PARP Inhibitor Explosion Continues in Ovarian Cancer

Ursula A. Matulonis, MD

At the close of 2016, the FDA approved the PARP inhibitor rucaparib (Rubraca) for the treatment of patients with BRCA-positive advanced ovarian cancer who have received at least 2 prior lines of chemotherapy. Rucaparib was the second PARP inhibitor approved in the field, following the 2014 approval of olaparib (Lynparza) for the treatment of women with BRCA-positive advanced ovarian cancer following 3 or more prior lines of chemotherapy.

These agents were recently joined by the PARP inhibitor niraparib (Zejula), which was just approved in March for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, regardless of BRCA mutation status. This approval was based on the phase III NOVA trial, where niraparib reduced the risk of progression or death by 74% compared with placebo in patients with germline BRCA-positive, platinum-sensitive, recurrent ovarian cancer.^1,2

Shortly thereafter, olaparib was granted a priority review as a maintenance therapy in ovarian cancer. In the phase III SOLO-2 trial, maintenance olaparib showed a 70% reduction in the risk of progression or death versus placebo in patients with platinum-sensitive, relapsed, BRCA-mutant ovarian cancer.

“It is exciting in that there are now options for the patients, but also that more research is being done on ovarian cancer and more drugs are being approved,” said Ursula A. Matulonis, MD, a senior author on the NOVA trial, and director, Gynecologic Oncology, Dana-Farber Cancer Institute, professor of Medicine, Harvard Medical School.

Agents with broader labels, such as niraparib, are a particularly meaningful advancement, adds Matulonis. Niraparib—unlike olaparib and rucaparib—does not require patients to have a BRCA mutation, allowing for a wider range of women to be treated.

In an interview with OncLive, Matulonis discussed the latest regulatory advances with PARP inhibitors and their continued growth in the treatment of patients with ovarian cancer.

OncLive: Can you provide an overview of the data that led to the approval of niraparib?

Matulonis: This was data from a phase III trial that was published in The New England Journal of Medicine in late 2016 and was presented at EMSO in the fall of 2016. It was a randomized trial of 500 women with high-grade ovarian cancer who had recurrent cancer and were in receipt of platinum-based chemotherapy. Eligibility included many different things, but mainly, they had to be sensitive—meaning the cancer needed to be sensitive to the current platinum based chemotherapy, which would mean the patient was having a reduction in her CA125 and tumor burden. Often though, these patients had to have cancer that was sensitive to the previous platinum, called the penultimate platinum—so it was the second-to-last platinum. There is a theme here—all of these patients had to have platinum-sensitive cancers.

They were then randomized 2:1 to either niraparib or placebo and underwent germline BRCA tests, then put into 2 groups—germline BRCA positive or germline BRCA negative. Then the germline BRCA negative group underwent retrospective homologous recombination deficiency (HRD) testing on the cancer. And this was shown in all of these different groups—germline BRCA, non-germline BRCA, and HRD negative—all of the groups showed a benefit of receiving niraparib as compared to placebo.

Simply put, when the patients finished chemotherapy, they were then randomized to niraparib or placebo. Niraparib was not added to chemotherapy, but was used more as a maintenance therapy, much like tamoxifen is used after initial breast cancer treatment.

Niraparib was approved with a broad label, not requiring a BRCA mutation. Do you think that signifies that it will be widely used?

I do think that niraparib is going to be widely used because of the broad label. But, why is that significant? Because it broadens the applicability of a PARP inhibitor to non-BRCA cancers, allowing more women to be candidates for this trial—it broadens the patient population, as well. It also gives patients more choices about their treatment.

This is exciting because ovarian cancer is unlike other cancers, where you read about FDA approvals nearly every week. This is really only the third drug that has been approved for ovarian cancer since 2006. That’s 3 drugs in 11 years.

What lead to the priority review of olaparib in the maintenance setting?

The SOLO2 trial was done as a second trial for Study 19. Study 19 was published in The New England Journal of Medicine a number of years ago, and was the first trial to show the benefit of a maintenance PARP inhibitor post platinum-based chemotherapy. At that point, in 2014, the decision to go for olaparib maintenance in a BRCA-mutated group was made based upon that data.

If you follow PARP inhibitor history, you would have stumbled upon the Oncologic Drugs Advisory Committee (ODAC) meeting from 2014, where we presented the olaparib data to the ODAC committee down at the FDA, and they voted it down. Then, the FDA made the decision based upon data from a certain trial published in the Journal of Clinical Oncology to kind of pick out olaparib and use it as a treatment for women with germline BRCA cancer, but only in those who had received 3 or more prior lines of chemotherapy. The FDA essentially said that there needed to be a confirmatory phase III study [to approved maintenance olaparib]. So, the confirmatory phase III trial was SOLO-2.

On the European side, the European Medicines Agency approved maintenance olaparib in patients with a BRCA-mutated cancer after chemotherapy. So, right now, there is a difference in what PARP inhibitor a patient will have access to depending on where they are. In the United States, you have olaparib and rucaparib as treatment, and niraparib as maintenance therapy. The niraparib maintenance label in the United States is broader than the olaparib maintenance label in Europe, extending beyond BRCA-mutated cancer.

SOLO2 is kind of what we saw in Study 19—that there was a benefit of the PARP inhibitors in BRCA-mutated ovarian cancer. But SOLO2 specifically looked at patients whose cancers have an underlying BRCA mutation. How is that going to change things? I do not know, but I do know that it is good because it provides more options for patients.

What is the significance of platinum sensitivity in this setting?

I think platinum sensitivity is a more subjective measurement. But, it is also a clinical characteristic of the tumor. You really distilled out a patient population whose cancers will be most sensitive to PARP inhibitors. High-grade cancers showing penultimate platinum sensitivity and then current platinum sensitivity. Those are the cancers that are going to have the most underlying defects in DNA repair, because of that characteristic of platinum sensitivity.

In the maintenance population, you are selecting the patients that are going to benefit most from a PARP inhibitor. When you think about the olaparib and rucaparib labels, that is more treatment. And it has been pretty consistently shown that the response to a PARP inhibitor is higher in patients that have platinum sensitive cancers, as well as in cancers that have been less heavily pretreated. That has been true of rucaparib, olaparib, and veliparib.

I think the clinical significance of platinum sensitivity is that, at least in one label now, it is what you are basing your decision to use a PARP inhibitor on. Although, the underlying BRCA mutation of olaparib and rucaparib is driving that label.

What would you like community oncologists to take away from the continued progress of PARP inhibitors in ovarian cancer?

They have to understand that these drugs are available; they have to understand the mechanisms of action and when they are appropriate to used based on the labels. I do think PARP inhibitors are going to be more widely used than just in ovarian cancer. We’re going to see them used in prostate cancer, breast cancer, and other tumors that have underlying DNA repair.

There is certainly a lot of excitement about immunotherapy, but I think there should also be a lot of excitement about PARP inhibitors as a new class of agents that explore the underlying DNA repair defects in certain cancers. We are just beginning to understand what cancers are going to respond best to single-agent PARP inhibitors, and we are getting that from ovarian cancer where the BRCA mutation is a major driver of response. But then, what is beyond the BRCA mutation? What else is in the cancer that is going to be able to predict for PARP inhibitor sensitivity? High-grade tumors, high-grade sensitivity, less heavily pretreated—those are the clinical characteristics that help you decide where PARP inhibitors can be best used in ovarian cancer.

We have not yet talked about PARP inhibitor combinations, PARP inhibitor plus immuno-oncology agents, PARP inhibitors plus antiangiogenic agents, PARP inhibitors plus other DNA-repair inhibiting agents. So, it really is an exciting new field in cancer in general, and it’s nice to know that ovarian cancer is really leading the way here.

References

1. Mirza MR, Monk BJ, Oza A, et al. A randomized, double-blind phase 3 trial of maintenance therapy with niraparib vs placebo in patients with platinum-sensitive recurrent ovarian cancer (ENGOT-OV16/NOVA trial). Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA3_PR.
2. Mirza MR, Monk B, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive recurrent ovarian cancer [published online October 8, 2016]. N Engl J Med. DOI: 10.1056/NEJMoa1611310.