Janssen Submits NDA to FDA for Niraparib-Abiraterone Dual-Action Tablet as First-Line Treatment for BRCA-Positive mCRPC

On February 28, Johnson & Johnson announced the submission of a New Drug Application (NDA) to the U.S. FDA for the niraparib + abiraterone acetate Dual Action Tablet (DAT), seeking FDA approval for this combination in conjunction with prednisone to treat BRCA-positive metastatic castration-resistant prostate cancer (mCRPC) patients. If approved, this would be the first DAT formulation in the U.S. approved for mCRPC patients carrying BRCA mutations.

Prostate cancer is one of the most common cancers in the United States, with an estimated 268,490 new cases diagnosed in 2022. Approximately 10%-50% of these cases are expected to progress to mCRPC within three years, and it is estimated that 10%-15% of these patients carry BRCA mutations.

The combination of Niraparib (a highly selective PARP inhibitor) and Abiraterone Acetate (a CYP17 inhibitor), along with Prednisone, targets two oncogenic drivers in mCRPC patients: the androgen receptor axis and HRR gene alterations. BRCA mutations are one type of homologous recombination repair (HRR) gene alteration.

This NDA is supported by data from the Phase III randomized, double-blind, placebo-controlled, multicenter MAGNITUDE study. It evaluated the safety and efficacy of niraparib in combination with abiraterone acetate and prednisone (AAP) as a first-line treatment for patients with mCRPC, regardless of whether HRR-related genes were altered. Patients with HRR gene alterations were randomly assigned to receive either niraparib + AAP (n=212) or placebo + AAP (n=211). The primary endpoint of the trial was rPFS determined by blinded independent central review, with secondary endpoints including TCC, TSP, and overall survival.

The second interim analysis (IA2) of the MAGNITUDE study showed that, with a median follow-up of 26.8 months, in the HRR-positive population, the time to symptom progression (TSP) was significantly delayed in the Niraparib plus AAP group compared to placebo, with a statistically significant difference. The time to cytotoxic chemotherapy commencement (TCC) was continuously delayed, and TSP was notably postponed in the HRR-positive BRCA subgroup. The updated review of the primary endpoint, radiographic progression-free survival (rPFS), was consistent with the initial results.

Notably, in the BRCA subgroup, the median rPFS was 19.5 months in the niraparib + AAP group and 10.9 months in the placebo + AAP group (HR: 0.55; 95% CI: 0.39-0.78). For BRCA-positive mCRPC patients, a pre-planned sensitivity analysis also demonstrated an rPFS benefit with niraparib + AAP (HR: 0.46; 95% CI: 0.32-0.67). Detailed results were presented at the ASCO GU 2023 conference.

Based on the MAGNITUDE study results, for use in combination with prednisone or prednisolone as a first-line treatment for adult patients with clinically non-chemotherapy-indicated BRCA1/2-mutated mCRPC.

In the first-line treatment scenario for metastatic castration-resistant prostate cancer (mCRPC), niraparib is facing competition from olaparib and Talzenna (talazoparib). The indication for the combination of olaparib and abiraterone as a first-line treatment for mCRPC was the first to be approved in the EU on December 21, 2022. Similarly, Pfizer announced the phase III TALAPRO-2 study data on talazoparib combined with enzalutamide as a first-line treatment for mCRPC at this year's ASCO GU conference. Regardless of whether patients have HRR gene mutations or not, talazoparib plus enzalutamide significantly improved rPFS in mCRPC patients, reducing the risk of disease progression or death by 37%. Pfizer has submitted an sNDA to the FDA and has been granted priority review status.

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