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.

First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: the phase 3 TALAPRO-2 trial

“…Exploratory analysis in the BRCA1/BRCA2 subgroup showed an HR of 0.24 (95% CI, 0.12 to 0.45) 32 . The MAGNITUDE ( NCT03748641 ) trial also showed improved rPFS with the combination of niraparib plus abiraterone versus placebo plus abiraterone for patients with HRR gene alterations (HR, 0.73; 95% CI, 0.56 to 0.96), with particular benefit in the BRCA1/BRCA2 subgroup (HR, 0.53; 95% CI, 0.36 to 0.79) 33 . Exploratory single-gene analysis of the MAGNITUDE trial, although underpowered, showed potential benefit of combined PARP and androgen receptor inhibition in patients with a Fanconi anemia pathway gene alteration ( PALB2 , BRIP1 and FANCA ) beyond BRCA1/BRCA2 (ref.…”

HuR promotes castration-resistant prostate cancer progression by altering ERK5 activation via posttranscriptional regulation of BCAT1

“…Novel androgen synthesis and androgen receptor inhibitors, such as abiraterone and enzalutamide, significantly improve the prognosis of CRPC patients, but androgen receptor mutations limit their long-term efficacy [ 3 , 4 ]. Poly (ADP-ribose) polymerase inhibitors, such as olaparib and niraparib, have been approved for use in CRPC treatment by the FDA and EMA, but these agents are limited to CRPC patients bearing mutations in genes involved in homologous recombination repair [ 5 , 35 ]. Hence, there is a great unmet medical need for CRPC treatment due to a lack of effective and nonselective therapeutic targets.…”

Double trouble for prostate cancer: synergistic action of AR blockade and PARPi in non-HRR mutated patients

“…However, in MAGNITUDE, there was a preselection based on HRR-mutation status, while in TALAPRO-2 and PROpel, an unselected (all-comer) population with a substratification based on HRR-mutation status was included. All three studies showed a marked increase in radiographic progression-free survival (rPFS), time to first subsequent therapy or death (TFST), and a trend towards better overall survival (OS) with the use of PARPi in combination with an ARSI, compared to an ARSI alone in the HRR-mutated population, with the greatest benefit in the BRCA-mutated patients (6)(7)(8). MAGNITUDE (Niraparib and Abiraterone Acetate and Prednisone [AAP]) discontinued the non-HRR mutated arm prematurely due to ineffectiveness in the pre-planned futility analysis (6).…”

“…All three studies showed a marked increase in radiographic progression-free survival (rPFS), time to first subsequent therapy or death (TFST), and a trend towards better overall survival (OS) with the use of PARPi in combination with an ARSI, compared to an ARSI alone in the HRR-mutated population, with the greatest benefit in the BRCA-mutated patients (6)(7)(8). MAGNITUDE (Niraparib and Abiraterone Acetate and Prednisone [AAP]) discontinued the non-HRR mutated arm prematurely due to ineffectiveness in the pre-planned futility analysis (6). Both TALAPRO-2 (Talazoparib and Enzalutamide) and PROpel (Olaparib and AAP) were conducted in a population of unknown HRR status and showed a benefit for rPFS in the entire population.…”