Regulatory Decision Summary for Zejula

Review decision

The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.

Product type:


Medicinal Ingredient(s):


Control Number:


Therapeutic Area:

Antineoplastic agents

Type of Submission:

Supplement to a New Drug Submission

Decision issued:

Authorized; issued a Notice of Compliance in accordance with the Food and Drug Regulations

What was the purpose of this submission?

In March 2022, the sponsor submitted a Supplement to a New Drug Submission (SNDS) (control # 262892) to update the product monograph with the removal of interim overall survival (OS) data of the NOVA trial. To support this proposal the sponsor presented an updated Clinical Study Report dated 1 October 2020, which provided safety and efficacy data including final overall survival (OS) results. Overall, the report confirmed the progression-free survival (PFS) benefit of niraparib as second line maintenance (2LM) therapy in patients with recurrent ovarian cancer regardless of breast cancer gene (BRCA) mutation status. However, the OS results for the different BRCA and homologous recombination deficiency (HRD) mutational subtypes raised concerns, specifically that OS may not be demonstrated after longer follow-up in some subgroups. These findings made the sponsor consider restricting the indication only to those patients with BRCA germline mutations (gBRCA). However, the sponsor informed Health Canada of the existence of new data from a regional Phase III study that would support leaving the 2LM indication intact. Since there was new relevant information not included in the original SNDS, the review process was halted and a Notice of Deficiency (NOD) was issued. The purpose of the current review was to assess the sponsor's response to the NOD (R-NOD), which includes updated data from the NOVA trial, preliminary OS results from the regional phase III NORA trial and a real-world evidence (RWE) study.

Why was the decision issued?

In response to the NOD, the sponsor provided updated OS information from the NOVA pivotal trial, preliminary OS data from the NORA phase III regional study and a RWE study.

NOVA is a phase III study evaluating the efficacy and safety of niraparib as a 2L maintenance treatment for patients with platinum-sensitive recurrent ovarian cancer who responded to platinum-based chemotherapy. A total of 553 patients were randomized into 2 cohorts: Cohort 1 included patients with germline BRCA mutations (gBRCAmut), and Cohort 2 included patients without germline BRCA mutations (non-gBRCAmut). Patients within this latter cohort were retrospectively tested for HRD and classified as HRD positive (HRDpos); HRD negative (HRDneg); and indeterminate HRD (HRDnd). The primary efficacy endpoint of the NOVA trial was progression-free survival (PFS). Secondary endpoints included time to use of first or second subsequent therapy (TFST, TSST), chemotherapy-free interval (CFI), second progression (PFS2), overall survival (OS), and patient-reported outcomes (PRO). Updated results from the NOVA trial confirmed that niraparib as a 2LM therapy continued to provide substantial PFS benefit, regardless of BRCA mutation status, with support from TFST, TSST and PFS2 secondary endpoints. The latest dataset provided in this response to NOD showed continued improvement of OS hazard ratios compared to previous datacuts. In the gBRCAmut cohort, a median OS difference between niraparib and placebo of 2.9 months favoring niraparib (Hazard Ratio [HR] = 0.85; 95% confidence interval [CI] 0.61, 1.20) was observed, whereas in the non-gBRCAm cohort, the OS hazard ratio between niraparib and placebo remained slightly above 1 (HR = 1.06, 95% CI: 0.81 to 1.37). No reason could be found to explain why the benefit observed in PFS failed to reach statistical significance for OS. However, the analysis of OS in this trial was challenged by the differences in use of post-progression therapies in the different treatment arms, missing data, and the exploratory nature of OS, which was not sufficiently powered to detect differences in survival between the cohorts. In terms of safety, the additional data did not provide evidence of emerging safety concerns, and the safety profile was generally consistent with that reported in previous reports and with what is already known for this product and for the therapeutic class.

In addition to the recent data from the NOVA study, the sponsor presented preliminary survival data from the NORA study, a phase III, double-blind, randomized, placebo-controlled, multicenter study conducted in China to demonstrate the efficacy and safety of niraparib in Chinese patients with platinum-sensitive, recurrent, high grade serous ovarian cancer who had received at least 2 platinum-based regimens and had a partial or complete response to their last platinum-based chemotherapy. In this trial, 265 patients were randomized to receive niraparib at an individualized starting dose (ISD) of 300 or 200 mg based on patient’s baseline body weight and the platelet count or Placebo. The primary study endpoint was PFS and secondary endpoints included CFI, TFST, and OS. In consistency with the pivotal NOVA trial, the NORA trial demonstrated a PFS benefit with niraparib over placebo in all populations studied, primarily driven by patients with gBRCA mutations. Regarding OS, preliminary data (44% maturity) showed that in the gBRCAmut cohort, the median OS was not reached with niraparib and was 47.6 months with placebo (HR = 0.76, CI 95%: 0.40, 1.46), while in the non-gBRCAmut cohort, the OS difference between niraparib and placebo was 4.7 months in favor of niraparib (HR = 0.86, 95% CI: 0.40, 1.46). %: 0.53, 1.38). However, the interpretation of the NORA study findings is limited by the exclusively Chinese patient population, the lower average dose used in the NORA study, the absence of HRD status determination in the NORA study, fewer OS events in the NORA study and the greater use of post-progression therapies than in the NOVA study.

As further supporting evidence, the sponsor provided an RWE study in a sample of all patients diagnosed with ovarian cancer and patients treated with niraparib identified through electronic medical records and selected based on Internation Classification of Diseases (ICD) codes from a United States national database between January 2011 to May 2022. Patients were stratified into two cohorts based on whether they had received second-line niraparib maintenance monotherapy (2LM) or active surveillance (AS). The primary objective of this study was to compare OS in BRCA wild-type (BRCAwt) patients with recurrent ovarian cancer (OC) receiving niraparib 2LM or AS. Secondary objectives were to describe OS in a BRCAwt and in a NOVA-like subgroup. Study results showed in the BRCAwt all commers a median OS difference between niraparib 2LM and AS of 5.7 months favoring niraparib (HR of 0.77, 95% CI: 0.66, 0.89). In the NOVA-like subgroup, the median OS difference between niraparib 2LM and AS was of 6.6 months favoring niraparib (HR of 0.63, 95% CI: 0.45, 0.88). In conclusion, the RWE study results showed an OS benefit with niraparib 2LM over AS in BRCAwt patients. However, important limitations included the retrospective nature of the study (which increases the risk of bias), the inclusion of BRCAwt patients only the limited documentation provided which hindered assessment of the internal validity of the study and the quality of the data. In summary, the additional evidence provided by the sponsor had limitations that prevented establishing the real impact of niraparib on overall survival. Therefore, the pivotal NOVA study was considered the main support for the regulatory review and recommendation.

Recurrent ovarian cancer is a therapeutic challenge due to its poor prognosis, high recurrence pattern, and few treatment options. Despite the uncertainties associated with overall survival, it was considered that in the context of recurrent ovarian cancer, delaying disease progression is a highly important therapeutic goal. Therefore, it is recommended that the current indication for niraparib as 2L maintenance therapy in recurrent ovarian cancer be maintained, regardless of BRCA status, based on the robust PFS benefit observed in both the gBRCAmut and non-gBRCAmut cohorts, the evidence provided in this submission, and manageable safety profile.

For further details about Zejula, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database

Date of Decision:


Manufacturer / Sponsor:

GlaxoSmithKline Inc.

Drug Identification Number(s) Issued:


Prescription status:

Available by prescription only

Date Filed: