Niraparib-abiraterone-prednisone combo improves multiple outcomes in HRR+ mCRPC

In patients with metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations*, combining niraparib with abiraterone acetate plus prednisone (AAP) in the first-line setting improved radiographic progression-free survival (rPFS) and other outcomes, results of the phase III MAGNITUDE study showed.

The population comprised patients with mCRPC and ECOG performance status 0–1. Prior AAP for ≤4 months was allowed. Patients were divided into two groups, biomarker (BM) positive or negative, with patients in each group randomized to receive either niraparib (200 mg QD) + AAP** or placebo + AAP.

Prespecified early futility analysis showed no radiographic or prostate-specific antigen (PSA) progression benefit with the addition of niraparib to AAP in patients who were HRR BM-negative (hazard ratio [HR], 1.09, 95 percent confidence interval [CI], 0.75–1.59). This was accompanied by a higher level of grade 3–4 toxicity in the niraparib–AAP compared with the placebo–AAP arm, which led to independent data monitoring committee recommending cessation of enrolment in this group.

A total of 423 HRR BM+ patients were included in the present analysis (median age 69 years). Twenty-three percent had previously received AAP, 21 percent had visceral metastases, and 53 percent had BRCA1/2 mutations.

Of the patients with BRCA 1/2 mutations, after a median follow-up of 16.7 months, rPFS, as per blinded independent central review, was significantly improved with niraparib–AAP compared with placebo–AAP (median 16.6 vs 10.9 months; HR, 0.53, 95 percent CI, 0.36–0.79; p=0.0014), with consistent results in the investigator analysis (median 19.3 vs 12.4 months; HR, 0.50, 95 percent CI, 0.33–0.75; p=0.0006). [ASCO GU 2022, abstract 12]

In the total HRR BM+ cohort, rFS was also improved with niraparib–AAP vs placebo–AAP after a median 18.6 months follow-up, both in central review (median 16.5 vs 13.7 months; HR, 0.73, 95 percent CI, 0.56–0.96; p=0.0217) and investigator analysis (median 19.0 vs 13.9 months; HR, 0.64, 95 percent CI, 0.49–0.86; p_nominal=0.0022).

Time to cytotoxic chemotherapy initiation was extended with niraparib–AAP vs placebo–AAP among all HRR BM+ patients (median not estimable [NE] vs 26.0 months; HR, 0.59, 95 percent CI, 0.39–0.89; p=0.0108), with a trend in that direction among patients with BRCA 1/2 mutations (median NE vs 26.0 months; HR, 0.58, 95 percent CI, 0.33–1.01; p_nominal=0.0495).

Time to symptomatic progression was also longer with niraparib–AAP vs placebo–AAP, though the results were only significant among all HRR BM+ patients (median NE for both groups; HR, 0.69; p=0.0444) and not the BRCA 1/2 mutation subgroup (median NE vs 19.8 months; HR, 0.68; p_nominal=0.1224). Time to PSA progression was also longer with niraparib–AAP vs placebo–AAP with a 43 percent improvement among all HRR BM+ patients (median 18.5 vs 9.3 months; HR, 0.57; p=0.0001) and 54 percent improvement in the BRCA 1/2 mutation subgroup (median NE vs 9.2 months; HR, 0.46; p_nominal=0.0002).

Overall survival, though immature at analysis, showed a benefit favouring niraparib–AAP vs placebo–AAP (HR, 0.767; p_nominal=0.1682).

Overall response rate was almost doubled with niraparib–AAP vs placebo–AAP in HRR BM+ patients (60 percent vs 28 percent; relative risk [RR], 2.13; p_nominal<0.001) and in the BRCA 1/2-mutated group (52 percent vs 31 percent; RR, 1.66; p_nominal=0.035). Complete responses were achieved in 22 percent vs 11 percent (HRR BM+) and 18 percent vs 14 percent (BRCA 1/2-mutated), respectively.

Acceptable safety

Grade 3–4 treatment-emergent adverse events (TEAEs) occurred in 67.0 and 46.4 percent of niraparib–AAP and placebo–AAP recipients, respectively. Serious AEs occurred in 35.8 and 24.6 percent, respectively, 11.3 and 2.8 percent, respectively, considered drug related. Among niraparib–AAP recipients, 19.8 percent had AEs leading to dose reduction compared with 3.3 percent of placebo–AAP recipients, while 10.8 and 4.7 percent, respectively, discontinued niraparib or placebo due to AEs. The most common AEs leading to dose reduction in niraparib–AAP recipients were anaemia (13.2 percent) and thrombocytopenia (2.8 percent).

Within 30 days of the last dose, eight and 12 deaths occurred due to prostate cancer in niraparib–AAP and placebo–AAP recipients, respectively, and 11 and seven due to AEs.

“Niraparib–AAP had a manageable safety profile with no new safety signals identified and health-related quality of life was maintained,” noted study author Professor Kim Chi from the University of British Columbia, BC Cancer – Vancouver Center, Vancouver, British Columbia, Canada.

HRR testing vital

“The MAGNITUDE study results support niraparib + AAP as a new first-line treatment option for patients with mCRPC and alterations in genes associated with HRR,” said Chi.

“MAGNITUDE [also] highlights the importance of testing for HRR gene alterations in patients with mCRPC, to identify who will optimally benefit from the combination of niraparib + AAP,” he said.