PARP Inhibitor Improves Outcomes in Patients with Ovarian Cancer

A PARP inhibitor significantly improved the primary endpoint of progression-free survival compared with placebo in platinum-sensitive recurrent ovarian cancer, meeting its primary endpoint.

The phase 3 ENGOT-OV16/NOVA trial enrolled 553 patients to evaluate the safety and efficacy of the niraparib as maintenance therapy in individuals with recurrent ovarian cancer who respond to platinum-based chemotherapy. Participants were assigned to cohorts by BRCA mutation status, randomized 2:1 to receive niraparib 300-mg or placebo once daily.

Of the 553 enrolled patients, 203 had the germline BRCA mutation and 350 did not. The findings were published in the New England Journal of Medicine (NEJM), and presented at the ESMO 2016 Congress in Copenhagen.

“There are limited treatment options in recurrent ovarian cancer,” said lead study author Mansoor Raza Mirza. “Cumulative toxicity with platinum-based chemotherapy and lack of additional benefit limits its use. We then pause treatment until the next relapse and start combination chemotherapy.

“The current options for maintenance therapy in the EU are bevacizumab, which can only be given once and improves progression-free survival by just a few months, and the PARP inhibitor olaparib, which is only approved in patients with a germline BRCA mutation (about 10-15% of ovarian cancer patients). No maintenance therapy is approved outside the EU.”

The results of the study found that niraparib significantly improved the primary endpoint of progression-free survival compared with placebo in both cohorts, and in all subgroups.

Median progression-free survival with niraparib was 21.0 months, compared with 5.5 months with placebo in the germline BRCA mutation arm (HR 0.27, 95% CI 0.173 to 0.410, p<0.0001); 9.3 months vs 3.9 months, respectively, in the non-germline BRCA mutation group (HR 0.45, 95% CI 0338 to 0.607, p<.0001); and 12.9 versus 3.8 months in a subgroup of the non-mutation cohort who had homologous recombination DNA repair deficiencies (HR 0.38, 95% CI 0.243 to 0.586, p<0.0001).

Niraparib-induced grade 3/4 adverse events occurred in more than 10% of participants, and included thrombocytopenia, anemia, and neutropenia. These were resolved after dose adjustments, which allowed patients to continue treatment.

Patient-reported outcomes were found to be similar between niraparib and placebo. However, patients in the niraparib arm maintained symptom control and had a quality of life comparable to patients who received placebo.

“This is a breakthrough for patients with ovarian cancer,” Mirza said. “We have never seen such large benefits in progression-free survival in recurrent ovarian cancer. Niraparib significantly improved all endpoints across a broad patient population representing 70% of all ovarian cancer patients. These landmark results could change the way we treat this disease. Once it is approved by the regulatory authorities, I’ll consider niraparib for all my patients with recurrent ovarian cancer who respond to platinum regardless of BRCA status.”

Additionally, significant improvement in all secondary endpoints was also seen. Compared with placebo, researchers found that niraparib significantly prolonged the second progression-free survival, time to first subsequent treatment, and chemotherapy-free interval in the mutation and mutation-free groups, and in the HRD subgroup, the study found.

“This study more than doubles the population of patients who benefit from a PARP inhibitor,” said researcher Andrés Poveda. “Personalized medicine has arrived in high grade serous ovarian cancer. This was the first trial to use HRD to select patients for treatment and showed that it is a useful strategy. We also know that PARP inhibitors benefit patients with BRCA mutations.

“Future studies are needed to unravel which patients with HRD are not responders to PARP inhibitors and why, and which patients are long responders and why. We also need to know if there are other non-HRD factors, such a cyclin E positivity, that predict which patients will respond to treatment.”