Do PARP Inhibitors Work & When Can Women With Ovarian Cancer Get Them?

Ovarian cancer treatment is complex and often includes a variety of therapeutic options. One therapy, PARP inhibitors, is increasingly showing promise in the fight against ovarian cancer.

“PARP inhibitors are a class of drugs that are taken orally,” says Dr. Heidi Gray, gynecologic oncologist at the Seattle Cancer Care Alliance. “Their basic mechanism is that they inhibit DNA repair.”

What does that really mean in the case of ovarian cancer? The drugs block the body’s natural DNA repair mechanisms so cancerous cells are unable to divide and thrive.

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.

The PARP Advantage

Treatment for ovarian cancer typically involves first-line treatment, usually a combination of surgery and chemotherapy. Since ovarian cancer cells can be stubborn, some doctors also recommend maintenance therapy to help prevent recurrence.

Recent studies suggest that using PARP inhibitors as maintenance therapy, significantly extends the length of time patients are cancer-free or their cancer worsens. The three PARP inhibitors currently approved for the treatment of ovarian cancer are:

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

Tailored Treatment

Not every ovarian cancer patient responds the same way to treatment with PARP inhibitors. Instead, how you respond to treatment depends on a variety of factors, including the extent of disease, your genetic or hereditary risk, and whether the tumor itself has a mutation that a PARP inhibitor can use as a target.

The two groups that seem to benefit the most:

• Women with a BRCA1 or BRCA2 mutation: “Patients who have BRCA one and BRCA two mutations are more susceptible to not being able to repair the DNA in the cancer cells, so the PARP inhibitors act as a sort of one-two hit in their ability to kill off the cancer cells,” Dr. Gray says.
• Women whose tumors express something called a homologous recombination deficiency profile (HRD): With HRD, there’s a switch in DNA that allows the cancer cell to continue to divide. When you have a deficiency in the homologous recombination, that makes it so that the cancer cells can’t repair themselves and are more vulnerable to PARP inhibitors.

“Patients who have BRCA mutations, or who have HR deficient tumors, should be counseled to consider maintenance therapy with a PARP inhibitor,” Dr. Gray says. Interestingly, studies suggest that all ovarian cancer patients, regardless of genetics may benefit from treatment with a PARP inhibitor.

Common Side Effects of PARP Inhibitors

Unfortunately, like all cancer therapies, PARP inhibitors come with side effects. Whether or not you’ll experience significant side effects from PARP inhibitors depends on several factors, including which PARP inhibitor you’re taking, what dose you’re ingesting, and whether you’re using it alone or in combination with other therapies.

Still, the side effects of most PARP inhibitor protocols include:

• Nausea
• Vomiting
• Stomach upset
• Fatigue

These side effects can be intolerable for some patients, but in almost every case, doctors can offer options to alleviate or even eliminate them. 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

Since PARP inhibitors disrupt how cells repair damaged DNA, killing off tumor cells and healthy cells simultaneously, the bone marrow and blood cells may take a hit. As a result, a subset of patients encounter side effects of PARP inhibitor treatment related to bone marrow suppression. Two of the most common:

• Reduced blood cells counts: Since bone marrow makes both red and white blood cells, PARP inhibitor treatment may cause a drop in these cell counts. Patients may notice fatigue, reduced immunity, and light-headedness.
• Reduced platelet counts: Platelets play a role in blood clotting, so low platelet counts can cause excessive bleeding, easy bruising, and blood in the urine or stool.

As with all cancer-related treatment, it will be important to incorporate counseling about the risks and benefits of PARP inhibitor maintenance, and help patients understand their individual likelihood of benefit given their cancer’s specific characteristics.

Quick Guide to Current PARP Eligibility & Uses 

Newly Diagnosed Ovarian Cancer:

1. 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.
2. 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.
3. The PARP inhibitor Lynparza (olaparib) is approved for women newly diagnosed with ovarian cancer and with a germline or somatic mutation in BRCA1/2.
4. 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:

1. 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.
2. 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.
3. The different PARP inhibitors do have some varying side effects, which oncologists need to evaluate carefully. Some of these considerations are explained here.

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