Initial results from Phase 3 MAGNITUDE study, to be featured in a late-breaking oral presentation at ASCO GU, highlight subset of patients with mCRPC most likely to benefit from treatment in a first line setting
The Janssen Pharmaceutical Companies of Johnson & Johnson has announced initial results from the Phase 3 MAGNITUDE study evaluating the investigational use of niraparib, a selective poly-ADP ribose polymerase (PARP) inhibitor, in combination with abiraterone acetate plus prednisone (AAP) as a first line therapy in patients with metastatic castration-resistant prostate cancer (mCRPC) with or without specific homologous recombination repair (HRR) gene alterations.
At the final analysis for radiographic progression-free survival (rPFS), the treatment combination of niraparib and AAP demonstrated a statistically significant improvement in patients with HRR gene alterations as compared to placebo and abiraterone acetate plus prednisone. Results will be featured in a late-breaking oral presentation (Abstract #12; Oral Abstract Session A) at the American Society of Clinical Oncology’s Genitourinary (ASCO GU) Cancers Symposium, taking place in San Francisco and virtually from February 17-19, 2022.
“Despite treatment advances for metastatic castration-resistant prostate cancer, long-term survival is often severely shortened, and this is especially the case for prostate cancer harbouring (or containing) HRR gene alterations that we now know behave more aggressively,” commented Professor Gerhardt Attard, Primary Study Investigator and Clinician Scientist and Team Leader at University College London Cancer Institute. “It is therefore encouraging to see the results from the MAGNITUDE study, that confirms a very real benefit for treatment with niraparib in combination with abiraterone acetate plus prednisone in selected groups of patients.”
MAGNITUDE (NCT03748641) is a Phase 3, randomised, double-blind, placebo-controlled, multicentre study evaluating the safety and efficacy of niraparib combined with AAP as a first-line therapy in patients with mCRPC. The MAGNITUDE study was intentionally designed and powered with two independent cohorts based on patient biomarker status to evaluate the efficacy of the combination of niraparib and AAP relative to placebo and AAP in subjects with and without HRR gene alterations (including ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2 alterations).
In a third, open-label cohort, all patients received a fixed dose combination tablet of niraparib and abiraterone and a separate tablet of prednisone. The cohort of patients with prospectively-identified HRR gene alterations enrolled 423 patients, with patients randomised to receive the combination of niraparib and AAP (combination arm [n=212]) or placebo and AAP (control arm [n=211]).
At 18.6-month median follow-up, patients in the combination arm of the cohort with HRR gene alterations showed a significant clinical improvement in rPFS, with a reduction in the risk of progression or death of 27 percent (hazard ratio [HR] 0.73; p=0.022). This improvement was most pronounced in patients with BRCA1/2 gene alterations, where a 47 percent risk reduction was observed for rPFS (HR 0.53; p=0.001), as analysed by blinded independent central review (BICR). A consistent but greater improvement was observed in investigator-assessed rPFS, which showed an overall 36 percent risk reduction in patients with HRR gene alterations (HR: 0.64; p=0.0022), and a 50 percent risk reduction in patients with BRCA1/2 gene alterations (HR: 0.50; p=0.0006).
The cohort without HRR gene alterations (n=233) met the predefined futility criteria in August 2020, showing no benefit from the treatment combination (HR>1) in the HRR biomarker negative population. Enrolment into this cohort was stopped at the time of futility at the recommendation of the Independent Data Monitoring Committee. Investigators and patients were unblinded and patients were given the opportunity to continue treatment with niraparib and AAP or receive only AAP at the discretion of the study investigator.
In patients with HRR gene alterations, clinically relevant improvements in outcomes were also seen at this first interim analysis for secondary endpoints including time to initiation of cytotoxic chemotherapy, time to symptomatic progression and time to PSA progression. Additionally, objective response rate was improved by the combination of niraparib and AAP. Overall survival data were immature at this interim analysis and follow-up will continue for all secondary endpoints.
Patients with HRR gene alterations, such as BRCA1/2, are at an increased risk of developing prostate cancer, and BRCA-related prostate cancer is usually aggressive. Long-term survival is low for patients with mCRPC and those who have HRR gene alterations face a worse prognosis, driving a significant unmet medical need for novel therapies in this disease.
“The MAGNITUDE study demonstrates that in people with metastatic castration-resistant prostate cancer with HRR gene mutations, the treatment combination of niraparib and abiraterone acetate plus prednisone significantly improves radiographic progression free survival with a reduction in the risk of progression or death. These data reinforce the importance of biomarkers in helping to provide an individualised treatment plan for these patients,” said Martin Vogel, MD, EMEA Therapeutic Area Lead Oncology, Janssen-Cilag GmbH.
The observed safety profile of the combination of niraparib and AAP was in line with the known safety profile of the two individual drugs, and manageable, with no new safety signals identified. Of the patients with HRR gene alterations, 67 percent and 46.4 percent experienced Grade 3/4 adverse events (combination of niraparib and AAP, and placebo and AAP respectively), largely driven by anaemia and fatigue. Discontinuation rates for the combination arm and control arm were 10.8 percent and 4.7 percent respectively. The combination of niraparib and AAP also maintained overall quality of life in comparison with placebo and AAP as measured on the Functional Assessment of Cancer Therapy–Prostate (FACT-P) scale.
