How do PARP Inhibitors Treat Ovarian Cancer?

PARP inhibitors are an oral form of therapy, taken as a pill. These drugs have been shown to be particularly effective against ovarian cancer in women who carry certain genetic markers, including BRCA mutations, which are the most common gene mutations linked to ovarian cancer.

"These [patients] are who we initially determined the PARP inhibitors would work best on," says Dr. Engle. "Therefore, all ovarian cancer patients are now offered genetic testing to see if this is somethinga mutationthat they have potentially inherited from their family. And that's important, because we have actually figured out that ovarian cancer has the highest rate of inheritance of any cancer. Up to 25 percent of ovarian cancers can potentially be inherited from a gene from one of your parents."

These drugs work especially well in women with the BRCA mutation because they prevent the cancer cells from repairing damaged strands of DNA. The BRCA genes code for the production of proteins that are also involved in DNA repair. When those genes are defective, the cancer becomes even more susceptible to the effects of PARP inhibitors.

One PARP inhibitor, niraparib (brand name ZEJULA), is now approved for use in almost all women as maintenance therapy after you've had a response to chemotherapy to try and extend remission.  It should be noted that the potential benefit is more likely for women with the BRCA mutation and can be considerably less for women without these molecular characteristics. 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.

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.

How Are PARP Inhibitors Used? 

PARP inhibitors are used in two different waysas an initial treatment and as maintenance therapy.

In the past, PARP inhibitors were used as a second and third line of treatment in women with ovarian cancer, after surgery and chemotherapy. "We can use it in place of an IV chemotherapy, as all PARP inhibitors are oral tablets," says Dr. Engle.

More recently, researchers discovered that, in addition to treating ovarian cancer, PARP inhibitors were also effective when used in a maintenance setting, meaning they could help keep cancer from recurring. "The purpose of that is to maintain this progression-free survival status, meaning to keep that cancer away or to try and help prevent it from recurring so quickly," adds Dr. Engle.

Currently, three PARP inhibitors are FDA-approved for maintenance therapy in ovarian cancer. Depending on the genetic factors of the tumor and your own personal case, your doctor may recommend one of the following:

• Olaparib (Lynparza)
• Niraparib (Zejula)
• Rucaparib (Rubraca)

Common Side Effects

While studies show that women treated with PARP inhibitors have significantly improved survival times without disease progression. But these drugs, like all cancer drugs, do come with side effects. Some of these can include:

• Nausea
• Vomiting
• Upset stomach
• Fatigue

Whether or not you'll experience a specific side effect depends on what dosage you’re receiving and whether you're using the drug alone, or in combination with other therapies. If you do experience any side effects, be sure to communicate this with your doctor. They’ll be able to modify your treatment schedule to reduce side effects, which might include reducing the dosage, trying another PARP inhibitor, or discontinuing treatment for a brief period of time.

Ways to Manage Side Effects

No matter which PARP inhibitor protocol you've embarked on, doctors can modify your treatment schedule to reduce side effects. A few possibilities:

• Discontinue treatment for a brief time period
• Reduce the dose
• Transition to another PARP inhibitor to see if there's any improvement

In fact, navigating treatment with a PARP inhibitor is really no different from any other form of therapy. In every case, it's about getting the maximum benefit from treatment while weathering the fewest side effects.

Dr. Amanika Kumar of The Mayo Clinic who spoke to SurvivorNet, cautioned that women still need to speak with their doctor to evaluate the benefit of taking a PARP inhibitor to extend life, because there are very real side effects due to the toxicity of the drug. "Patients with HRD (homologous recombination deficiency) have a far better response than those without and those with BRCA mutations even more so. It is on us as clinicians to help patients understand the risks and benefits of treatment. Patients that have no mutation or HRD may choose not to go on maintenance (in fact I recommend they don't) because there is real toxicity to these meds."

As with all cancer-related treatment, don't hesitate to request counseling about the risks and benefits of PARP inhibitor treatment. Partnering with your health care team, educating yourself, and taking advantage of counseling can help you make informed decisions about your cancer treatment, including PARP inhibitors.

Dr. Engle is a gynecologic oncologist at Baptist Medical Group. 

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