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PARP Inhibition Enhanced Through Combination in Ovarian Cancer

Angelica Welch
Published: Friday, Jan 26, 2018

Mansoor Raza Mirza, MD
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.

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.

OncLive: Please discuss the combination of niraparib and bevacizumab.

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. 

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. 

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

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.

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

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.

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

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.

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