FDA Approval Sought for Niraparib Plus Abiraterone/Prednisone as First-line Treatment 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 (Zytiga), in the form of a dual-action tablet, and prednisone, for the first-line treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA mutations.¹

The NDA is supported by data from the phase 3 MAGNITUDE trial (NCT03748641). First results presented at the 2022 Genitourinary Cancers Symposium showed that at a median follow-up of 18.6 months, patients with homologous recombination repair (HRR) gene alterations who were treated with niraparib, abiraterone, and prednisone experienced a significant improvement in radiographic progression-free survival (rPFS) compared with those treated with placebo plus abiraterone and prednisone, translating to a 27% reduction in the risk of progression or death (HR, 0.73; P =.022).²

Notably, the rPFS benefit was higher in patients with BRCA1/2 gene alterations. The niraparib combination was associated with a 47% reduced risk of progression or death compared with the placebo-based combination (HR, 0.53; P = .001), as analyzed by blinded independent central review (BICR).²

“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 [NDA] reinforce the importance of biomarker testing to identify the subgroups of patients that are most likely to respond to a targeted treatment option,” Peter Lebowitz, MD, PhD, head, Global Therapeutic Area, Oncology, Janssen Research & Development, stated in a news release.¹ “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.”

The phase 3, randomized, double-blind, placebo-controlled multicenter MAGNITUDE trial evaluated niraparib plus abiraterone and prednisone in patients with mCRPC with or without certain HRR gene alterations who have not received prior therapy for mCRPC.²

One cohort included patients with predefined HRR gene alterations, including ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, and PALB2. The other cohort included patients who did not have HRR gene alterations.

Patients were randomly assigned to receive niraparib or placebo plus abiraterone and prednisone.

The primary end point of the trial was rPFS per BICR. Secondary end points included time to initiation of cytotoxic chemotherapy, time to symptomatic progression (TSP), and overall survival.

In additional data from the first results of MAGNITUDE, investigator-assessed rPFS showed that patients with HRR gene alterations treated with niraparib experienced a 36% reduction in the risk of progression or death (HR, 0.64; P = .002), and those with BRCA mutations had a 50% reduction in the risk of progression or death (HR, 0.50; P = .0006).²

Notably, the cohort of patients without HRR gene alterations met the predefined futility criteria and displayed no benefit from the addition of niraparib to abiraterone and prednisone.

In updated data from the second interim analysis of the trial presented at the 2023 Genitourinary Cancers Symposium, niraparib plus abiraterone and prednisone demonstrated a statistically significant increase in TSP and continued improvement of time to initiation of cytotoxic chemotherapy in the HRR-positive population, and a strong improvement in TSP for the BRCA subgroup of the HRR-positive population.³

The updated median rPFS per BICR for the BRCA subgroup was 19.5 months for those treated in the niraparib arm compared with 10.9 months for the placebo arm (HR, 0.55; 95% CI, 0.39-0.78). Investigator-assessed rPFS again favored the niraparib arm in the BRCA-mutated subgroup (HR, 0.46; 95% CI, 0.32-0.67).

Patients harboring BRCA mutations who received niraparib plus abiraterone and prednisone experienced a trend toward delayed time to worst pain intensity (HR, 0.70; 95% CI, 0.44-1.12) and pain interference (HR, 0.67; 95% CI, 0.40-1.12) compared with the placebo-based combination.

Regarding safety, data from the first interim analysis showed findings for niraparib plus abiraterone and prednisone were consistent with the known safety profiles for each agent.2 In patients with HRR gene alterations, 67% of patients experienced grade 3 adverse effects (AEs), and 46.4% had grade 4 AEs, with the most common being anemia and fatigue. Additionally, 10.8 percent of patients in the experimental arm discontinued treatment compared with 4.7% in the control arm.

References

1. 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. Janssen. February 28, 2023. Accessed March 1, 2023. https://www.jnj.com/janssen-submits-new-drug-application
2. Janssen presents new data demonstrating the combination of niraparib and abiraterone acetate plus prednisone significantly improved radiographic progression-free survival as a first-line therapy in patients with HRR gene-mutated metastatic castration-resistant prostate cancer. News release. Janssen. February 14, 2022. Accessed March 1, 2023. https://www.jnj.com/janssen-presents-new-data
3. Janssen presents updated data demonstrating improved outcomes from the use of niraparib in combination with abiraterone acetate plus prednisone as a first-line therapy in patients with BRCA-positive metastatic castration-resistant prostate cancer. News release. Janssen. February 16, 2023. Accessed March 1, 2023. https://www.jnj.com/janssen-presents-updated-data