PARP Inhibition Enhanced Through Combination in Ovarian Cancer

Mansoor Raza Mirza, MD

The combination of a PARP inhibitor and a VEGF inhibitor is a logical strategy in the treatment of relapsed patients with platinum-sensitive epithelial ovarian cancer, according to Mansoor Raza Mirza, MD.

In the phase I stage of the phase I/II ENGOT-OV24/AVANOVA1 study of the combination of niraparib (Zejula) plus bevacizumab (Avastin), the objective response rate was 45%. Of the 11 evaluable patients, 1 achieved a complete response, 4 reached a partial response, and 5 had stable disease.

The recommended phase II dose is bevacizumab at 15 mg/kg on day 1 plus 300 mg of oral niraparib once daily. The phase II part of the trial is currently being conducted in 94 patients with platinum-sensitive ovarian cancer.

OncLive: Please discuss the combination of niraparib and bevacizumab.

In an interview with OncLive, Mirza, who is the chief oncologist at Copenhagen University Hospital and lead author of the ENGOT-OV24/AVANOVA1 trial, discussed the initial findings and next steps for the promising niraparib plus bevacizumab combination in ovarian cancer, as well as overall advances with PARP inhibitors in the field.Mirza: Previously, we presented the results of the phase III trial with niraparib. It showed tremendous benefit for patients who received niraparib versus placebo, and it is already labeled by the FDA for treatment in the maintenance setting. The next step will be to further improve the treatment of our patients, but the question is, “Do these patients have to receive a cytotoxic chemotherapy every time they relapse?”

One of the biologically obvious ways to answer this question was to combine the PARP inhibitor niraparib to a VEGF inhibitor—bevacizumab in this case—so that was the trial we started with. We presented the phase I data of the 12 patients who tolerated it very well, and we reached the optimal dose level; we needed 300 mg of niraparib and 15 mg/kg of bevacizumab. Therefore, the combination was well tolerated, we still have patients who are on treatment beyond 2 years, and the response rates are very encouraging. There is a very small group of patients who received 50% response rates and a median PFS of 49 weeks. This is very comparable with patients who receive platinum-based combination therapy.

Can you discuss some of the biologic rationale for why this combination might be ideal?

Is it too early to see differences between BRCA-positive and BRCA-negative patients?

Looking at the larger phase III trial of niraparib alone, were there any differences between these 2 groups?

This is a very active combination, and right now we are performing part 2 of this study—the randomized trial comparing niraparib versus niraparib plus bevacizumab. I am really curious to see the results of that phase II randomized study and if we have a very effective regimen for our patients so they will not progress for a long time. The biological rationale for combining PARP with VEGF is probably because VEGF inhibitors cause hypoxia, and hypoxia triggers the homologous recombination deficiency—meaning that PARP should work better. The "cold" tumor becomes "hot" for the PARP inhibitor. There are preclinical and clinical data which show that the combination is much superior to a single-agent VEGF.It is too early to tell about the difference. We only have 12 patients in the phase I trial, so we need to wait about another year where we can have more than 100 patients. Therefore, I cannot answer that question today, but it will be possible in the near future when we have phase II results.Clearly, the BRCA-mutant population is the group that benefits most from any PARP inhibitor. We saw that in the trial, which showed that the hazard ratio was extremely significant, with half of the patients active on the drug without progression at the data cutoff.

There was a study presented at the 2017 ESMO Congress looking at the quality of life in the phase III trial of niraparib. Could you comment on that?

Now that there are so many PARP inhibitors available, what is your advice to clinicians who are choosing among them?

Having said that, patients who are BRCA wild-type are also having a clear clinical benefit, and we performed homologous repair deficiency (HRD) testing to find out about BRCA-ness. The hazard ratio was again very impressive at 0.38. Even in BRCA wild-type, HRD-negative disease, the hazard ratio was 0.58. Unfortunately, the HRD test has not been good enough to split the patients between responders and nonresponders; that is why it is important to treat all of the patients with PARP. But clearly, the BRCA-positive patients are the ones who respond most.It assures us that patients do not have a negative impact of receiving once daily niraparib for potentially many years to come. They can stay home and go about their daily life while on maintenance therapy. This is a very important message to tell your patients when you are putting them on treatment. We have 3 front-runners in PARP inhibitors: olaparib (Lynparza), niraparib, and rucaparib (Rubraca). When it comes to the BRCA-mutant population, we have level 1 evidence for all 3 PARP inhibitors that the given agent is efficacious. When it comes to the BRCA wild-type population, 2 of the drugs—niraparib and rucaparib—have been used in phase III trials and have shown true benefit. However, the FDA approved olaparib in BRCA wild-type patients, so that means we now have 3 drugs in that population.

What is the next step in this field?

[Regarding efficacy] all of the PARP inhibitors mentioned are equal; regarding toxicity, there is a little bit of difference but all of the agents are well tolerated. I would think about the socioeconomic factors and how much it is going to cost our taxpayers. In Denmark, no patients pay for these treatments—our taxes do. Therefore, what will likely happen is that the government will bargain for the cheapest of the 3. A lot is happening with PARP inhibitors. [There are] combinations with VEGF inhibitors, combinations with immunotherapies, and we now have trials looking at upfront therapy that are currently completing recruitment. All of these trials are going to be read out in the near future, meaning that PARP may move out of the relapsed setting. If these studies show that a patient on a PARP inhibitor will not relapse, that would be great.

Mirza MR, Wang J, Mau-Sorensen M, et al. A phase 1 study to evaluate the safety and tolerability of bevacizumab-niraparib combination therapy and determine the recommended phase 2 dose (RP2D) in women with platinum-sensitive epithelial ovarian cancer (ENGOT-OV24/AVANOVA1). In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract 953P.