(UroToday.com) In a moderated poster presentation at the 2022 American Urologic Association Annual Meeting held in New Orleans and virtually, Dr. Tutrone presented results of the phase 2 QUEST study examining the role of combination therapy with niraparib and abiraterone acetate and prednisone in metastatic castration resistant prostate cancer (mCRPC). Approximately 20% of patients with metastatic prostate cancer will have alterations in genes associated with homologous recombination repair deficiency (HRD) which may sensitize to polyadenosine diphosphate-ribose polymerase (PARP) inhibition. Niraparib is a highly selective PARP inhibitor. Abiraterone acetate (AA) is a standard of care treatment approach in mCRPC which acts through inhibition of androgen axis signaling, which has a role in DNA repair. Targeting both of these pathways may enhance efficacy in metastatic castration-resistant prostate cancer (mCRPC), a hypothesis tested in the phase 2 QUEST study (NCT03431350). In this study, Dr. Tutrone reported safety, tolerability and efficacy results of the combination of niraparib with AA + prednisone (AAP).
This trial enrolled patients with mCRPC and alterations in HRD genes who had evidence of progression on one line of next generation AR-targeted therapy. All patients received niraparib 200mg once daily + AAP. Patients were divided into three cohorts on the basis of the HRD alterations.
The primary study endpoints were the incidence and severity of adverse events (AEs) and composite response rate (CRR), defined as proportion of patients with at least one of the following: objective response, circulating tumor cell (CTC) response, or prostate specific antigen (PSA) decline ≥50% (PSA50). Further, the authors considered key secondary endpoints including CTC response rate, objective response rate (ORR), and radiographic progression-free survival (rPFS). The response rates are presented with 90% 2-sided confidence intervals (CI) while time-to-event endpoints were evaluated by the Kaplan-Meier method.
The authors included 24 patients of whom 41.7% had soft tissue or nodal metastasis and 29.2% had received prior docetaxel. Of the 24 patients (all who had to have HRD alterations), 17 had BRCA1/2 alterations, 2 each had ATM or CHEK2, and 1 each had PALB2 or FANCA alterations. Over a median follow-up of 18 months, 8 of 24 patients (33%) remain on treatment. The median duration of niraparib therapy was 10.3 months (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%) patients and discontinuation in 2 patients. Serious drug-related AEs occurred in 3 patients though no deaths due to AEs were observed. Among 23 patients included in the efficacy population (1 patient was excluded as they were HRD-negative), the composite response rate was 52.2% (90% CI, 33.5‒70.4) and objective response rate was 50% (5/10 patients; 90% CI, 9.0–40.4). Among responders, the duration of response was 4.73 months (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).
The median rPFS was 11.0 months (90% CI, 9.7‒not estimable).
The authors concluded that among patients with mCRPC and HRD alterations who had previously received AR-targeted therapy the combination of niraparib and abiraterone acetate shows promising efficacy and manageable toxicity. Thus, these data formed the basis of the phase 3 MAGNITUDE study which further evaluates this combination as first-line therapy in patients with newly diagnosed mCRPC.Presented by: Ronald F. Tutrone, MD, Director of Research, Chesapeake Urology Research Associates
Written by: Christopher J.D. Wallis, University of Toronto Twitter: @WallisCJD during the 2022 American Urological Association (AUA) Annual Meeting, New Orleans, LA, Fri, May 13 – Mon, May 16, 2022.