Pairing PARP Inhibitors With Other Drug Types the Next Frontier for BRCA-Mutated Ovarian Cancers

The idea of interfering with DNA’s self-repair capabilities has been at the heart of this decade’s progress in treating ovarian cancer, and combining the PARP inhibitors that accomplish that with other types of therapies will be the focus of treatment in the decade to come.

Those ideas were fleshed out during a June 10 talk by Elise C. Kohn, M.D., head of gynecologic cancer therapeutics in the Cancer Therapy Evaluation Program within the Division of Cancer Therapy and Diagnostics at the National Cancer Institute. She gave the talk in Orlando, Florida, during the 10^th Annual Conference of the patient advocacy group Facing Our Risk of Cancer Empowered (FORCE). FORCE’s mission is to improve the lives of individuals and families affected by hereditary breast, ovarian and related cancers.

Benefiting From PARP Inhibitors

Between the 1990s and today, several classes of treatments have been approved for use in ovarian cancer: platinum-based chemotherapies, taxane chemotherapies and then anti-angiogenesis drugs, like Avastin (bevacizumab), which interfere with the growth of the blood vessels that feed tumors. Since those agents, “PARP inhibitors are the first big things,” said Kohn, who credited the FORCE community for helping to push development of the drugs.

Lynparza (olaparib) was the first PARP inhibitor approved to treat ovarian cancer, in 2014, and Rubraca (rucaparib) followed in late 2016; both are used after treatment with chemotherapy. This year brought the approval of Zejula (niraparib) as a maintenance drug after chemotherapy, and now Lynparza, too, is being considered for use in maintaining response to chemotherapy. All the drugs except Zejula are approved specifically for BRCA-positive women.

Kohn explained why PARP inhibitors are appropriate for women with mutations in the BRCA1 and BRCA2 genes. These mutations cause susceptibility to breast and ovarian cancers by allowing problems to occur with the DNA repair process. Once DNA mistakes have ignited disease, these cancers depend on the PARP enzyme manufactured by the body to facilitate DNA repair. Medications that inhibit PARP get in the way of DNA repair and can lead to cancer cell death.

The drugs work particularly well with chemotherapy, since cytotoxic drugs damage DNA and PARP inhibitors prevent repair. “It’s like breaking your leg and never getting it fixed,” Kohn said.

She cited two studies that support the idea of using chemotherapy followed by a PARP inhibitor to help maintain response.

One, the NOVA trial, showed that Zejula improved progression-free survival (PFS) in patients with ovarian cancer following platinum-based chemotherapy. The median PFS was 21 months in BRCA-associated cancers versus 5.5 months with placebo. The SOLO2 trial, conducted only in women who were BRCA mutation—positive, found that maintenance Lynparza sparked a 70 percent improvement in PFS compared with placebo; the median PFS was 30.2 months versus 5.5 months for the control group.

A new trial is testing Lynparza as a maintenance drug in the front-line setting in women with ovarian cancer and a BRCA mutation, Kohn said. None of the studies are mature enough to offer information on whether overall survival was improved.

PARP inhibitor side effects can include nausea, anemia, fatigue, headaches and white blood cell and platelet imbalances.

In studying PARP inhibitors in BRCA-associated cancers, scientists have learned some principles that might apply to the treatment of women who don’t have the mutation. They’ve found that some ovarian cancers, while not associated with BRCA mutations, have patterns of behavior that are similar to those of BRCA-related tumors. For instance, patients with these tumors, which are deemed HRD-positive, did not respond as well as BRCA-positive patients to Zejula in the NOVA trial, but they fared better than patients who were neither BRCA mutation- nor HRD-positive.

Whether the HRD classification will prove meaningful in treatment, however, has not been confirmed. One reason is that, unlike BRCA-associated tumors, those that test HRD-positive may lose those characteristics as they change and evolve during treatment, Kohn said.

Exploring Drug Combinations

Unfortunately, PARP inhibitors don’t work for all patients with ovarian cancer, so researchers are exploring whether combining them with other drugs might lead to broader efficacy.

Kohn’s team studied carboplatin, a platinum-based chemotherapy, in combination with Lynparza and found that “women with germline mutations responded phenomenally and longer,” and, in general, that “women with ovarian cancer were more likely to respond than expected.”

A trial that looked at Lynparza paired with the experimental cediranib — an angiogenesis drug — found that their mechanisms are synergistic. “In women with platinum-sensitive ovarian cancer, many with BRCA mutations, the combination was scary good,” Kohn said, although non-BRCA mutation carriers experienced the most benefit. Now, in the NRG GY-004 study, the team is testing that concept in BRCA mutation—positive women with high-grade serous ovarian cancers, who will take platinum-based chemotherapy, Lynparza or Lynparza plus cediranib.

In a second, related phase 2/3 study, NRG GY-005, the team is studying the responses of women with platinum-resistant ovarian cancers — some of them BRCA mutation—positive — by administering single-agent chemotherapy versus Lynparza, cediranib or a combination of the two.

Studying Newer Drugs

Additional techniques are being studied as potential therapies for ovarian cancer.

The enzyme WEE1 is involved in cell division, and the experimental drug AZ1775, which inhibits that enzyme, is being studied in combination with carboplatin and taxol chemotherapies, Kohn said.

The drug prexasertib inhibits the activity of the proteins made by mutated CHEK1 and CHEK2 genes, and this interference stops cancer cells from dividing. In a study presented at the European Society for Medical Oncology 2016 Congress, results were dramatic in women with high-grade serous or germline mutation-unknown ovarian cancers, Kohn said.

The drug triapine potently blocks ribonucleotide reductase (RNR), which ovarian and breast cancers use to make new DNA or repair DNA injury. The strategy works very well in combination with radiation, Kohn said.

While the immune system tends not to notice cancers caused by germline mutations, adding abnormalities to cells with chemotherapy and PARP inhibitors may wake it up, Kohn said. As a result, she said, combinations of the immunotherapy drug Imfinzi (durvalumab) with Lynparza or cediranib may prove valuable.