Summary Basis of Decision for Zejula

The clinical review of Zejula was completed by Health Canada as part of a work-sharing initiative with Australia, Singapore, and Switzerland. The review of the submission was collaborative, with each regulatory agency sharing the outcome of their review with the others. However, each regulatory agency made their decision regarding authorization independently.

Clinical Pharmacology

Niraparib, the medicinal ingredient in Zejula, is an inhibitor of the poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2, which are involved in deoxyribonucleic acid (DNA) repair.

The results of in vitro studies indicate that niraparib may inhibit PARP enzymatic activity, promoting the formation of PARP-DNA complexes which then lead to DNA damage, apoptosis, and cell death.

Niraparib may affect pulse rate and blood pressure in patients receiving the recommended dose of 300 mg once daily. This may be due to pharmacological inhibition of the dopamine, norepinephrine, and serotonin transporters. In the pivotal study (described in the Clinical Efficacy section below), increases in the mean pulse rate and blood pressure were observed in patients treated with niraparib compared to patients receiving the placebo at all on-study assessments.

A separate clinical study was conducted to examine whether niraparib can prolong the QTc interval. Patients were randomized to receive either 300 mg niraparib once daily (number of patients [n] = 367) or a placebo (n = 179). No large differences in the mean QTc interval (>20 ms) were detected in the patients receiving niraparib.

The major pharmacokinetic aspects of niraparib have been well characterized. Systemic exposure to niraparib was observed to increase in a dose-proportional manner within a range of 30 mg to 400 mg, which corresponds to 0.1 times to 1.3 times the recommended dose, respectively. The absolute bioavailability of niraparib is approximately 73%, and the peak plasma concentration is reached after approximately three hours. Niraparib is 83% bound to human plasma proteins.

Niraparib is metabolized by carboxylesterases, with M1 and M10 as the major circulating metabolites. The half-life of niraparib was determined to be approximately 48 hours. Niraparib and its metabolites are eliminated through multiple pathways, including liver metabolism, hepatobiliary excretion, and renal elimination.

Mild hepatic impairment and mild to moderate renal impairment did not have clinically significant effects on the pharmacokinetics of niraparib. The effects of moderate to severe hepatic impairment, severe renal impairment, and end-stage renal disease on the pharmacokinetics of niraparib remain unknown.

Overall, the clinical pharmacological data support the use of Zejula for the approved indication.

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

Clinical Efficacy

The clinical efficacy of Zejula was evaluated primarily in the pivotal Phase III study ENGOT-OV16/NOVA (NOVA). The NOVA study was conducted in 553 female adult patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. To be eligible for this trial, patients must have already undergone at least two platinum-based treatment regimens. One of these platinum-based treatment regimens must also have been the patient's most recent therapy, to which she had a partial or complete response.

Patients were assigned to one of two cohorts depending on the presence of a deleterious germline mutation in either the BRCA1 or BRCA2 gene. These genes have been implicated in the development of breast cancer and ovarian cancer, as well as fallopian tube cancer and primary peritoneal cancer. Patients assigned to the germline BRCA mutation (gBRCAmut) cohort tested positive or were suspected for the mutation (number of patients [n] = 203). Patients without this mutation (n = 350) were assigned to the non-germline BRCA mutation (non-gBRCAmut) cohort.

All 553 patients were randomized in a 2:1 ratio to receive either 300 mg Zejula once daily, or the placebo. Patients were monitored through consecutive 28-day cycles, for a median duration of 250 days.

The primary efficacy endpoint was progression-free survival (PFS), determined mainly by central independent assessment according to version 1.1 of the Response Evaluation Criteria in Solid Tumours (RECIST). In some cases, other criteria were also applied to evaluate PFS. These included clinical signs and symptoms, as well as increasing levels of cancer antigen 125 (CA125) in the blood.

A statistically significant increase in PFS was observed in both cohorts in patients treated with Zejula, compared to those who received the placebo. In the gBRCAmut cohort, the median PFS was 21.0 months in patients treated with Zejula, versus 5.5 months in patients who received the placebo (hazard ratio [HR] = 0.26; p<0.0001). In the non-gBRCAmut cohort, the median PFS was 9.3 months in patients who received Zejula, and 3.9 months in patients who received the placebo (HR = 0.45; p<0.0001).

Overall survival was designated as a secondary efficacy endpoint. However, the available overall survival data were limited at the time of PFS analysis, with deaths occurring in 17% of the patient population.

Indication

The proposed indication was revised to better reflect the patient population in the pivotal study in which Zejula was shown to be an effective treatment.

For more information, refer to the Zejula Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The outcomes of the NOVA study have established both the clinical safety and efficacy of Zejula in the intended patient population, and are described in the Clinical Efficacy section.

In the overall safety population, the following events were reported at a higher frequency in patients receiving Zejula than in patients receiving the placebo: Grade 3 or 4 treatment-emergent adverse events (TEAEs; 74% versus 23%), serious adverse events (30% versus 15%), TEAEs leading to treatment interruption (69% versus 5%), TEAEs leading to dose reduction (67% versus 15%), and TEAEs leading to treatment discontinuation (15% versus 2%).

In patients receiving Zejula, the most frequently reported adverse reactions (in ≥10% of patients) include nausea, thrombocytopenia, fatigue/asthenia, anemia, constipation, vomiting, abdominal pain/distension, neutropenia, insomnia, headache, decreased appetite, nasopharyngitis, rash, mucositis/stomatitis, diarrhea, dyspnea, hypertension, myalgia, dyspepsia, back pain, dizziness, leukopenia, cough, urinary tract infection, arthralgia, anxiety, palpitations, dry mouth, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevation, and dysgeusia.

Treatment-emergent thrombocytopenia and anemia were the most frequently reported serious adverse reactions (in >1% of patients). One on-treatment death was reported during this trial, and was associated with acute myeloblastic leukemia.

Grade 3 and 4 hematologic TEAEs reported in patients who received Zejula occurred most commonly in the initial days and weeks of treatment. These events were managed through strict dose adjustments based on the individual tolerability of each patient.

The most common hematologic TEAEs of any grade in both treatment arms (Zejula or placebo) were anemia (49% versus 7%), thrombocytopenia (46% versus 3%), and neutropenia (18% versus 3%). The most common non-hematologic TEAEs of any grade were nausea (74% versus 35%), fatigue (46% versus 32%), constipation (40% versus 20%), and vomiting (34% versus 16%).

Due to the adverse events observed with the 300 mg starting dose, a post hoc analysis was conducted by the sponsor with the objective of providing evidence to support a lower starting dose of 200 mg based on the baseline platelet counts and body weight of the patients. However, the analysis did not provide sufficient evidence that a niraparib starting dose other than the 300 mg, used in the pivotal study, would produce the required efficacy in the patient population for which Zejula is intended. Therefore, the dosing recommendations were not changed. However, the Product Monograph states that clinicians may consider a starting dose of 200 mg for patients weighing less than 58 kg, as Grade 3 and 4 adverse reactions were observed to be more common in patients with low body weight.

A Serious Warnings and Precautions box is included in the Zejula Product Monograph to highlight specific safety concerns. These include the risk of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML, including some cases that have been fatal), bone marrow suppression, hypertension (including hypertensive crisis), and the potential to cause fetal harm if administered to a pregnant woman.

Dose modification (interruption or reduction) or discontinuation may be considered as options to manage intolerable adverse events. The Zejula Product Monograph contains comprehensive instructions on dose modification, based on the individual tolerance of the patient as well as results of hematological laboratory tests. During the NOVA study, the adverse events that most often led to dose reduction were thrombocytopenia (31%), anemia (18%), and decreased platelet count (10%).

Health Canada has determined that appropriate risk management measures are in place to address the safety concerns identified for Zejula, and to promote its safe and effective use. Overall, the benefit-harm-uncertainty profile of Zejula is favourable. For more information, refer to the Zejula Product Monograph, approved by Health Canada and available through the Drug Product Database.