Niraparib regimen ‘new first-line option’ for certain men with metastatic prostate cancer
SAN FRANCISCO — The addition of niraparib to abiraterone acetate and prednisone improved outcomes for certain men with prostate cancer, according to randomized phase 3 study results presented at ASCO Genitourinary Cancers Symposium.
The regimen significantly extended radiographic PFS for men with metastatic castration-resistant disease and alterations in homologous recombination repair genes, results of the MAGNITUDE study showed. It also significantly delayed time to cytotoxic chemotherapy, symptomatic progression and PSA progression.
“MAGNITUDE really highlights the importance of testing for homologous recombination repair gene alterations among men with metastatic castration-resistant prostate cancer,” Kim N. Chi, MD, FRCPC, medical oncologist and chief medical officer of BC Cancer, told Healio. “This is how we practice precision medicine, and this is how we will identify those who will optimally benefit from a combination such as this.”
Approximately 25% of men with metastatic castration-resistant prostate cancer have alterations in genes associated with homologous recombination repair.
“After androgen receptor pathway inhibitors, the use of subsequent therapy begins to decline for several reasons,” Chi told Healio. “Patients may have very aggressive disease and not make it to that next line of therapy, or there may be concerns about the perceived benefit vs. toxicity — particularly for this older patient population.
“Patients who have DNA repair alterations often have the worst prognosis, and can have the poorest response to androgen receptor pathway inhibitors,” Chi added. “Therefore, it is very important that we try to improve first-line therapy as much as possible.”
Evidence suggests co-targeting androgen receptor signaling and poly (ADP-ribose) polymerase (PARP) inhibition could be beneficial for men with or even without alternations in DNA repair genes involved with homologous recombination repair, Chi said.
Niraparib (Zejula), an orally administered PARP inhibitor, is approved in the United States for maintenance treatment of women with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who achieved complete or partial response to first-line platinum-based chemotherapy. GlaxoSmithKline markets niraparib in ovarian cancer, and Janssen has the rights for niraparib in prostate cancer.
Chi and colleagues conducted MAGNITUDE to evaluate whether the addition of niraparib to abiraterone acetate (Zytiga, Janssen) and prednisone improved outcomes for men with metastatic castration-resistant prostate cancer with or without alterations in homologous recombination repair-associated genes.
The double-blind study included men with or without homologous recombination repair biomarker-positive disease. 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. Eligible men had less than 4 months of prior treatment with abiraterone acetate and prednisone as first-line therapy for metastatic castration-resistant disease.
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 homologous recombination repair biomarker-positive disease, served as the primary endpoint.
Secondary endpoints included time to initiation of cytotoxic chemotherapy, time to symptomatic progression and OS. Additional endpoints included time to PSA progression and objective response rate.
The analysis included 423 men (median age, 69 years) with homologous recombination repair biomarker-positive disease, of whom 212 received the niraparib regimen and 211 received placebo. In this group, 23% had received prior abiraterone acetate and prednisone, 21% had visceral metastases, and 53% had BRCA1 or BRCA2 mutations.
Median follow-up was 18.6 months.
Results by blinded independent central review showed significantly longer median radiographic PFS among niraparib-treated men in the BRCA1/BRCA2 subgroup (16.6 months vs. 10.9 months; HR = 0.53; 95% CI, 0.36-0.79) and among all men with homologous recombination repair biomarker-positive disease (16.5 vs. 13.7 months; HR = 0.73; 95% CI, 0.56-0.96).
“We are seeing a bit of a diminishing effect when you add the various other genes that were evaluated,” Chi told Healio. “We know that different genes have different associations with susceptibility to PARP inhibition, and a gene-by-gene analysis will be forthcoming. But when we look at secondary and other endpoints, the benefit seems to be very similar between the BRCA1/BRCA2 cohort and the overall biomarker-positive cohort.”
In the overall biomarker-positive cohort, researchers reported improved outcomes among niraparib -treated men with regard to time to cytotoxic chemotherapy (HR = 0.59; 95% CI, 0.39-0.89), time to symptomatic progression (HR = 0.69; 95% CI, 0.47-0.99), time to PSA progression (HR = 0.57; 95% CI, 0.43-0.76) and ORR (RR = 2.13; 95% CI, 1.45-3.13).
OS data had not matured by the first interim analysis but, based on trends observed after relatively few events, Chi said he is “very optimistic” that an OS advantage in favor of the niraparib regimen will emerge in subsequent analyses.
A preplanned futility analysis of 233 men with homologous recombination repair biomarker-negative disease showed no benefit of niraparib with regard to the prespecified composite endpoint, which included the first of radiographic progression or PSA progression (HR = 1.09; 95% CI, 0.75-1.57).
Researchers observed no new safety signals with niraparib. In the group of men with homologous recombination repair biomarker-positive disease, a higher percentage of those assigned the niraparib regimen developed grade 3 or grade 4 treatment-emergent adverse events (67% vs. 46.4%) and discontinued treatment (9% vs. 3.8%).
“The increase in grade 3/grade 4 adverse events was driven by anemia, which is manageable with dose reductions, dose interruptions and supportive care,” Chi said. “Overall, the median relative dose intensity was about 99% for niraparib, so we were able to deliver adequate dosing.”
Investigators reported no clinically meaningful differences in overall quality of life per assessment with the Functional Assessment of Cancer Therapy-Prostate scales.
“The study results support the use of this regimen as a new first-line treatment option for men with metastatic castration-resistant prostate cancer who have alterations in genes associated with homologous recombination repair, particularly BRCA1 and BRCA2,” Chi said.
Perspective
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At first glance, this would appear to be a stratified biomarker design trial but, in fact, there are differences. The advantage of this type of design is that you can look at the treatment effect within each biomarker as well as across groups. … But there are disadvantages because, in order to do this type of trial, you need a large number of patients and there is a potential for overtreatment of biomarker-negative patients, which I think MAGNITUDE was trying to take into account with the futility analysis.
The futility analysis … looks pretty futile, but look at how many events there were: 83 PSA progression events and only 65 [radiographic PFS] events. I wonder if there was a missed opportunity here to better understand the interaction between the experimental arm and this group of [homologous recombination repair]-negative patients, given the results of the PROpel trial. In addition, we know very well metastatic [castration-resistant prostate cancer] does not correlate with much. It can go up and down and is not necessarily really related to radiographic PFS, so I do have some issues with that.
With respect to MAGNITUDE, should one use niraparib and abiraterone as first-line therapy for all patients with [homologous recombination repair] mutations? No. I think we have to await the OS data, and I will be interested in seeing the planned biomarker analysis, where I’m assuming we’re going to be looking at BRCA- vs. non-BRCA-stratified patients.
Should one use use niraparib and abiraterone as first-line therapy for patients with BRCA1/2 before the OS data are mature? I think statisticians might say no, but I would say maybe, because as a clinician I know this is a very poor-prognosis subset and it appears to have significant benefit in terms of [radiographic] PFS. So, it might be reasonable to treat such patients even before OS data are available, given the poor outcomes with abiraterone alone.
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Chi KN, et al. Abstract 12. Presented at: ASCO Genitourinary Cancers Symposium; Feb. 17-19, 2022; San Francisco.