Among patients with platinum-sensitive, recurrent ovarian cancer, the median duration of progression-free survival was significantly longer among those receiving niraparib than among those receiving placebo, regardless of the presence or absence of [germline] BRCA mutations or homologous recombination deficiency status, with moderate bone marrow toxicity.

— Mansoor R. Mirza, MD, and colleagues

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In a phase III trial (ENGOT-OV16/NOVA) reported at the 2016 ESMO (European Society for Medical Oncology) Congress and in The New England Journal of Medicine by Mansoor R. ­Mirza, MD, of the Rigshospitalet–Copenhagen University Hospital, and colleagues, maintenance therapy with the PARP (poly ADP-ribose polymerase) 1/2 inhibitor niraparib significantly prolonged progression-free survival vs placebo in women with platinum-sensitive recurrent ovarian cancer.¹ The benefit of niraparib was observed irrespective of germline BRCA mutation status. (For more on this phase III trial by Dr. Mirza from the 2016 ESMO Congress, see the November 25, 2016, issue of The ASCO Post.)

Study Details

In this double-blind trial, 553 patients were enrolled at 107 sites in the European Network for Gynaecological Oncological Trial countries, the United States, Canada, and Hungary beginning in August 2013. All patients had exhibited sensitivity to platinum-based treatment and had received at least two regimens.

Patients were categorized according to the presence or absence of a germline BRCA mutation and the type of non–germline BRCA mutation and were randomized 2:1 to receive oral niraparib at 300 mg or placebo once daily. Among 203 patients in the germline BRCA cohort, 138 were randomized to niraparib and 65, to placebo; among 350 in the non–germline BRCA cohort, 234 were randomized to receive niraparib and 116, to placebo. The primary endpoint was progression-free survival in the intent-to-treat population.

Median age ranged from 57 to 63 years. Stage III or IV disease was present in 83% to 85% of patients in the germline BRCA cohort, and in 90% to 95% in the non–germline BRCA cohort; time to disease progression after the penultimate platinum therapy was ≥ 12 months in 60% in the in the germline BRCA cohort and 62% in the non–germline BRCA cohort; and 49% to 54% in the germline BRCA cohort and 33% to 34% in the non–germline BRCA cohort had received at least three previous lines of chemotherapy.

Improved Progression-Free Survival

Median duration of follow-up at data cutoff was 16.9 months in the intent-to-treat population, including 16.4 months in the germline BRCA cohort and 17.5 months in the non–germline BRCA cohort. For the niraparib vs placebo groups, median progression-free survival was 21.0 vs 5.5 months in the germline BRCA cohort (hazard ratio [HR] = 0.27, P < .001), 12.9 vs 3.8 months in the non–germline BRCA cohort among patients with tumors with homologous recombination deficiency (HR = 0.38, P < .001), and 9.3 vs 3.9 months in the entire non–germline BRCA cohort (HR = 0.45, P < .001). Hazard ratios favored niraparib in all examined subgroups and were significant for virtually all.

Prespecified exploratory analyses showed that median progression-free survival was 9.3 vs 3.7 months (HR = 0.38, P < .001) among patients with homologous recombination deficiency–positive tumors with wildtype BRCA and 20.9 vs 11.0 months (HR = 0.27, P = .02) among patients with homologous recombination deficiency–positive tumors and somatic BRCA mutation. Median progression-free survival was 6.9 vs 3.8 months (HR = 0.58, P = .02) among patients with homologous recombination deficiency–negative tumors.

The chemotherapy-free interval was significantly longer in the niraparib group in both germline BRCA (HR = 0.26, P < .001) and non–germline BRCA cohorts (HR = 0.50, P < .001), as was the time to first subsequent treatment (HR = 0.31, P < .001; HR = 0.55, P < .001). Data on progression-free survival were not mature but suggested benefit of niraparib in both cohorts (HR = 0.48, P = .006; HR = 0.69, P = .03). Overall survival data were not mature; during follow-up, death occurred in 16.1% of the niraparib group and 19.3% of the placebo group.

Adverse Events

Hematologic adverse events of any grade were more common with niraparib, including thrombocytopenia (61.3% vs 5.6%), anemia (50.1% vs 6.7%), and neutropenia (30.2% vs 6.1%). Grade 3 or 4 adverse events occurred in 74.1% of the niraparib group and 22.9% of the placebo group, with the most common in the niraparib group being thrombocytopenia (33.8% vs 0.6%), anemia (25.3% vs 0%), and neutropenia (19.6% vs 1.7%). The most common grade 3 or 4 nonhematologic adverse events were fatigue (8.2% vs 0.6%) and hypertension (8.2% vs 2.2%). Myelodysplastic syndrome occurred in 1.4% of niraparib patients.

Grade 3 or 4 hematologic abnormalities were managed with dose reduction. Most of the hematologic abnormalities in the niraparib group occurred during the first three treatment cycles, with individualized niraparib dose adjustment resulting in a lower rate of grade 3 or 4 events thereafter. Treatment was discontinued due to an adverse event in 14.7% vs 2.2%. No on-treatment deaths were reported. Three patients (one in the niraparib group) died during follow-up due to myelodysplastic syndrome or acute myeloid leukemia; one death in each group was considered related to treatment.

The investigators concluded: “Among patients with platinum-sensitive, recurrent ovarian cancer, the median duration of progression-free survival was significantly longer among those receiving niraparib than among those receiving placebo, regardless of the presence or absence of [germline] BRCA mutations or homologous recombination deficiency status, with moderate bone marrow toxicity.” ■

Disclosure: This study was funded by Tesaro, the maker of niraparib. For full disclosures of the study authors, visit www.nejm.org.

Reference

1. Mirza MR, Monk BJ, Herrstedt J, et al: Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 375:2154-2164, 2016.