Niraparib effective in BRCA-positive and BRCA-negative ovarian cancer

The ENGOT-OV16/NOVA trial found that in patients who had the germline BRCA mutation, niraparib showed a 73% improvement in PFS, while those without the BRCA mutation, still showed a 55% improvement. “These landmark results could change the way we treat this disease,” reported Dr Mansoor Raza Mirza, Chief Oncologist, Rigshospitalet, Copenhagen University Hospital, Denmark, and lead author of the study.

“This is a breakthrough for patients with ovarian cancer. We have never seen such large benefits in progression-free survival in recurrent ovarian cancer.” Dr Mansoor Raza Mirza, Chief Oncologist, Rigshospitalet, Copenhagen University Hospital, Denmark

Niraparib showed efficacy in all patient subgroups of the trial: BRCA positive, BRCA negative and homologous recombination DNA repair deficiencies (HRD) status, representing 70% of all ovarian cancer patients.
“This is a breakthrough for patients with ovarian cancer,” added Dr Mirza. “We have never seen such large benefits in progression-free survival in recurrent ovarian cancer.”
Dr Mirza explained the importance and urgency of finding an effective maintenance therapy for these patients. Patients with ovarian cancer who relapse typically get six courses of chemotherapy, because the toxicity means they pause therapy and re-start on relapse. “The treatment intervals get shorter and shorter and eventually all patients die of their disease. There is a real need to extend the time from one therapy to another with less toxicity.”

Ovarian cancer is a genetically heterogenous disease with BRCA and non-BRCA mutations that can affect the DNA repair mechanisms involved. “PARP inhibitors can hinder cancer cell repair and in this way control the disease. It is a highly targeted mechanism of action,” Dr Mirza said.

Current options for maintenance therapy in the EU are limited. Bevacizumab, can only be given once and improves PFS by a few months only. The PARP inhibitor olaparib is only approved in patients with a germline BRCA mutation, covering only 10-15% of ovarian cancer patients. No maintenance therapy is approved outside the EU.

The phase III trial, that was performed in collaboration with European Network of Gynaecological Oncology Trial groups (ENGOT), hypothesised that all patients with platinum-sensitive recurrent ovarian cancer would experience clinical benefit regardless of BRCA-mutational status and HRD status.

Typically, when patients relapse they get six courses of standard of care therapy, and at this point patients were invited into the trial. After a germline BRCA test, patients were grouped into two cohorts according to BRCA-mutation status, and were randomised 2:1 to receive niraparib 300 mg or placebo once daily. A total of 203 patients had the germline BRCA mutation, and 350 did not. In the non-BRCA mutation group, patients were sub-divided into HRD positive and HRD negative. Treatment was continued until disease progression.

Niraparib significantly improved the primary endpoint of PFS compared to placebo in both cohorts, as well as in all subgroups.
In the germline BRCA mutation group, median PFS improved with a hazard ratio of 0.27 (p<0.0001), at 21.0 versus 5.5 months in niraparib and placebo respectively. In the non-BRCA mutation group, PFS was 9.3 months versus 3.9 months (HR 0.45, p<0.0001) respectively. In the HRD positive subgroup the PFS was 12.9 versus 3.8 months (HR 0.38 p<0.0001).
“The Kaplan-Meier curves separate all the way, nicely flattening at the end with half the patients in active treatment at 18 months,” said Dr Mirza. “This shows the durability of the treatment efficacy all along.”

HRD negative showed improvement

In the non-BRCA mutation group, those patients who were HRD negative showed a statistically significant improvement in PFS with durable efficacy and hazard ratio of 0.58, or a 42% reduction in risk of relapse. “One fifth of these patients are still on active treatment after data cut off.”
Grade 3 and 4 adverse events were experienced by 10% of patients on niraparib. Of these, 28% had thrombocytopenia, 25% had anaemia, and 11% had neutropenia, but these were resolved with dose adjustments and patients continued treatment. “Most patients were kept on trial and did not discontinue due to toxicity. For thrombocytopenia, 3% discontinued, otherwise they remained on treatment until disease progression.”
Patient-reported outcomes were similar with niraparib and placebo, with similar symptom control and comparable quality of life. “This means patients can stay home and come in once a month to receive their tablets.”

Based on Mirza M, Monk B 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) (LBA3_PR). Presented on Saturday 8 October 2016

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