The addition of the PARP inhibitor niraparib (Zejula) to abiraterone acetate (Zytiga) plus prednisone (AAP) led to a significant improvement in radiographic progression-free survival (PFS) versus AAP alone in men with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene alterations, according to the final analysis of the primary end point of a phase 3 trial. These results were presented at the 2022 ASCO Genitourinary Cancers Symposium by lead investigator Kim Chi, MD, Chief Medical Officer and Vice President, BC Cancer Center, Vancouver, British Columbia, Canada.
“When choosing a treatment plan for patients, physicians must consider individual needs, particularly for patients with mCRPC with HRR gene alterations who face a poor prognosis. The MAGNITUDE data provide important context about the subgroup of patients who may benefit from treatment with niraparib in combination with AAP in the first-line setting, as well as those patients who may be better served by other treatment options,” Dr Chi said.
At a median follow-up of 18.6 months, patients with HRR-positive mCRPC treated with niraparib plus AAP had a significant 27% reduction in risk for radiographic PFS versus those treated with placebo plus AAP (P = .0217). The improvement was of a greater magnitude in men with BRCA1/2 gene alterations, who experienced a 47% reduction in risk for disease progression or death (P = .0014) versus those treated with AAP alone. Investigator-assessed radiographic PFS was even greater with the niraparib plus AAP regimen, with a 36% reduction in risk in patients with HRR alterations and a 50% reduction in risk in those with BRCA1/2 alterations versus the placebo plus AAP regimen (P = .0022 and P = .0006, respectively).
The MAGNITUDE Trial
The phase 3, randomized, placebo-controlled, multicenter MAGNITUDE trial enrolled 3 cohorts of men with mCRPC: those with prospectively defined HRR alterations and those without HRR alterations, who were randomized to receive niraparib plus AAP or placebo plus AAP, and a third cohort who received open-label treatment with the niraparib plus AAP regimen. Patients with HRR alterations (N = 423) were randomized to receive niraparib plus AAP (N = 212) or placebo plus AAP (control arm, N = 211).
The prespecified HRR genetic alterations included ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, and PALB2 alterations.
Among the cohort of patients without HRR gene alterations (N = 233) a preplanned futility analysis showed no evidence of benefit with the addition of niraparib to AAP. Enrollment in this cohort was stopped and unblinded, with the option to continue the assigned treatment at the discretion of the study investigator.
Among all HRR-positive patients, median radiographic PFS (the primary end point) was 16.5 months with niraparib plus AAP and 13.7 months with AAP alone (P = .0217). In the BRCA-positive subgroup, median radiographic PFS was 16.6 months versus 10.9 months, respectively (P = .0014).
“The benefit of the niraparib plus AAP combination was consistent across all prespecified subgroups,” Dr Chi said.
In patients with HRR gene alterations, the combination of niraparib plus AAP was superior to placebo plus AAP for all secondary end points at the first interim analysis. These included time to initiation of cytotoxic chemotherapy, time to symptomatic progression, and time to prostate-specific antigen progression. In addition, the objective response rate was higher with niraparib plus AAP versus AAP alone in the HRR-positive cohort.
“Niraparib plus AAP nearly doubled time to [prostate-specific antigen] progression, and complete response and partial response compared with AAP alone,” Dr Chi noted.
The observed safety profile of niraparib plus AAP was consistent with the known safety profile of each agent in the regimen. Among patients with HRR gene alterations, 67% of those in the niraparib plus AAP group had grade 3 adverse events and 46.4% of those in the AAP-alone group had grade 4 adverse events, largely driven by anemia and fatigue. Treatment discontinuation rates for the niraparib and placebo groups were 10.8% and 4.7%, respectively. The combination of niraparib plus AAP also maintained overall quality of life in comparison with placebo plus AAP, according to the Functional Assessment of Cancer Therapy-Prostate instrument.
Complexity of Trial Design
“MAGNITUDE had patients preselected according to biomarker status, and there are advantages and disadvantages for this, including the potential for overtreating biomarker negative patients. The statistics of this trial are quite complex, and there really are 2 separate trials—the biomarker-negative and biomarker-positive cohorts. Within the biomarker-positive cohort, there are 2 separate analyses for BRCA-positive and all HRR-positive patients,” said invited discussant Celestia S. Higano, MD, FACP, Medical Director, Prostate Cancer Supportive Care Program, Vancouver Prostate Centre, Canada, and Adjunct Professor, Department of Urologic Sciences, University of British Columbia, Vancouver.
Dr Higano noted that patients with BRCA1/2-positive mutations comprised a larger percentage of the MAGNITUDE population than other recent phase 3 trials. “These patients [ie, BRCA1/2] are known to have a worse outcome and more aggressive disease. Including all HRR-positive patients in the trial waters down the differences between the BRCA1/2 patients and all HRR positives,” she explained.
Based on MAGNITUDE results to date, “the combination of niraparib plus AAP should not be used in all HRR-positive patients until we have overall survival data and more detailed biomarker analysis. For BRCA1/2-positive patients, I would hedge my bets, and the combination might be a reasonable option given the poor outcomes of these patients. We still need overall survival data for those patients as well,” Dr Higano cautioned.