Niraparib With Abiraterone Acetate and Prednisone for Metastatic Castration-Resistant Prostate Cancer: Results From the Phase 2 Quest Study
Journal of Urology
INTRODUCTION AND OBJECTIVE:
Approximately 20% of metastatic prostate cancers have alterations in genes associated with homologous recombination repair deficiency (HRD). Niraparib (NIRA) is a highly selective polyadenosine diphosphate-ribose polymerase (PARP) inhibitor and abiraterone acetate (AA) inhibits androgen axis signaling, which has a role in DNA repair. Targeting both oncogenic drivers may enhance efficacy in metastatic castration-resistant prostate cancer (mCRPC). The phase 2 QUEST study (NCT03431350) evaluated NIRA combinations in patients (pts) with mCRPC. We report safety, tolerability and efficacy of NIRA with AA + prednisone (AAP).
Pts with mCRPC and alterations in HRD genes with progression on 1 line of next generation AR-targeted therapy received NIRA 200mg once daily + AAP. Primary endpoints were incidence and severity of adverse events (AEs) and composite response rate (CRR), defined as proportion of pts with 1 of the following: objective response, circulating tumor cell (CTC) response, or prostate specific antigen (PSA) decline ≥50% (PSA50). Key secondary endpoints were CTC response rate, objective response rate (ORR), and radiographic progression-free survival (rPFS). Responses are presented with 90% 2-sided confidence intervals (CI); time-to-event endpoints were evaluated by the Kaplan-Meier method.
24 pts were enrolled. 41.7% had soft tissue or nodal metastasis, 29.2% had prior docetaxel. 17 pts had BRCA1/2 alterations, 2 pts each had ATM or CHEK2, 1 each had PALB2 or FANCA. With a median follow-up of 18 mos, 8 pts remain on treatment. Median duration of NIRA was 10.3 mos (range 0.7‒22.0). The most common grade ≥3 AEs were anemia (41.7%), thrombocytopenia (20.8%), fatigue (16.7%), and neutropenia (12.5%). Treatment-emergent AEs (TEAE) led to dose interruption/reduction in 14 (58.3%) pts and discontinuation in 2 pts. There were serious drug-related AEs in 3 pts and no deaths due to AEs. Of 23 pts in the efficacy population (1 pt was HRD-negative), CRR was 52.2% (90% CI, 33.5‒70.4). ORR was 50% (5/10 pts; 90% CI, 9.0–40.4); duration of response was 4.73 mos (range 3.7‒8.2). CTC response rate was 26.1% (90% CI, 12.0–45.1) and PSA50 was 30.4% (90% CI, 15.2‒49.6). Median rPFS was 11.0 mos (90% CI, 9.7‒not estimable).
In pts with mCRPC and HRD alterations and prior AR-targeted therapy, NIRA+AAP has promising efficacy and a manageable safety profile. The phase 3 MAGNITUDE study further evaluates this combination in pts with newly diagnosed mCRPC.
Chi K, Fleshner N, Chiuri VE, Van Bruwaene S, Hafron J, McNeel DG, et al. Niraparib with abiraterone acetate and prednisone for metastatic castration-resistant prostate cancer: results from the phase 2 QUEST study. J Urol. 2022 May;207(Suppl 5):e456-e457. doi:10.1097/JU.0000000000002570.17.