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.
Alterations in homologous recombination repair genes (HRR+) involve approximately 20-30% of mCRPC patients and sensitise those to the therapy with PARP inhibitors (PARPi). Olaparib and rucaparib have shown a benefit in males with mCRPC and HRR+ previously treated with androgen-receptor pathway inhibitor (ARPI) compared to standard of care, with a particularly pronounced advantage in men with BRCA1/2 mutations. Preclinical studies suggest a synergic effect combining PARPi with ARPI. Indeed, ARPI downregulates expression of DNA repair genes and therefore sensitises prostate cancer cells to PARP inhibition.
MAGNITUDE is a randomised phase III trial that evaluated efficacy and safety of adding niraparib to abiraterone as first line treatment in patients with mCRPC with or without HRR alterations (2 cohorts: HRR+ and HRR-). The HRR panel tested was comprised of 9 genes (ATM, BRCA1, BRCA2, BRIP1, CDK12, CHECK2, FANCA, HDAC2, PALB2). The primary endpoint was radiological progression-free survival (rPFS) assessed by a central review. The cohort HRR- was prematurely stopped after enrolment of 233 patients due to futility after the pre-planned analysis. Regarding the cohort HRR+, the rPFS was statistically longer in the niraparib + abiraterone arm (16.5 vs 13.7 months, HR 0.73, 95%CI, 0.56-0.96, p=0.022). In the BRCA 1/2 population (n=190/423), the benefit was even greater (16.6 vs 10.9 months, HR, 0.53, CI95%, 0.36-0.79, p=0.001). A trend was observed in terms of overall survival (secondary endpoint) but was not statistically significant (HR, 0.77, 95%CI, 0.53-1.12). Regarding safety profile, incidence of grade ≥3 adverse events (AE) was higher in the niraparib + abiraterone group (67% vs 46%). The most frequent adverse events were: anaemia (46% vs 20%), hypertension (31% vs 21%), constipation (31% vs 14%), fatigue (26% vs 17%), nausea (24% vs 14%) and thrombocytopenia (21% vs 8%). Almost 20% (n=42) of patients had a dose reduction in niraparib arm (vs 3% in placebo arm) and 11% had to stop niraparib due to AE (compared to 5% in placebo arm).
MAGNITUDE confirms that adding the PARPi niraparib to abiraterone prolonged PFS in patients with HRR+ mCRPC, especially in BRCA1/2 patients. However, the lack of benefit observed in HRR- population contrasts with the results of TALAPRO-2 and PROPEL trials, in which the PFS delay was observed regardless of HRR status. Therefore, the European Medicine Agency adopted a positive opinion for marketing authorisation of niraparib in association with abiraterone as first line treatment in mCRPC but restricted its use to patients harbouring BRCA1/2 germline and/or somatic mutations who are not able to receive chemotherapy. A molecular testing should still be performed at mCRPC setting.