As reported in the Journal of Clinical Oncology by Kim N. Chi, MD, and colleagues, the phase III MAGNITUDE trial showed that the addition of niraparib to abiraterone acetate and prednisone improved radiographic progression–free survival as first-line treatment in patients with metastatic castration-resistant prostate cancer with BRCA1/2 alterations and among all patients with homologous recombination repair (HRR) gene alterations.

As stated by the investigators, “HRR gene alterations, including BRCA1/2 alterations, can sensitize cancer cells to poly (ADP-ribose) polymerase inhibition, which may improve outcomes in treatment-naive metastatic castration-resistant prostate cancer when combined with androgen receptor signaling inhibition.”

Kim N. Chi, MD

Study Details

In the international double-blind trial, 423 patients with HRR gene alterations (HRR-positive cohort) were randomly assigned between May 2019 and March 2021 to receive niraparib at 200 mg once daily (n = 212) or placebo (n = 211) plus abiraterone acetate at 1,000 mg once daily and prednisone at 5 mg twice daily; treatment was continuous in 28-day cycles until unequivocal clinical progression or unacceptable toxicity. A total of 247 patients without HRR gene alterations (HRR-negative cohort) were randomly assigned between March 2019 and March 2020 to the niraparib group (n = 123) or the control group (n = 124).

The primary endpoint was radiographic progression–free survival as assessed by central review, with analysis first in the BRCA1/2 subgroup and then in the full HRR-positive cohort. A preplanned futility analysis was performed in the HRR-negative cohort.

Radiographic Progression–Free Survival

Median duration of follow-up in the HRR-positive cohort was 18.6 months (range = 0.3–29.0 months). In the BRCA1/2 subgroup (n = 190; 98 in niraparib group, 92 in control group), median radiographic progression–free survival was 16.6 months in the niraparib group vs 10.9 months in the control group (hazard ratio [HR] = 0.53, 95% confidence interval [CI] = 0.36–0.79, P = .001). In the total HRR-positive cohort, median radiographic progression–free survival was 16.5 vs 13.7 months (HR = 0.73, 95% CI = 0.56–0.96, P = .022).

In the HRR-positive cohort, patients in the niraparib group had significant benefits in time to symptomatic progression (HR = 0.69, 95% CI = 0.47–0.99, P = .04) and time to initiation of cytotoxic chemotherapy (HR = 0.59, 95% CI = 0.39–0.89, P = .0110).

In the HRR-negative cohort, the niraparib group showed no benefit vs the control group in the composite endpoint of time to prostate-specific antigen progression or radiographic progression–free survival (HR = 1.09, 95% CI = 0.75–1.57, P = .66). Futility was declared based on the prespecified criteria, and enrollment in the cohort was stopped based on Independent Data Monitoring Committee recommendation.

Adverse Events

In the HRR-positive cohort, the most common adverse events of any grade in the niraparib group were anemia (46.2% vs 20.4% in control group), hypertension (31.1% vs 20.9%) and constipation (30.7% vs 13.7%). Grade ≥ 3 adverse events occurred in 67.0% of the niraparib group vs 46.4% of the control group, with the most common being anemia (29.7% vs 7.6%) and hypertension (14.6% vs 12.3%). Other notable grade 3 or 4 adverse events included thrombocytopenia (6.6% vs 2.4%) and neutropenia (6.6% vs 1.4%).

The investigators concluded, “Combination treatment with niraparib plus abiraterone acetate and prednisone significantly lengthened radiographic progression–free survival in patients with HRR-positive metastatic castration-resistant prostate cancer compared with standard-of-care abiraterone acetate plus prednisone.”

Dr. Chi, of BC Cancer-Vancouver Center, University of British Columbia, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Janssen Research & Development, LLC. For full disclosures of the study authors, visit ascopubs.org.