FDA Receives NDA for Niraparib Plus Abiraterone and Prednisone for BRCA+ mCRPC

A new drug application (NDA) has been submitted to the FDA seeking the approval of niraparib (Zejula) in combination with abiraterone acetate, in the form of a dual-action tablet (DAT), plus prednisone, for patients with BRCA-positive metastatic castration-resistant prostate cancer (mCRPC).¹

Data from the phase 3 MAGNITUDE study (NCT03748641), a randomized, multicenter study assessing the combination of niraparib plus abiraterone acetate and prednisone as a first-line treatment for patients with mCRPC, with or without alterations in homologous recombination repair (HRR) associated genes, support the NDA.

If approved, this will be the first available DAT formulation in the United States for the treatment of patients with mCRPC harboring BRCA mutations.

"Patients with mCRPC and BRCA mutations face a more aggressive form of prostate cancer and high unmet needs in terms of treatment options. The data supporting this submission reinforce the importance of biomarker testing to identify the subgroups of patients that are most likely to respond to a targeted treatment option," said Peter Lebowitz, MD, PhD, global therapeutic area head, oncology, Janssen Research & Development, LLC, in the press release. "This submission further represents our commitment at Janssen to discover and develop precision medicine approaches and combination therapies to help improve outcomes for patients living with genetically defined disease."

In the phase 3, double-blind, placebo-controlled, MAGNITUDE study, 212 patients with HRR gene alterations were randomized to receive niraparib at a dose of 200 mg once a day plus abiraterone acetate and prednisone and 211 were given placebo plus abiraterone acetate and prednisone.²

The primary end point is radiographic progression-free survival (rPFS) and secondary end points of the trial include overall survival, time to symptomatic progression (TSP), time to initiation of cytotoxic chemotherapy (TCC), observed plasma concentrations of niraparib, observed trough plasma concentrations of abiraterone, and safety, including number of treatment-emergent adverse events (TEAEs).

Findings from the second interim analysis of the phase 3 MAGNITUDE study were recently presented at the 2023 Genitourinary Cancers Symposium, showing that the combination of niraparib, abiraterone acetone, and prednisone led to prolonged survival, an extended TCC, and delayed progression in this patient population.³

These findings were presented at 8 months of follow-up since the first interim analysis, and here, the median rPFS was 16.7 months for patients given the addition of niraparib vs 13.7 months for those given placebo (HR, 0.76; 95% CI, 0.60-0.97; nominal P = .0280). A statistically significant benefit in TSP was also seen for niraparib vs placebo, with a hazard ratio of 0.60 (95% CI, 0.42-0.84; P = .0029). This was the same for TCC, which had a hazard ratio of 0.67 (95% CI, 0.47-0.94; P = .0206).

Patients harboring BRCA alterations had a median rPFS of 19.5 months with niraparib vs 10.9 months with placebo (HR, 0.55; 95% CI, 0.39-0.78; nominal P = .0007), respectively. In the BRCA subgroup, TSP progression was not evaluable (NE) in the niraparib arm compared with 23.6 months in the placebo arm (HR, 0.54; 95% CI, 0.35-0.85; P = .0071). Patients in the BRCA subgroup had a TCC of NE with niraparib vs a median of 27.3 months in the placebo arm (HR, 0.56; 95% CI, 0.35-0.90; P = .0152), respectively.

Additionally, overall survival was higher in the BRCA subgroup at a median of 29.3 months with niraparib arm vs 28.6 months in the placebo arm (HR, 0.88; 95% CI, 0.58-1.34; P = .5505). Patients administered niraparib also had a delayed time to worst pain intensity (HR, 0.70; 95% CI, 0.44-1.12; nominal P = .1338) and pain interference (HR, 0.67; 95% CI, 0.40-1.12; nominal P = .1275) in the BRCA subgroup vs placebo.

For safety, the toxicity profile was the same as what was observed in the first interim analysis, and no new safety signals were reported. AEs were more frequent for patients treated with niraparib with the most common AEs in the niraparib and placebo groups consisting of anemia (50.0% vs 22.7%), hypertension (33.0% vs 22.3%), and constipation (33.0% vs 15.6%).

REFERENCES:

Janssen submits new drug application to the U.S. food and drug administration seeking approval of niraparib and abiraterone acetate dual-action tablet, plus prednisone, as a first-line targeted treatment for patients with metastatic castration-resistant prostate cancer with BRCA gene mutations. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. March 1, 2023. Accessed March 1, 2023. https://prn.to/3xXHgrv

Study of niraparib in combination with abiraterone acetate and prednisone versus abiraterone acetate and prednisone for treatment of participants with metastatic prostate cancer (MAGNITUDE). ClinicalTrials.gov. Updated February 15, 2023. Accessed March 1, 2023. https://clinicaltrials.gov/ct2/show/NCT03748641

Efstathiou E, Smith MR, Sandhu S, et al. Niraparib with abiraterone acetate and prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis (IA2) of MAGNITUDE. J Clin Oncol. 2023;41(suppl 6):170. doi:10.1200/JCO.2023.41.6_suppl.170