exciting it is.”

This type of drug may be used at several points along the treatment journey, including:

• As part of front-line (or initial) treatment
• During the maintenance therapy phase
• After cancer has recurred

When to use PARP inhibitors depends a lot on a woman’s individual disease and how she responds to treatment.

How PARP Inhibitors Work

Poly ADP ribose polymerase (PARP) inhibitor drugs work by preventing cancer cells that have been damaged—often during the course of chemotherapy treatment—from naturally healing. To accomplish this, and, in turn, effectively kill the cancer cell, the PARP-inhibitor drug blocks the necessary mechanism of repair, the PARP enzyme, which the cancer cell requires to fix single-strand breaks in its DNA.

PARPs for Newly-Diagnosed Ovarian Cancer

The PARP inhibitor Zejula has been approved by the FDA for all women with newly-diagnosed ovarian cancer irrespective of whether the woman’s cancer cells have a high degree of homologous recombination deficiency (HRD). The drug is used after successful treatment with a platinum-based chemotherapy, the mainstay chemotherapy for ovarian cancer.

The PARP inhibitor Lynparza (olaparib) is approved for women with newly diagnosed ovarian cancer who have 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.

PARPs and HRD

The differing approvals, Dr. Birrer explains, has to do with whether a woman’s cancer cells have a high degree of a characteristic called “homologous recombination deficiency” — which can come hand in hand with a BRCA mutation. Homologous recombination-deficient (HRD) cells lack the ability to accomplish a specific type of DNA repair pathway on their own, which, in turn, makes them much more sensitive and responsive to PARP inhibitors.

“Who should get a PARP inhibitor is the fundamental question,” Dr. Birrer says, adding that, for many women diagnosed with ovarian cancer, the “when” is an equally pressing question.

PARPs for Maintenance

Because the drugs work by blocking damaged cells from healing, they’re usually used in the “maintenance” period of treatment, after a woman has already undergone chemotherapy and possibly surgery. When used as maintenance therapy, PARP inhibitors can potentially prevent recurrence and prolong remission.

Having said that, the effect a PARP inhibitor may have on your specific ovarian cancer will vary greatly depending on the specific genetic makeup of your tumor—making it necessary for your doctor to carefully choose the right time to prescribe one of these drugs.

“When a PARP is used would relate a lot to the characteristics of that specific tumor,” Dr. Birrer says.

PARPs for Women With BRCA Mutations

For some women, particularly those who carry a BRCA gene mutation like BRCA1 or BRCA2, PARP inhibitors may be used early on during treatment, perhaps directly after initial surgery or chemotherapy. For other women, the drugs might be prescribed down the line, after multiple rounds of chemotherapy, surgery, or other means of treatment.

PARPs for Cancer 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.

Who Benefits from PARP Inhibitors?

If your doctor does not bring up PARP inhibitors early-on during the course of your treatment, you should absolutely ask. Having this conversation could be vital to your long-term and progression-free survival.

With the promising outcomes for those treated with PARP inhibitors, which Dr. Birrer points out has shown a “flattening curve,” indicating progression-free survival in the median population of ovarian cancer patients, doctors are recognizing a huge curative potential for these new drugs. It is important to note that the “flattening curve” is seen mostly in the upfront setting as maintenance therapy.

Education and transparent provider-patient discussions about PARP-inhibitor eligibility, as well as the side effects and high prices associated with these drugs, can make a dramatic difference in treatment results. No two cancers are the same, and every patient has a different level of tolerance for side effects and financial burdens. So, although PARP inhibitors are giving many women with ovarian cancer a tremendous amount of hope, they shouldn’t be universally prescribed.

Learn more about the side effects of PARP inhibitors here.

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