Regulatory Decision Summary for Zejula

The primary safety and efficacy data supporting the proposed indication of Zejula is the pivotal Phase III trial ENGO-OV16/NOVA (NOVA). This trial was designed to determine the efficacy of Zejula in the maintenance treatment of female patients with platinum-sensitive, recurrent ovarian cancer and who demonstrated response to platinum-based chemotherapy. The primary endpoint was Progression Free Survival (PFS). Patients were divided into two main cohorts: those with germline breast cancer susceptibility gene (BRCA) mutation tumours (gBRCAmut) and those who were not gBRCAmut carriers (non-gBRCAmut).

A significant clinical benefit to patients was demonstrated in the two main cohorts when comparing the PFS benefit in the Zejula treatment arms and the placebo treatment arms. In the gBRCAmut cohort, the median PFS in patients receiving Zejula versus placebo was found to be 21.0 months versus 5.5 months, respectively (Hazard Ratio (HR), 0.27; p<0.0001) and in the non-gBRCAmut cohort, median PFS values of 9.3 months versus 3.9 months (HR, 0.45; p<0.0001), respectively, were identified.

In the total safety population, the most frequently reported (>40%) adverse events (AEs) in Zejula-treated patients were nausea, anemia, thrombocytopenia, fatigue, and constipation. Significant AEs, including gastrointestinal disturbances, hematologic laboratory abnormalities and fatigue, were reported more frequently in the Zejula treatment arms compared to the placebo arm. Grade 3/4 treatment-emergent adverse events (TEAEs) (74% vs 23%), serious adverse events (SAEs) (30% vs 15%), TEAEs leading to treatment interruption (69% vs 5%), TEAEs leading to dose reduction (67% vs 15%), and TEAEs leading to treatment discontinuation (15% vs 2%) were all reported more frequently in the Zejula arms compared to the placebo arms. The most frequently reported Grade 3/4 TEAEs in Zejula-treated patients included thrombocytopenia, anemia, neutropenia, hypertension and fatigue.

There was one on-treatment death reported, due to myeloblastic leukemia. Myelodysplastic syndrome (MDS)/Acute myeloid leukemia (AML) is an adverse event of special interest with PARP inhibitors.

The half-life (t½) of Zejula in humans is approximately 2 days, and accumulates following daily dosing, with steady state being reached after approximately 2 weeks. The 300 mg dose of Zejula that was chosen for the clinical trials was based on a maximum tolerated dose of 300 mg from previous studies.

The women enrolled in this trial, as well those who would be expected to use Zejula in the real world clinical setting, are a heavily pre-treated population of patients with ovarian cancer who have had multiple platinum-based regimens. Even in the placebo group of the pivotal trial, 96% of the patients reported at least one treatment-emergent adverse event. Due to the medical history of the patients and the associated confounding factors, it is not possible to identify up front who might be at risk for these events. These risks are therefore addressed in Product Monograph (PM) labelling, which provides recommendations regarding required on-going laboratory testing.

The PM is the primary risk management strategy to manage the risks associated with Zejula. A Serious Warnings and Precautions box is included in the PM to highlight the risks of MDS/AML, bone marrow suppression, hypertension and fetal toxicity. Additionally, management of hematologic and non-hematologic adverse events is addressed in the Warnings and Precautions section, and recommendations for adverse event monitoring and dose modifications are also provided. The PM is considered an appropriate measure for risk management of Zejula.

The non-clinical assessment was considered supportive of the Zejula phamocodynamic, pharmacokinetic and safety profile. Zejula was shown in vitro to inhibit poly ADP-ribose polymerase (PARP) 1 and 2, and demonstrated increased selectivity against cancer cell lines that were engineered to be homologous recombination deficient via BRCA1 or BRCA2 silencing, or those which carried BRCA1/2 mutations, as compared to wildtype. Issues of concern included reproductive toxicity, and hematological and non-hematologic adverse events. These are expected adverse events based on the action of PARP inhibitors.

The overall benefit-harm-uncertainty of Zejula for the maintenance treatment of female adult patients with recurrent ovarian cancer, fallopian tube, or primary peritoneal cancer and who demonstrated response to platinum-based chemotherapy is considered favourable.