First-line treatment with niraparib significantly improves PFS in HRR-mutated mCRPC

The first results of the MAGNITUDE trial demonstrated that the addition of niraparib to abiraterone acetate and prednisone (AAP) improved radiographic progression-free survival (rPFS) and other clinically relevant outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) and alterations in HRR-associated genes. No evidence was found of a benefit of adding niraparib to AAP in HRR non-mutated patients.

Up to 30% of patients with mCRPC have alterations in genes associated with homologous recombination repair (HRR; e.g. BRCA2), which have been associated with poor prognosis but confer sensitivity to PARP inhibition [1,2]. Androgen receptor signalling regulates DNA repair in prostate cancer, providing a rationale for combined androgen receptor targeting with PARP inhibition [3]. The PARP inhibitor niraparib has shown anti-tumour activity in heavily pre-treated patients with HRR gene-altered mCRPC.

The phase 3 MAGNITUDE trial (NCT03748641) was initiated to assess the combination of niraparib plus AAP for mCRPC in prospectively selected patients with and without alterations in HRR-associated genes. Participants with HRR biomarker-positive and without specified gene alterations (HRR biomarker-negative) were randomised to receive niraparib plus AAP or placebo plus AAP. The primary endpoint was rPFS in the BRCA1/2-mutated subgroup followed by all HRR-positive participants. Secondary endpoints included time to initiation of cytotoxic chemotherapy, time to symptomatic progression, and overall survival. Dr Kim Chi (University of British Columbia, Canada) presented the first results [4].

HRR biomarker-positive patients (n=423) were randomised 1:1 to niraparib plus AAP or placebo plus AAP. After a median follow-up of 18.6 months, niraparib plus AAP significantly improved rPFS in the BRCA1/2-mutated subgroup (16.6 vs 10.9 months; HR 0.53; P=0.0014; see Figure). In addition, niraparib plus AAP significantly improved rPFS in all HRR biomarker-positive patients (16.5 vs 13.7 months; HR 0.73; P=0.0217). Niraparib plus AAP delayed time to cytotoxic chemotherapy (HR 0.59; P=0.0108), time to symptomatic progression (HR 0.69; P=0.0444), and time to PSA progression (HR 0.57; P=0.0001) in all HRR biomarker-positive patients. The overall response rate was 28% in the placebo arm versus 60% in the niraparib arm. The first interim analysis of overall survival is immature.

Figure: Radiographic progression-free survival in BRCA1/2-mutated participants [4]



AAP, abiraterone acetate and prednisone; CI, confidence interval; HR, hazard ratio; NIRA, niraparib; PBO, placebo; rPFS, radiographic progression-free survival.

The pre-planned futility analysis in 233 HRR biomarker-negative patients showed no benefit of adding niraparib to AAP in the prespecified composite endpoint (first PSA progression or rPFS; HR 1.095).

No new safety signals were seen. In HRR biomarker-positive patients, 67% and 46.4% had grade 3/4 adverse events and 10.8% and 4.78% discontinued treatment in the niraparib plus AAP and placebo plus AAP arms, respectively. There were no clinically significant differences in overall quality of life between arms.

Based on these results, Dr Chi concluded that “the MAGNITUDE study results support niraparib plus AAP as a new first-line treatment option for patients with mCRPC and alterations in genes associated with HRR. In addition, MAGNITUDE highlights the importance of testing for HRR gene alterations in patients with mCRPC to identify who will optimally benefit from the combination of niraparib plus AAP.”

Commenting on the results of PROpel and MAGNITUDE, discussant Dr Celestia Higano (University of British Columbia, Canada) cautioned to be aware of the differences in design between the 2 studies. In MAGNITUDE, HRR status was used to allocate patients to a cohort, while in PROpel patients were randomised regardless of their HRR status (which appeared to be well balanced in the end). In addition, due to the pre-specified futility analysis planned in the HRR-negative population in MAGNITUDE, the enrolment in this cohort was stopped after 200 patients (of the planned 600 patients). As a result, patient populations are not comparable in MAGNITUDE and PROpel, which could explain the differences in the results.

1. de Bono JS, et al. N Engl J Med 2020;382:2091–2102.
2. Hussain M, et al. N Engl J Med 2020;383:2345–2357.
3. Polkinghorn WR, et al. Cancer Discov 2013;3:1245–1253.
4. Chi KN, et al. Phase 3 MAGNITUDE study: First results of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) as first-line therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without homologous recombination repair (HRR) gene alterations. Abstract 12, ASCO GU 2022, 17–19 February.

 

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Posted on 8 April, 202215 February, 2024