Zejula Granted FDA Approval for Ovarian Cancer

The FDA has approved the PARP inhibitor Zejula (niraparib) for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.

The approval is based on the phase 3 NOVA trial, in which Zejula reduced the risk of progression or death by 74 percent compared with placebo for patients with germline BRCA-positive platinum-sensitive, recurrent ovarian cancer.

“Women with recurrent ovarian cancer often experience considerable fear and anxiety about future recurrences,” said Audra Moran, President and CEO of Ovarian Cancer Research Fund Alliance. “Zejula may offer patients and their families a treatment option during this stressful period. The ovarian cancer community is eager for new treatment options, and we are glad that Zejula will be available to women that have completed their platinum-based chemotherapy.”

After a median follow-up of 16.9 months, the median progression-free survival (PFS) with maintenance Zejula was 21 months compared with 5.5 months for placebo in patients with germline BRCA mutations. These findings remained consistent across subgroups of patients, including those without BRCA mutations.

The phase 3 NOVA study randomized patients in a 2:1 ratio across 2 independent cohorts. In the first cohort, 201 patients with germline BRCA mutations received Zejula at 300 mg daily (n = 138) or placebo (n = 65). In the second cohort, 345 patients with non-germline BRCA-mutant tumors received the PARP Inhibitor (n = 231) or placebo (n = 114). Patients in this group were tested for homologous recombination deficiency (HRD), and could be either positive (n = 162) or negative (n = 134). Of those who tested positive, 47 had somatic BRCA mutations and 115 were wild-type.

Patient demographics were well balanced between the arms for each cohort. In the germline BRCA group, the median age was 57 years and 65.9 percent had an ECOG performance status (PS) of 0. In the placebo group, the median age was 58 years and 73.8 percent of patients had an ECOG PS of 0. Overall, 48.6 percent and 53.8 percent of patients had received ≥3 prior therapies, in the Zejula and placebo arms, respectively.

Across both cohorts, the majority of patients had stage III cancer (68.8 percent to 74.1 percent). Approximately half of patients had achieved a complete response to prior platinum-based therapy and a quarter had received prior bevacizumab. In the non-BRCA-mutant arm, 33.8 percent and 32.8 percent of patients had received ≥3 prior therapies.

In the germline BRCA mutation group, the chemotherapy-free interval was 22.8 months with Zejula compared with 9.4 months for placebo. The median time to subsequent therapy was 21 months with Zejula versus 8.4 months with placebo.

The median time to progression or death during the first subsequent therapy following the study (PFS2) was 25.8 months for those who received maintenance Zejula versus 19.5 months for placebo.

Findings for overall survival were not yet mature (fewer than 20 percet of events). At the time of the analysis, Zejula had reduced the risk of death by 27 percent versus placebo, although this finding was not statistically significant.

In patients with HRD-positive, BRCA wild-type tumors, median PFS was 9.3 versus 3.7 months for Zejula and placebo, respectively. In those with HRD-positive, somatic BRCA-mutated tumors, the median PFS was 20.9 months with Zejula versus 11.0 months for placebo . In patients with HRD-negative, non-germline BRCA-mutated tumors, median PFS was 6.9 versus 3.8 months for Zejula and placebo, respectively.

In those with non-germline BRCA mutations regardless of HRD status, the median chemotherapy-free interval was 12.7 versus 8.6 months for Zejula and placebo, respectively. The median time to subsequent therapy was 11.8 versus 7.2 months and the median PFS2 was 18.6 and 15.6 months for the Zejula and placebo arms, respectively .

Across cohorts, 14.7percent of 367 Zejula-treated patients discontinued therapy due to an adverse event (AE) compared with 2.2 percent of the 179 patients in the placebo arm. There were no treatment-related deaths in the study. In the follow-up period, 1 patient in the Zejula arm and 2 in the placebo group died of myelodysplastic syndrome or acute myeloid leukemia. One of these deaths in each arm was deemed to be treatment related.

The most common all-grade AEs for Zejula versus placebo, respectively, were nausea (73.6 percent vs 35.2 percent, respectively), thrombocytopenia (61.3 percent vs 5.6 percent), fatigue (59.4 percent vs 41.3 percent), anemia (50.1 percent vs 6.7 percent), constipation (39.8 percent vs 20.1 percent), vomiting (34.3 percent vs 16.2 percent), and neutropenia (30.2 percent vs 6.1 percent).

The most common grade 3/4 AEs in the Zejula arm were hematologic, and included thrombocytopenia (33.8 percent), anemia (25.3 percent), and neutropenia (19.6 percent). The most common non-hematologic AEs were hypertension (8.2 percent), fatigue (8.2 percent), and nausea (3 percent). A majority of hematologic AEs were experienced in the first 3 cycles.

Tesaro initiated a rolling submission of data from the NOVA trial for a new drug application in September 2016, after receiving a fast track designation from the FDA.