Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations represent a distinct molecular subtype of mCRPC patients with a more aggressive clinical phenotype and worse prognosis. The results of a secondary analysis of the MAGNITUDE trial, recently published in Annals of Oncology, demonstrate that the combination of niraparib with abiraterone acetate and prednisone (AAP) significantly improves the radiographic progression-free survival and other clinical outcomes in this patient population.
Despite treatment advancements, mortality among patients with metastatic castration-resistant prostate cancer (mCRPC) remains high. About 30% of mCRPC patients carry DNA damage repair gene mutations, including homologous recombination repair (HRR) genes, linked to therapy resistance and poor outcomes. Increasing evidence suggests that patients with mCRPC and BRCA1/2 alterations represent a distinct molecular subtype of mCRPC with a more aggressive clinical phenotype and worse prognosis. Poly adenosine diphosphate-ribose polymerase (PARP) inhibitors have demonstrated significant activity in patients with prostate cancer and HRR mutations, with the most pronounced clinical benefit in patients harbouring a BRCA1/2 mutation. The first interim analysis (IA1) of the MAGNITUDE trial revealed that a combination of the PARP inhibitor niraparib with abiraterone acetate and prednisone (AAP) improves the radiographic progression-free survival (rPFS) in mCRPC patients with HRR alternations, compared to AAP alone. Recently, updated results from a second interim analysis (IA2) of this trial were published, focusing on the preplanned subgroup analysis of patients with a BRCA1/2 alteration.
The phase 3 MAGNITUDE trial enrolled mCRPC patients who did not receive prior therapy for mCRPC except for ≤4 months of prior AAP and ongoing androgen deprivation therapy. Patients were prospectively screened for HRR gene alterations (ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, or PALB2) from blood and/or tumour tissue (archival or recently collected) samples. In total, 423 patients were randomly assigned (1:1) to receive either niraparib (200 mg) plus AAP (n=212) or placebo plus AAP (n=211), all administered daily. The primary endpoint was rPFS. At IA2, secondary endpoints, including time to symptomatic progression, time to initiation of cytotoxic chemotherapy and overall survival (OS) were assessed.
After a median follow-up of 24.8 months, the risk of progression or death was reduced by 45% in BRCA1/2-altered mCRPC patients receiving niraparib plus AAP, compared to those receiving placebo plus AAP (median rPFS was 19.5 vs. 10.9 months, respectively; HR[95%CI]: 0.55[0.39-0.78]; p = 0.0007). Of note, the rPFS was also significantly longer with the niraparib-AAP combination in the total HRR+ population [HR[95%CI]: 0.76[0.60-0.97]; p = 0.0280)]. Among BRCA1/2-mutated patients, the niraparib-containing regimen was also associated with a significantly longer time to symptomatic progression [HR[95%CI]: 0.54[0.35-0.85]; p = 0.0071) and time to initiation of cytotoxic chemotherapy (HR[95%CI]:0.56[0.35-0.90]; p = 0.0152) compared to AAP alone. The OS analysis initially showed no significant differences between the groups (HR[95%CI]: 0.88[0.58-1.34]; p = 0.5505). However, after accounting for imbalances in subsequent use of PARP inhibitors and other life-prolonging therapies, the prespecified inverse probability censoring weighting (IPCW) analysis of OS showed a 46% reduction in the risk of death with niraparib compared with placebo in the BRCA1/2 subgroup [HR[95%CI]: 0.54[0.33-0.90]; p = 0.0181). No new safety signals were observed. In the HRR+ population, the most common grade ≥3 AEs were anaemia (30.2% vs. 8.5% in the niraparib and placebo groups, respectively) and hypertension (15.6% vs. 12.3%). Observations were similar in the BRCA1/2 subgroup, with the exception of grade 3 hypertension, which occurred more frequently in the placebo group (15.2%) compared to the niraparib group (13.3%).
In conclusion, MAGNITUDE, enrolling the largest BRCA1/2 cohort in first-line mCRPC to date, demonstrated an improved rPFS and other clinically relevant outcomes when adding niraparib to AAP in patients with BRCA1/2-altered mCRPC. As such, these data underscore the clinical relevance of identifying this subset of mCRPC patients.
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