Regulatory Decision Summary for Akeega

This New Drug Submission (NDS) for Akeega, a fixed-dose combination tablet of niraparib and abiraterone acetate, was filed by Janssen Inc. to seek market authorization for the following indication:

"Akeega (niraparib/abiraterone acetate) is indicated with prednisone or prednisolone for the treatment of adult patients with prostate cancer who have progressed to metastatic castration resistant prostate cancer (mCRPC) and are positive for homologous recombination repair (HRR) gene alterations (germline and/or somatic)."

Upon review, Health Canada recommended granting approval for the following indication under the Notice of Compliance with Conditions (NOC/c) pathway:

"Akeega (niraparib and abiraterone acetate) is indicated with prednisone or prednisolone for the treatment of adult patients with deleterious or suspected deleterious BRCA mutated (germline and/or somatic) metastatic castration resistant prostate cancer (mCRPC), who are asymptomatic/mildly symptomatic, and in whom chemotherapy is not clinically indicated. Patients must have confirmation of BRCA mutation before Akeega treatment is initiated."

A NOC/c Qualifying Notice (QN) was issued on May 29, 2023. On May 30, 2023, the Response to NOC/c QN (R-QN) by Janssen Inc. was received by Health Canada.

The clinical benefit of Akeega was determined by the MAGNITUDE study, a Phase 3 randomized, double-blind, placebo-controlled, multi-center trial designed to assess the safety and efficacy of niraparib when added to abiraterone acetate plus prednisone (AAP) in asymptomatic/mildly symptomatic adults with treatment-naïve metastatic castration-resistant prostate cancer (mCRPC). Subjects were prospectively tested for homologous recombination repair mutations (HRRm) and enrolled into either Cohort 1 and 3 (HRRm positive) or Cohort 2 (HRRm negative). Cohort 2 met the pre-specified futility criteria.

Cohort 1 enrolled 423 subjects with HRRm, of which 54% carried mutations in the BRCA genes (BRCAm subgroup) and 46% did not carry a BRCA mutation (non-BRCAm HRRm subgroup). Subjects in Cohorts 1 and 2 were randomized 1:1 to receive either 200 mg of niraparib or placebo plus 1,000 mg abiraterone acetate as single-agent combinations (SAC), plus 10 mg prednisone or prednisolone, once daily, until disease recurrence or unacceptable toxicity. Cohort 3 was an open-label cohort of 95 subjects receiving the fixed-dose combination (FDC) formulation treatment regimen.

The primary efficacy endpoint was radiographic progression-free survival (rPFS) as assessed by blinded independent central review (BICR). Secondary endpoints included time to cytotoxic chemotherapy (TCC), time to symptomatic progression (TSP) and overall survival (OS). The study was powered to first test statistical significance in the BRCAm subgroup, followed by cohort 1 (HRRm positive group). HRRm status was determined using plasma circulating tumour DNA and tumour tissue DNA testing methods.

The pivotal bioequivalence study 67652000PCR1001 was used to demonstrate that regular strength of Akeega (niraparib/abiraterone acetate 100 mg/500 mg) was bioequivalent to the SAC. The efficacy and safety of the single agents administered in combination, as evaluated in Cohort 1 of the MAGNITUDE study, can therefore be extrapolated to Akeega.

For the BRCAm subgroup, treatment with niraparib plus AAP led to a statistically significant 47% decrease in the risk of rPFS (HR = 0.53 [95% CI (confidence interval): 0.36,0.79], p = 0.0014). The median rPFS was 16.6 months in the niraparib+AAP arm compared to 10.9 months in the placebo+AAP arm at a median duration of follow-up of 18.6 months. The efficacy was similar between both HRRm testing methods. The primary efficacy results were supported by a positive trend towards a delay in TCC and TSP in favour of niraparib plus AAP.

For the HRRm positive group (cohort1), the study showed a statistically significant improvement of rPFS by BICR (HR = 0.78 [95% CI: 0.56, 0.96], p = 0.0217). However, the treatment effect was primarily driven by the BRCAm subgroup. Exploratory subgroup analyses demonstrated no clinical benefit with niraparib+AAP in the non-BRCAm HRRm subgroup (rPFS HR = 0.99 [95% CI 0.68, 1.45]).

Except for the non-BRCAm HRRm subgroup and for patients with visceral metastases, the treatment benefit was generally consistent across multiple pre-specified subgroups in cohort 1.

A new safety signal for venous thromboembolism, primarily pulmonary embolism was identified. The majority of adverse events (AEs) were Grade ≥3 in severity. Grade ≥3 adverse events occurred in 67% of subjects in the niraparib plus AAP arm compared to 46% of subjects in the placebo plus AAP arm. The most common adverse reactions (≥ 20%) observed in the niraparib+AAP arm were anemia, hypertension, constipation, fatigue, nausea, and thrombocytopenia.

AE’s leading to dose interruption occurred in 46% and 23% of subjects in the niraparib plus AAP vs. placebo plus AAP arms. The most common adverse reactions leading to dose modifications were anemia, thrombocytopenia, neutropenia and fatigue. The most common AEs leading to drug discontinuation in the niraparib plus AAP arm were COVID-19/COVID-19 pneumonia (3%) and anemia (2%). One treatment-related death (0.5%) due to pneumonia occurred in the niraparib plus AAP arm.

The majority of adverse reactions associated with niraparib plus AAP were consistent with the known safety profile of the individual components. The risks were mitigated by labelling to manage toxicities, drug-interactions and use in special populations.

The OS data were immature at Interim Analysis 1 with a BRCAm subgroup specific OS HR = 0.96 [95% CI: 0.57, 1.63]), where the upper bound of the 95% confidence interval (CI) exceeded 1.

The treatment benefit of niraparib plus AAP in subjects with visceral metastases was uncertain. In a pre-specified exploratory subgroup analysis of BRCAm subjects with visceral metastases (n = 48), the rPFS HR was 1.02 [95% CI 0.50, 2.06] and the OS HR was 2.3 [95% CI: 1.06, 5.1]. The biological mechanism for these results is unknown, although the analyses were limited by small sample sizes. The limitations in treatment effect for visceral metastases subjects were labelled in the Product Monograph (PM).

Routine pharmacovigilance to characterize the risks of hematological toxicities, cardiac disorders, respiratory infections and lack of efficacy based on stratification for visceral metastases were included in the RMP and accepted by the sponsor. A post-authorization safety study to characterize the risk of myelodysplastic syndromes and acute myeloid leukemia (MDS/AML) and secondary neoplasms in mCRPC patients was included in the RMP and accepted by the sponsor.

The risk-benefit-uncertainty assessment of Akeega was inconclusive for non-BRCAm HRRm patients but was promising for the BRCAm population. The indication was therefore restricted to patients with BRCAm mCRPC. The deleterious, or suspected deleterious nature of the BRCA mutation was specified in the indication to refer to mutations leading to non-functional BRCA protein and sensitivity to Poly (ADP-ribose) polymerase (PARP) inhibitors. The indication was also restricted to the asymptomatic or mildly symptomatic population and to subjects in whom chemotherapy is not clinically indicated to reflect the study inclusion/exclusion criteria.

Given the uncertainty in the magnitude of survival benefit in the BRCAm population, a NOC/C QN was recommended. The confirmatory data listed in the QN were to verify and describe the final OS results in the BRCAm subgroup from Cohort 1 of the MAGNITUDE study.

In this R-QN, a Letter of Undertakings was provided in which the sponsor has agreed to all commitments listed in the QN. The planned timeline for the submission of the final efficacy report from the MAGNITUDE study is the first quarter of 2024.