Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer

Abstract

Purpose: Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with current standard-of-care therapies. Homologous recombination repair (HRR) gene alterations, including BRCA1/2 alterations, can sensitize cancer cells to poly (ADP-ribose) polymerase inhibition, which may improve outcomes in treatment-naïve mCRPC when combined with androgen receptor signaling inhibition.

Methods: MAGNITUDE (ClinicalTrials.gov identifier: NCT03748641) is a phase III, randomized, double-blinded study that evaluates niraparib and abiraterone acetate plus prednisone (niraparib + AAP) in patients with (HRR+, n = 423) or without (HRR-, n = 247) HRR-associated gene alterations, as prospectively determined by tissue/plasma-based assays. Patients were assigned 1:1 to receive niraparib + AAP or placebo + AAP. The primary end point, radiographic progression-free survival (rPFS) assessed by central review, was evaluated first in the BRCA1/2 subgroup and then in the full HRR+ cohort, with secondary end points analyzed for the full HRR+ cohort if rPFS was statistically significant. A futility analysis was preplanned in the HRR- cohort.

Results: Median rPFS in the BRCA1/2 subgroup was significantly longer in the niraparib + AAP group compared with the placebo + AAP group (16.6 v 10.9 months; hazard ratio [HR], 0.53; 95% CI, 0.36 to 0.79; P = .001). In the overall HRR+ cohort, rPFS was significantly longer in the niraparib + AAP group compared with the placebo + AAP group (16.5 v 13.7 months; HR, 0.73; 95% CI, 0.56 to 0.96; P = .022). These findings were supported by improvement in the secondary end points of time to symptomatic progression and time to initiation of cytotoxic chemotherapy. In the HRR- cohort, futility was declared per the prespecified criteria. Treatment with niraparib + AAP was tolerable, with anemia and hypertension as the most reported grade ≥ 3 adverse events.

Conclusion: Combination treatment with niraparib + AAP significantly lengthened rPFS in patients with HRR+ mCRPC compared with standard-of-care AAP.

[Media: see text].

FIG 1.

CONSORT diagram. ^a3,283 includes those 2,984 patients who entered prescreening de novo (did not have known HRR status from local testing or from the local vendor in China, AmoyDx). ^bFourteen patients with CDK12 alterations were prospectively included in the HRR− cohort before amendment 4. Reasons for failed screening include AE, death, progressive disease, screen failure, withdrawal by patient, and others. HRR biomarker status was determined using the required assay on tissue and/or blood samples (FoundationOne tissue test [FoundationOneCDx], Resolution Bioscience HRD plasma test, AmoyDx blood and tissue assays, or accredited local laboratory biomarker tests with central review demonstrating a pathogenic germline or somatic alteration listed in the study biomarker gene panel). AAP, abiraterone acetate plus prednisone; AE, adverse event; HRD, homologous recombination deficiency; HRR, homologous recombination repair; NIRA, niraparib; PBO, placebo.

FIG 2.

Kaplan-Meier estimates of rPFS. (A) rPFS of the subgroup of patients with BRCA1/2 alterations as assessed by blinded independent central review. (B) rPFS of the overall HRR+ cohort as assessed by blinded independent central review. (C) Prespecified sensitivity analysis of rPFS of patients with BRCA1/2 alterations by investigator assessment. (D) rPFS of the overall HRR+ cohort by investigator assessment. AAP, abiraterone acetate plus prednisone; HR, hazard ratio; HRR, homologous recombination repair; NIRA, niraparib; PBO, placebo; PFS, progression-free survival; rPFS, radiographic progression-free survival.

FIG 3.

Forest plot of rPFS for subgroups defined by baseline clinical disease characteristics in the HRR+ cohort. AAP, abiraterone acetate plus prednisone; AR, androgen receptor; BPI-SF#3, Brief Pain Inventory–Short Form, Item 3; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; HRR, homologous recombination repair; NE, not evaluable; NIRA, niraparib; PBO, placebo; PSA, prostate-specific antigen; rPFS, radiographic progression-free survival.

FIG 4.

Kaplan-Meier estimates of secondary end points. (A and B) Kaplan-Meier estimates of TCC and TSP in the HRR+ cohort, respectively. (C and D) Kaplan-Meier estimates of TCC and TSP in the BRCA1/2 subgroup, respectively. (E) Kaplan-Meier estimate of OS in the HRR+ cohort. AAP, abiraterone acetate plus prednisone; HR, hazard ratio; HRR, homologous recombination repair; NE, not evaluable; NIRA, niraparib; OS, overall survival; PBO, placebo; TCC, time to initiation of cytotoxic chemotherapy; TSP, time to symptomatic progression.

FIG 5.

Kaplan-Meier estimates of time to PSA progression and ORRs. (A and B) Kaplan-Meier estimates of time to PSA progression and ORRs in the HRR+ cohort, respectively. (C and D) Kaplan-Meier estimates of time to PSA progression and ORRs in the BRCA1/2 subgroup, respectively. AAP, abiraterone acetate plus prednisone; CR, complete response; HR, hazard ratio; HRR, homologous recombination repair; NE, not evaluable; NIRA, niraparib; ORR, objective response rate; PBO, placebo; PR, partial response; PSA, prostate-specific antigen; RR, relative risk.