We have never seen such large benefits in progression-free survival in recurrent ovarian cancer. These landmark results could change the way we treat this disease.

— Mansoor R. Mirza, MD

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A landmark study showed that the investigational PARP (poly ADP-ribose polymerase) 1/2 inhibitor niraparib, when used as maintenance therapy, significantly improves the outcome of platinum-sensitive recurrent ovarian cancer. Specifically, niraparib significantly prolonged progression-free survival in patients with germline BRCA–mutated tumors, non–germline BRCA–mutated tumors, as well as tumors with homologous recombination deficiency. Niraparib was granted Fast Track status by the U.S. Food and Drug Administration in September 2016.

“This is a breakthrough for patients with ovarian cancer. 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 about 70% of all ovarian cancer patients. These landmark results could change the way we treat this disease,” said lead author Mansoor R. Mirza, MD, of the Rigshospitalet–Copenhagen University Hospital, ­Denmark.

“A much higher percentage of patients will benefit from niraparib compared with olaparib [Lynparza], which is approved for patients with BRCA mutation, which represents only about 20% of patients with ovarian cancer. In this trial, niraparib has not shown any detrimental effect on overall survival (hazard ratio [HR] = 0.74, < 20% events). This is a huge benefit in the whole study population—those with the BRCA mutations and those without,” Dr. Mirza declared.

“This is the first phase III trial of a PARP inhibitor in recurrent ovarian cancer,” he told listeners. Dr. Mirza presented the results of the European Network of Gynaecological Oncology Trial groups (ENGOT)-OV16/NOVA study at the 2016 ESMO (European Society for Medical Oncology) Congress.¹ The study was simultaneously published in The New England Journal of Medicine.²

Patients with ovarian cancer who relapse are typically treated with six courses of chemotherapy and then wait until the next relapse for another round of therapy. The intervals between relapses get shorter and shorter, and patients die of their disease. The rationale for maintenance therapy is to extend the interval from one round of therapy to the next with a less toxic treatment, Dr. Mirza explained.

Study Details

The study was conducted in 15 countries and enrolled 553 patients with platinum-sensitive ovarian cancer. “Our hypothesis was that a PARP 1/2 inhibitor will provide a clinical benefit to all patients with platinum-sensitive ovarian cancer, regardless of BRCA mutation status,” Dr. Mirza explained.

Patients who relapsed and then responded to standard-of-care treatment with about six courses of chemotherapy were eligible for the trial. Patients were tested upfront for BRCA status and classified as either germline BRCA–mutated ovarian cancer (n = 203) and non–germline BRCA-mutated ovarian cancer (n = 350).

Once the response to platinum-based therapy was determined, 553 responding patients were randomized in a 2:1 ratio to receive niraparib at 300 mg/d or placebo and treated until disease progression. There were no baseline imbalances in demographic or clinical factors between BRCA-mutated patients and non–germline BRCA-mutated patients.

Primary Endpoint Met

The study met the primary endpoint of significant improvement in progression-free survival for niraparib vs placebo. There was a 73% improvement in progression-free survival in the germline BRCA group: median progression-free survival was 21 months vs 5.5 months, respectively (HR = 0.27, P < .0001). In non–germline BRCA patients, niraparib improved progression-free survival by 55% over placebo: median progression-free survival was 9.3 months vs 3.9 months, respectively (HR = 0.45, P < .0001). In a subgroup of the nonmutated BRCA group with homologous recombination DNA repair deficiencies, niraparib also significantly improved progression-free survival to 12.9 months from 3.8 months with placebo (HR = 0.38, P < .0001), representing a 62% improvement. Although it was an exploratory endpoint, niraparib significantly improved progression-free survival in homologous recombination deficiency–negative patients, with a 42% reduction in risk of disease progression (HR = 0.58), he said.

“We thought the homologous recombination deficiency test would discriminate between responders and nonresponders, but that didn’t happen. These results suggest you have to treat both homologous recombination deficiency–negative and –positive patients with niraparib, because all patients have a benefit,” Dr. Mirza stated.

Toxicity

The most common adverse events seen with niraparib were hematologic laboratory abnormalities and fatigue, which are common with PARP inhibitors. “The majority of patients remained on treatment until disease progression, and one-third were still on treatment at the 18-month data cutoff point, with no detrimental effect on quality of life according to patient-reported outcomes. The efficacy of treatment was durable,” revealed Dr. Mirza.

Adverse events were well managed by dose interruptions or reductions. “Most patients can take their niraparib tablet at home and go to work, continuing with their lives,” he added.

“These landmark results warrant niraparib maintenance treatment for the groups represented in the whole study population,” Dr. Mirza stated. Ongoing trials will evaluate niraparib as upfront therapy in platinum-sensitive patients. ■

Disclosure: The study was supported by Tesaro, the maker of niraparib. Dr. Mirza reported no potential conflicts of interest.

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). 2016 ESMO Congress. Abstract LBA3_PR. Presented October 8, 2016.

2. Mirza MR, Monk BJ, Herrstedt J, et al: Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. October 7, 2016 (early release online).