PARP Inhibitors: Recent Approvals

Who Should Use PARP Inhibitors?

Weighing the risks and benefits of PARP inhibitors is a balancing act that is determined by doctors and patients together. Others add that the side effects, while severe, are relatively mild when compared with other kinds of chemotherapy.

Originally prescribed after a cancer has come back in women with BRCA mutations, PARP inhibitors can now be offered after initial surgery and chemotherapy, and continued for months, or even years, as long as the side effects are tolerated. The option to offer these drugs to women even after their first course of a different treatment increases the number of patients who can benefit.

For newly-diagnosed patients, Zejula (niraparib) has been approved by the FDA for all women with newly-diagnosed ovarian cancer regardless of HRD or BRCA status. The drug is used after successful treatment with a platinum-based chemotherapy, the mainstay chemotherapy for ovarian cancer.

In a study called PRIMA, using niraparib showed an improved, progression-free survival advantage of five to six months. The niraparib approval is not limited to women with a BRCA mutation, in contrast to FDA approvals for other PARP inhibitors. Niraparib is approved for all women after a response to chemotherapy, regardless of the presence of a BRCA mutation.

Lynparza 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.

PARP Inhibitors can also be used to help suppress recurrence of the disease, possibly extending life expectancy by four or five months. Again, the decision making process here will vary greatly among women, and will likely include the potential benefit the drugs can have (based again on genetics and molecular information unique to you).

For women with ovarian cancer who have had a recurrence and responded to platinum-based chemotherapy, Lynparza, Zejula and Rubraca are FDA approved for use as a maintenance therapy, regardless of whether a woman has a BRCA mutation or HRD (homologous recombination deficiency). 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 American Society of Clinical Oncology (ASCO) also has 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 either as first-line therapy, maintenance therapy, or both  significantly extends the length of time patients are cancer-free or their cancer worsens.

In patients with advanced cancer, who have a high chance of their cancer returning, PARP inhibitors may reduce the risk of recurrence. They are most effective for patients who have a BRCA1 or BRCA2 gene mutation, and for those who have fast-growing, high-grade disease. Recent studies suggest that niraparib in particular may be an appropriate therapy for all ovarian cancer patients, regardless of whether they carry a BRCA mutation.

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:

1.  Women with a BRCA1 or BRCA2 mutation: “Patients who have BRCA 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.
2.  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.

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 such as reduced blood cell and platelet counts.

Your doctor, patient education, and counseling can help you make decisions about cancer treatment, including PARP inhibitors like niraparib. Learning more about the drugs can help you understand your individual risks and benefits, given your own genetic profile and the disease you’re dealing with.

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