Niraparib/Abiraterone Acetate Combo Approved in Europe for BRCA1/2+ mCRPC

Gerhardt Attard, MD, PhD

The European Commission has granted marketing authorization to the dual action tablet (Akeega) comprised of niraparib (Zejula) and abiraterone acetate (Zytiga) to be administered with prednisone or prednisolone (AAP) in adult patients with BRCA1/2-mutated metastatic castration-resistant prostate cancer (mCRPC) in whom chemotherapy is not clinically indicated.¹

The regulatory decision, which marks the first worldwide approval for the tablet, is supported by findings from the phase 3 MAGNITUDE trial (NCT03748641). At a median follow-up of 16.7 months, niraparib plus AAP resulted in a 27% reduction in the risk of radiographic disease progression or death vs placebo plus AAP in all patients with alterations in homologous recombination repair (HRR)–associated genes (HR, 0.73; 95% CI, 0.56-0.96; P = .022). The median radiographic progression-free survival (rPFS) by central review in the investigative and control arms was 16.5 months and 13.7 months, respectively.²

Notably, the improvement with the niraparib regimen was reported to be most pronounced in the subset of patients whose tumors harbored BRCA1/2 mutations. In this group, niraparib plus AAP resulted in a 47% reduction in the risk of radiographic disease progression or death vs AAP alone (HR, 0.53; 95% CI, 0.36-0.79; P = .0014). The median rPFS by central review in the investigative arm was 16.6 months vs 10.9 months in the control arm.

With an additional 8 months of follow-up in the BRCA-positive group, the median rPFS by central review was 19.5 months with the niraparib regimen vs 10.9 months with AAP alone (HR, 0.55; 95% CI, 0.39-0.78; P = .0007).3 In this group, the addition of niraparib to AAP also delayed time to symptomatic progression (HR, 0.54; 95% CI, 0.35-0.85) and time to initiation of cytotoxic chemotherapy (HR, 0.56; 95% CI, 0.35-0.90; P = .0152) vs AAP alone. A trend toward improved overall survival (OS) was also observed with niraparib plus AAP vs AAP alone (HR, 0.88; 95% CI, 0.58-1.34; P = .5505).

“mCRPC remains a lethal disease, with high unmet needs in terms of treatment options, particularly for patients with BRCA1/2 gene mutations,” Professor Gerhardt Attard, MD, PhD, oncologist at the University of College London, in London, United Kingdom, stated in a press release.1 “We’ve seen that in these patients, niraparib combined with [AAP] significantly reduced the risk of disease progression or death compared [with] AAP [alone]. The dual action tablet of niraparib with abiraterone acetate is a promising first-line targeted treatment option for men with mCRPC and BRCA1/2 mutations.”

Patients with frontline mCRPC who had an ECOG performance status of 0 or 1 and Brief Pain Inventory-Short Form worst pain score of up to 3 were enrolled to MAGNITUDE.³ For those with mCRPC, up to 4 months of prior AAP was permitted.

These patients were prescreened for biomarker status, which was done using an HRR+ panel testing for several mutations, including BRCA1 and BRCA2. Study participants were then randomly assigned 1:1 to receive niraparib plus AAP (n = 212) or AAP alone (n = 211).

Key stratification factors included previous taxane-based chemotherapy for metastatic castration-sensitive prostate cancer (mCSPC), previous androgen receptor inhibitors for nonmetastatic castration-resistant prostate cancer or mCSPC, and previous AAP for frontline mCRPC.

Those who were HRR positive were stratified based on whether they had BRCA1/2 mutations or other HRR gene alterations. Of those who comprised the niraparib/AAP arm, 113 had BRCA1/2 mutations and 99 had other HRR gene alterations; in the AAP-alone arm, 112 patients had BRCA1/2 mutations and 99 had other HRR gene alterations.

The primary end point of the trial was rPFS by central review, and secondary end points included time to cytotoxic chemotherapy, time to symptomatic progression, and OS. Other prespecified end points comprised time to prostate-specific antigen progression, objective response rate, PFS on first subsequent therapy, and patient-reported outcomes.²

For the second interim analysis, the data cutoff date was June 17, 2022.3 The median treatment duration for niraparib plus AAP was 17.9 months vs 15.2 months in the AAP-alone arm.

The arms were generally well balanced at baseline. However, numerically more patients with an ECOG performance status of 1 and visceral metastases were noted to be in the investigative arm. In the niraparib arm, 38.7% of patients had an ECOG performance status of 1 vs 30.8% in the control arm; 24.1% and 18.5% of patients, respectively, had visceral metastasis. Investigators noted that the characteristics of those in the BRCA-positive group were comparable to those in the HRR-positive group.

Additional data reported at the 2023 Genitourinary Cancers Symposium showed that in the BRCA-positive subgroup, those who received niraparib plus AAP also experienced a delay in time to worst pain intensity (HR, 0.70; 95% CI, 0.44-1.12; nominal P = .1338) and in pain interference (HR, 0.67; 95% CI, 0.40-1.12; nominal P = .1275) vs those given AAP alone.

The safety profile of the niraparib combination proved to be consistent with the known profiles of each individual agent.1 Sixty-seven percent of patients in the investigative arm experienced grade 3 or 4 toxicities vs 46.4% of those in the control arm. The most common grade 3 adverse effects experienced in the niraparib and control arms, respectively, were anemia (28.3% vs 7.6%) and hypertension (14.6% vs 12.3%).

In March 2023, a new drug application was submitted to the FDA seeking the approval of the dual action tablet of niraparib and abiraterone acetate plus prednisone for frontline treatment of patients with mCRPC harboring BRCA mutations.⁴ The application is also supported by MAGNITUDE data.

References

1. Janssen marks first approval worldwide for Akeega (niraparib and abiraterone acetate dual action tablet) with EC authorisation for the treatment of patients with metastatic castration resistant prostate cancer with BRCA1/2 mutations. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. April 21, 2023. Accessed April 24, 2023. https://www.janssen.com/janssen-marks-first-approval-worldwide-akeegar-niraparib-and-abiraterone-acetate-dual-action-tablet
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 (NIRA) with abiraterone acetate and prednisone (AAP) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) 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
4. 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 April 24, 2023. https://www.janssen.com/janssen-submits-new-drug-application-us-food-and-drug-administration-seeking-approval-niraparib-and