Niraparib/abiraterone tablet nears EU approval for BRCA+ mCRPC

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of niraparib (Zejula) combined with abiraterone acetate (Zytiga) in a dual-action tablet (DAT) plus prednisone or prednisolone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA1/2 mutations in whom chemotherapy is not clinically indicated.¹

Overall, the MAGNITUDE study enrolled patients with mCRPC who had received no more than 4 months of prior abiraterone and prednisone for mCRPC.

The recommendation is supported by findings from the phase 3 MAGNITUDE study, which showed that adding the PARP inhibitor niraparib to the antiandrogen agent abiraterone significantly extended radiographic progression-free survival (rPFS) in patients with mCRPC and homologous recombination repair (HRR) gene alterations, such as BRCA1/2.

Data from the MAGNITUDE study presented during the 2022 Genitourinary (GU) Cancers Symposium showed that compared with placebo plus abiraterone, niraparib plus abiraterone led to a 47% reduction in the risk of progression or death in patients with BRCA1/2 mutations and a 27% reduction in the risk of progression or death in all patients with HRR gene alterations.² The median follow-up time was 18.6 months.

In the BRCA1/2 population, the median rPFS was 16.6 months with niraparib plus abiraterone vs 10.9 months with placebo plus abiraterone (HR, 0.53; 95% CI, 0.36-0.79; P = .0014). The investigator-assessed rPFS was 19.3 months with niraparib/abiraterone and 12.4 months with placebo/abiraterone (HR, 0.50; 95% CI, 0.33-0.75; P = .0006).

The European Commission will now make a final approval decision on the niraparib/abiraterone tablet.

“Metastatic castration-resistant prostate cancer remains a lethal disease, with high unmet needs in terms of treatment options, particularly for patients with BRCA1/2 gene mutations,” Elena, MD, PhD, Castro, Consultant Oncologist, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre, Madrid, Spain, stated in a press release. “We’ve seen that in these patients, niraparib combined with abiraterone acetate and prednisone significantly reduces the risk of disease progression or death compared to AAP. This niraparib-based regimen is a welcomed targeted treatment option and, if approved, has the potential to impact the standard of care for men with mCRPC BRCA who are treated with first-line therapy.”

Overall, the MAGNITUDE study enrolled patients with mCRPC who had received no more than 4 months of prior abiraterone and prednisone for mCRPC; had an ECOG performance status of 0 or 1; and had a Brief Pain Inventory-Short Form worst pain score of 3 or less. Eligible patients were screened for HRR alterations in ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, and PALB2. Patients were randomized 1:1 to receive 200 mg of niraparib once daily plus abiraterone or placebo plus abiraterone in each of the cohorts.

Sixty-seven percent (n = 142) of patients in the niraparib arm experienced grade 3/4 AEs vs 46.4% (n = 98) of patients in the placebo arm. The most common grade 3/4 AEs in the niraparib arm were anemia (29.7%; n = 63), hypertension (15.6%; n = 33), and thrombocytopenia and neutropenia (each, 6.6%; n = 14) vs hypertension (14.2%; n = 30), anemia (7.6%; n = 16), and hepatotoxicity (4.7%; n = 10) in the placebo arm.

Updated MAGNITUDE data with an additional 8 months of follow-up were shared at the 2023 GU Cancers Symposium.³ With the additional follow-up, the median radiographic rPFS was 16.7 months in the niraparib group vs 13.7 months in the placebo arm (HR, 0.76; 95% CI, 0.60-0.97; nominal P = .0280). Niraparib also yielded a statistically significant benefit in time to symptomatic progression (TSP) vs placebo, with a hazard ratio of 0.60 (95% CI, 0.42-0.84; P = .0029), as well as in TCC, with a hazard ratio of 0.67 (95% CI, 0.47-0.94; P = .0206).

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

“In recent years, we’ve focused on precision medicine in prostate cancer because we know patients with gene mutations, such as BRCA1/2, face a worse prognosis than those without,” Martin Vogel, EMEA Therapeutic Area Lead Oncology, Janssen-Cilag GmbH, stated in the press release. “The positive CHMP opinion reinforces the benefit of this niraparib combination and marks an important milestone in addressing BRCA1/2 mutations as we continue to drive progress towards changing the outlook for patients with mCRPC.”

References

1. Janssen Receives Positive CHMP Opinion for AKEEGA® (Niraparib and Abiraterone Acetate Dual Action Tablet) Plus Prednisone or Prednisolone for the Treatment of Adult Patients with BRCA1/2 Gene-Mutated Metastatic Castration Resistant Prostate Cancer. Published online February 24, 2023. https://bit.ly/3y4qqao

2. Chi KN, Rathkopf DE, Smith MR, et al. Phase 3 MAGNITUDE study: first results of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) as first-line therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without homologous recombination repair (HRR) gene alterations. J Clin Oncol. 2022;40(suppl 6):12. doi:10.1200/JCO.2022.40.6_suppl.012

3. 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