CHMP approves niraparib and abiraterone acetate plus prednisone or prednisolone for the treatment of adult patients with BRCA1/2 gene-mutated mCRPC

27 Feb 2023
CHMP approves niraparib and abiraterone acetate plus prednisone or prednisolone for the treatment of adult patients with BRCA1/2 gene-mutated mCRPC

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended marketing authorisation for niraparib and AA, in the form of a DAT, given with P or prednisolone, for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA1/2 mutations (germline and/or somatic) in whom chemotherapy is not clinically indicated.

Niraparib is a highly selective polyadenosine diphosphate-ribose polymerase (PARP) inhibitor. Together with AA, a cytochrome P450 17α-hydroxylase (CYP17) inhibitor, the combination DAT regimen targets two oncogenic drivers (mutations responsible for both the development and maintenance of prostate cancer) in patients with mCRPC, namely androgen receptor axis (AR-axis) and BRCA1/2 gene mutations.

Prostate cancer is the most common cancer in men in Europe. Despite treatment advances, for those whose cancer has progressed to mCRPC, the impact can be devastating with an average overall survival ranging from 13-36 months. Patients with mCRPC and BRCA gene mutations are more likely to have aggressive disease, poor outcomes and a shorter survival time.

BRCA1/2 gene mutations have been identified in approximately 10-15 percent of patients with mCRPC. “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,” said Elena Castro*, Consultant Oncologist, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre, Madrid, Spain.

“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.”

“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,” said Martin Vogel, EMEA Therapeutic Area Lead Oncology, Janssen-Cilag GmbH. “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.” The positive CHMP opinion is based on results of the randomised, double-blind, placebo-controlled, Phase 3 MAGNITUDE study (NCT03748641) which assessed whether the addition of niraparib to AAP improved outcomes in those with first-line mCRPC, with or
without alterations in homologous recombination repair (HRR) associated genes.

Patients with HRR gene alterations were randomised to receive niraparib 200 mg once daily plus AAP [n=212], or placebo and AAP [n=211]. In MAGNITUDE, a total of 423 patients with HRR gene alterations were enrolled, 225 (53.2 percent) of whom had BRCA mutations. This is the largest cohort of BRCA1/2-positive patients with mCRPC.

First results, presented at the American Society of Clinical Oncology – Genitourinary Cancers Symposium (ASCO GU) 2022 Annual Meeting, showed niraparib plus AAP significantly improved rPFS (as analysed by blinded independent central review) in all HRR-positive patients. This improvement was most pronounced in patients with BRCA1/2 gene mutations, where a statistically significant 47 percent risk reduction was observed for rPFS (HR 0.53; p=0.001).

Updated results from the second interim analysis (IA2) of MAGNITUDE were presented at the recent ASCO GU 2023 Annual Meeting. In the IA2, at 24.8 months of median follow-up in the BRCA subgroup, rPFS by central review demonstrated a consistent and clinically meaningful treatment effect favouring niraparib plus AAP, with a median rPFS of 19.5 months compared with 10.9 months for placebo plus AAP. Additionally, in the BRCA subgroup, there was a trend towards improved overall survival (OS) with niraparib plus AAP, strong improvement in time to symptomatic progression (TSP) and continued consistent improvement of time-to-initiation of cytotoxic chemotherapy (TCC).

The observed safety profile of the combination of niraparib and AAP was consistent with the known safety profile of each agent.2 Of the patients with HRR gene alterations, 67 percent experienced Grade 3/4 adverse events (AEs) in the combination arm versus 46.4 percent in the control arm. Discontinuation rates due to AEs for the combination arm and control arm were 10.8 percent and 4.7 percent, respectively. The combination of niraparib and AAP also maintained the overall quality of life in comparison with placebo and AAP as measured on the Functional Assessment of Cancer Therapy–Prostate (FACT-P) scale.

“Prostate cancer is a heterogeneous disease made up of many biologically distinct subpopulations. The data from MAGNITUDE supports the significant value of biomarker testing to identify the subgroup of patients most likely to derive a clinical benefit from a targeted treatment, and overcome the poor prognosis of mCRPC with BRCA mutations,” said Kiran Patel, M.D., Vice President, Clinical Development, Solid Tumors, Janssen Research & Development, LLC. “At Janssen, we are dedicated to continued innovation in prostate cancer and now look forward to working with health authorities to bring this niraparib-based treatment option to patients as soon as possible.”

Source: Janssen Pharmaceutical Companies of Johnson & Johnson