Niraparib with Abiraterone Acetate and Prednisone for Metastatic Castration-Resistant Prostate Cancer: Phase II QUEST Study Results

Abstract Niraparib (NIRA) is a highly selective inhibitor of poly (adenosine diphosphate-ribose) polymerase, PARP1 and PARP2, which play a role in DNA repair. The phase II QUEST study evaluated NIRA combinations in patients with metastatic castration-resistant prostate cancer who were positive for homologous recombination repair gene alterations and had progressed on 1 prior line of novel androgen receptor-targeted therapy. Results from the combination of NIRA with abiraterone acetate plus prednisone, which disrupts androgen axis signaling through inhibition of CYP17, showed promising efficacy and a manageable safety profile in this patient population.


Introduction
Up to approximately 30% of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor alterations in genes associated with homologous recombination repair (HRR), rendering them susceptible to poly (adenosine diphosphate-ribose) polymerase (PARP) inhibition. 1,2 In addition, PARP1 has been found to regulate both androgen receptor (AR) function and response to DNA damage. Niraparib (NIRA), a potent and highly selective inhibitor of PARP1 and PARP2, is approved in the USA, Canada, Europe, and China for use in adult patients for several indications, including ovarian, fallopian tube, and primary peritoneal cancer [3][4][5][6] and is currently under study for the treatment of prostate cancer. The AR axis remains an important oncogenic driver and therapeutic target for mCRPC. 1 Therefore, targeting both oncogenic dependencies may result in improved outcomes in prostate cancer. 1,7,8 This QUEST study (ClinicalTrials.gov Identifier: NCT03431350) is a phase II, multicenter, openlabel clinical trial designed to evaluate NIRA in combination with other agents in separate cohorts of patients with mCRPC and alterations in genes associated with HRR. We report on the safety and efficacy of the combination of NIRA with abiraterone acetate plus prednisone (AAP).

Patients
Patients with mCRPC who were biomarker-positive for an alteration in genes associated with HRR (ATM, BRCA1, BRCA2, BRIP1, CHEK2, FANCA, HDAC2, and PALB2) by either blood or tissue assay (HDAC2 only by blood assay) and who had progressed on 1 prior line of novel AR-targeted therapy for mCRPC were eligible. Prior treatment with taxanebased therapy and AR-targeted therapy outside of the mCRPC e310 The Oncologist, 2023, Vol. 28, No. 5 setting was allowed. All patients provided written informed consent.

Trial Design and Interventions
This was an open-label, single-arm, single-stage, and phase II study. Patients received NIRA as two 100 mg capsules (200 mg total), abiraterone acetate as four 250 mg tablets (1000 mg total) once daily, and prednisone as 5 mg tablets twice daily (10 mg total).

Assessments
The primary endpoints were composite response rate (CRR; evaluated in the intent-to-treat [ITT] efficacy population) and frequency and severity of adverse events (AEs; evaluated in the safety population). CRR is defined as the proportion of patients with ≥1 of the following: objective radiographic response in subjects with measurable disease, overall circulating tumor cell (CTC) response, or prostatespecific antigen decline ≥50% (PSA50). Overall CTC response is defined as a patient with CTC0 response at 8 weeks (baseline CTC per 7.5 mL of blood >0 and 8 weeks post-baseline CTC = 0) or CTC conversion (baseline CTC per 7.5 mL of blood ≥5 and post-baseline CTC <5 with a confirmation CTC <5 taken ≥4 weeks later). Key secondary endpoints were overall CTC response rate, objective response rate (ORR) (per RECIST 1.1), and radiographic progression-free survival (rPFS).

Statistical Analysis
For the ITT population, 2-sided 90% CIs were calculated for CRR, ORR, and overall CTC response. rPFS was evaluated using the Kaplan-Meier method.

Patient Characteristics
Twenty-four patients were included in the safety analysis, of whom 1 was excluded from the ITT population (found to be HRR negative); 17 patients had BRCA2 alterations, 2 had ATM, 2 had CHEK2, 1 had FANCA, and 1 had PALB2. Of the total safety population, with a median age of 73 years, 15 (62.5%) patients had a Gleason score of ≥8 at the initial diagnosis. Twenty-two (91.7%) patients had skeletal metastases, 9 (37.5%) had lymph node metastases, and 1 had liver metastases at baseline. All ITT patients had received ≥1 prior therapy for prostate cancer, and all patients had received a prior next-generation AR inhibitor (Supplementary Table S1). The median duration of NIRA + AAP treatment was 10.3 months (range, 0.7-22.0). With a median follow-up of 18 months, 8 patients remained on treatment at the analysis cut-off.

Discussion
The results presented suggest NIRA + AAP has promising efficacy and a manageable toxicity profile in patients with mCRPC and alterations in genes associated with HRR who had progressed on 1 prior line of novel AR-targeted therapy. The current phase II study is limited by the open-label, single-arm trial design, and the small patient population. Whereas these findings are consistent with the BEDIVERE 9 study, further data are needed to assess the efficacy and safety of this combination. Two ongoing phase III studies evaluate NIRA + AAP versus placebo + AAP in patients with mCRPC 2 and metastatic castration-sensitive prostate cancer. 10 For MAGNITUDE, 2 the primary analysis showed a statistically significant and clinically meaningful improvement for rPFS with NIRA + AAP for patients with BRCA1/2 alterations (HR = 0.533 [95% CI, 0.361-0.789; 2-sided P = .0014]) as well as the combined HRR gene altered population (HR = 0.729 [95% CI, 0.556-0.956; P = .0217]).