Niraparib Benefits Demonstrated For First-Line mCRPC With HRR Gene Alterations

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: The MAGNITUDE study results show a significant improvement with the use of niraparib alongside first-line abiraterone plus glucocorticoids in the outcomes of men with metastatic castration-resistant prostate cancer (mCRPC) harbouring a homologous recombination repair (HRR) gene alteration.  

The investigators reported the phase III trial findings for the PARP inhibitor at the 2022 ASCO Genitourinary Cancers Symposium in San Francisco, California, USA. 

“MAGNITUDE highlights the importance of testing for HRR gene alterations in patients with mCRPC to identify those individuals who will optimally benefit from the combination of niraparib plus abiraterone”, said presenting author Kim Chi, from the University of British Columbia in Vancouver, Canada. 

“These study results support niraparib plus abiraterone as a new first-line treatment option for patients with mCRPC and alterations in genes associated with homologous recombination repair.” 

The primary endpoint of blinded independent central review radiographic progression-free survival (rPFS) was determined for 212 patients who were randomly assigned to receive first-line niraparib 200 mg/day with abiraterone plus prednisone or prednisolone and 211 patients instead given placebo with the anti-androgen therapy. 

Of these men, 23% had previously received up to 4 months of abiraterone acetate plus glucocorticoids for mCRPC, and 21% had visceral metastases. Almost half (44.9%) of these patients had alterations to BRCA1 or BRCA2, and the remainder had HRR alterations in ATM, BRIP1, CDK12, CHEK2, FANCA, HDAC2 or PALB2. 

After a median 16.7 months of follow-up, rPFS in the men with BRCA1 or BRCA2 mutations was a median 16.6 months with niraparib versus 10.9 months with placebo, translating to a significant 47% reduction in the risk of progression or death with the PARP inhibitor. 

And this significant benefit in rPFS with niraparib use extended to men with HRR alterations affecting any of the studied HRR genes, with a median duration of 16.5 months versus 13.7 months for controls, giving a 27% reduction in risk over a median 18.6 months of follow-up.  

Prespecified subgroup analysis for rPFS “showed consistency of effect” across patient age, race, ECOG performance status, baseline pain score, geographical region, prior treatment, baseline prostate-specific antigen (PSA) level, HRR gene alteration, and metastases factors, said Kim Chi. 

Interim analysis of overall survival (OS) was immature, although multivariate analysis adjusted for baseline characteristics showed a trend in favour of niraparib use, the presenter commented. 

Furthermore, niraparib use in men with any HRR gene alterations was associated with significant improvements in the other secondary endpoints of time to use of cytotoxic chemotherapy (hazard ratio [HR]=0.59) and time to symptomatic progression (HR=0.69), as well as time to PSA progression (HR=0.57) and the objective response rate (relative risk=2.13). 

Kim Chi noted that there were “no new safety signals” in the study. Grade 3 or 4 treatment-emergent adverse events occurred in 67.0% of men with HRR gene alterations given niraparib and 46.4% of those given placebo. Dose reductions were required in a corresponding 19.8% and 3.3% of patients, while treatment was discontinued by 10.8% and 4.7%, respectively.  

Nor was there a “clinically meaningful change” between these groups with regard to overall health-related quality of life, as measured by the FACT-P survey, the presenter said. 

Kim Chi also reported the results for the prespecified futility analysis for a second cohort of patients without HRR gene alterations, after 233 of the planned 600 patients had been recruited. At this time, there was no significant difference between men given niraparib plus abiraterone and controls for the composite endpoint of progression, defined as rPFS, PSA progression or death, and the HR of 1.09 met the criteria for futility. 

Noting that niraparib regimen was associated with increased grade 3–4 toxicity, the presenter said that the independent data monitoring committee recommended halting enrolment of men without HRR gene alterations to the study. 

Session discussant Celestia Higano, also from the University of British Columbia, observed that the median gain in rPFS with niraparib versus placebo was greater in the group of patients with BRCA1 or BRCA2 mutations versus the general HRR gene alteration group, at 5.7 versus 2.8 months. 

She recommended awaiting the mature OS findings before using niraparib plus abiraterone as first-line treatment for mCRPC in patients with HRR gene alterations, but noted that in the “poor prognosis subset” of men with BRCA mutations “it might be reasonable to treat such patients even before OS is available, given the poor outcomes with [abiraterone] alone.” 

Reference  

Chi KN, Rathkopf DE, Smith MR, et al. Phase 3 MAGNITUDE study: First results of niraparib (NIR) 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; abstr 12). DOI: https://doi.org/10.1200/JCO.2022.40.6_suppl.012