Niraparib regimen improves outcomes for men with prostate cancer, HRR gene alterations
SAN FRANCISCO — The addition of niraparib to abiraterone acetate and prednisone improved multiple outcomes for certain men with metastatic castration-resistant prostate cancer, according to randomized phase 3 study results.
A second interim analysis of the MAGNITUDE trial — presented at ASCO Genitourinary Cancers Symposium — showed the combination extended radiographic PFS for men with homologous recombination repair (HRR) gene alterations, consistent with previously reported results. The benefit appeared particularly strong among men with BRCA mutations.
Updated findings also showed the regimen extended time to symptomatic progression and time to cytotoxic chemotherapy, with a trend toward improved OS.
“All of the data is pointing toward a clear message that if a patient has a finding in line with a BRCA alteration, you should consider the combination. Just going for a [novel hormonal agent] alone is not enough,” researcher Eleni Efstathiou, MD, PhD, genitourinary oncology section chief at Houston Methodist Cancer Center, told Healio.
Background and methodology
Approximately 25% of men with metastatic castration-resistant prostate cancer have alterations in genes associated with HRR. Prognosis for these men — especially those with BRCA mutations — is poor.
Researchers conducted MAGNITUDE to evaluate whether the addition of niraparib (Zejula) — an orally administered poly (ADP-ribose) polymerase (PARP) inhibitor — to abiraterone acetate (Zytiga, Janssen) and prednisone would improve outcomes for men with metastatic castration-resistant prostate cancer.
GSK markets niraparib in ovarian cancer — for which there is an approved indication — and Janssen has the rights for niraparib in prostate cancer.
Prior to randomization, investigators used a nine-gene panel to determine biomarker status, assessing alterations in ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2 or PALB2.
Researchers randomly assigned men 1:1 to abiraterone acetate and prednisone plus either 200 mg niraparib once daily or placebo.
Radiographic PFS by blinded independent central review among men in the BRCA1/BRCA2-positive subgroup, as well as among all men with HRR biomarker-positive disease, served as the primary endpoint. Secondary endpoints included time to initiation of cytotoxic chemotherapy, time to symptomatic progression and OS.
The analysis included 423 men (median age, 69 years) with HRR biomarker-positive disease, of whom 212 received the niraparib regimen and 211 received placebo. About half (53%) of these men had BRCA1 or BRCA2 mutations.
As Healio previously reported, results presented at last year’s ASCO Genitourinary Cancers Symposium — based on median follow-up of 18.6 months — showed longer median radiographic PFS with niraparib among all men with HRR biomarker-positive disease (16.5 vs. 13.7 months; HR = 0.73; 95% CI, 0.56-0.96), as well in the BRCA1/BRCA2 subgroup (16.6 months vs. 10.9 months; HR = 0.53; 95% CI, 0.36-0.79).
‘Robust’ results
At this year’s ASCO GU, Efstathiou presented results of a second planned interim analysis based on a median 26.8 months’ follow-up.
Results showed continued improvement in radiographic PFS benefit with niraparib among all men with HRR biomarker-positive disease (median, 16.7 months vs. 13.7 months; HR = 0.76; 95% CI, 0.6-0.97), as well as in the BRCA1/BRCA2 subgroup (median, 19.5 months vs. 10.9 months; HR = 0.55; 95% CI, 0.39-0.78).
“In the BRCA subgroup, median PFS for placebo-abiraterone had the same PFS reported in the first interim analysis — 10.9 months. That is very grim,” Efstathiou said. “And men who harbor BRCA mutations and received nirparib plus abiraterone had almost double the PFS of abiraterone-placebo. That results in a very robust hazard ratio with about a 45% improvement in risk for progression or death.”
Approximately 35% of men assigned the niraparib regimen remained on treatment at data cutoff.
Analyses of secondary endpoints showed the niraparib regimen significantly extended time to symptomatic progression among all men with HRR biomarker-positive disease (median, not reached vs. 30.6 months; HR = 0.6; 95% CI, 0.42-0.84) and those with BRCA alterations (median, not reached vs. 23.6 months; HR = 0.54; 95% CI, 0.35-0.85).
“To me, time to symptomatic progression is more important even than [radiographic] PFS because the symptoms are what’s compromising our patients’ lives,” Efstathiou said. “It’s not as tangible as looking at a scan but, at the end of the day, that is what our patients and their families care about.”
The niraparib regimen also extended time to cytotoxic chemotherapy among all men in the HRR biomarker-positive cohort (median not reached in either group; HR = 0.67; 95% CI, 0.47-0.94) and those with BRCA alterations (median, not reached vs. 27.3 months; HR = 0.56; 95% CI, 0.35-0.9).
OS data remained immature. At data cutoff, stratified analyses of the BRCA1/BRCA2 cohort showed an HR of 0.88 (95% CI, 0.58-1.34) favoring niraparib. An inverse probability censored weighting analysis — which corrected for differences in baseline characteristics and subsequent treatments — showed a trend toward improved OS with niraparib (HR = 0.54; 95% CI, 0.33-0.9).
The safety profile of the niraparib regimen in the second interim analysis appeared consistent with prior reports. Researchers observed no new safety signals.
The most common adverse events in the niraparib group included anemia (50% for niraparib vs. 22.7% for placebo), hypertension (33% vs. 22.3%) and constipation (33% vs. 15.6%).
“PARP inhibitors do cause some myelotoxicity. Patients need to be monitored for that, along with fatigue,” Efstathiou said. “At the end of the day, it becomes a benefit-to-risk ratio.”
Clinical implications
The findings continue to support the use of niraparib with abiraterone acetate and prednisone for men with metastatic castration-resistant prostate cancer who harbor BRCA alterations or select other HRR gene alterations, researchers concluded.
They also support the importance of genomic testing and its potential to inform personalized treatment, Efstathiou said.
National Comprehensive Cancer Network guidelines have recommended genomic tumor testing for advanced prostate cancer since 2019.
“When a patient walks in my door, we check off PSA, biopsy, blood work and testosterone level,” she told Healio. “What are we missing? Genomics. It’s as clear and as simple a message as can be. Pathology is important, but it’s not enough. You need genomics.”
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Efstathiou E, at al. Abstract 170. Presented at: ASCO Genitourinary Cancers Symposium; Feb. 16-18, 2023; San Francisco.