SUMMARY

• QUEST (NCT03431350) is an ongoing, phase 1b-2, multicenter, open-label study evaluating the safety, tolerability, and efficacy of niraparib in combination with other anti-cancer therapies, including either cetrelimab, an investigational, intravenous, monoclonal antibody against programmed cell death receptor-1 (PD-1), or abiraterone acetate plus prednisone (AAP), for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in patients with homologous recombination repair (HRR) gene alterations who progressed on prior androgen-receptor targeted (ART) therapy for prostate cancer. For niraparib/AAP, the primary endpoints were incidence and severity of treatment-emergent adverse events (TEAEs) and composite response rate (CRR). Secondary endpoints included circulating tumor cell (CTC) response rate, objective response rate (ORR), and radiographic progression-free survival (rPFS).^1-3
• A summary of TEAEs in the niraparib/AAP group is described below. In patients receiving niraparib/AAP, the most common TEAEs leading to dose interruption/reduction in 58.3% (n=14) of patients were anemia (n=7), thrombocytopenia (n=5), and neutropenia (n=3).⁴ Serious treatment-related adverse events (TRAEs) were observed in 3 patients and included lower gastrointestinal (GI) hemorrhage (n=1), asthenia and noncardiac chest pain (n=1), and anemia (n=1).³
• Efficacy results for niraparib/AAP are summarized in Table: Primary and Secondary Efficacy Endpoints. In the niraparib/AAP intention-to-treat (ITT) population (n=23), CRR was 56.5% (90% CI, 37.5-74.2) after a median follow up of 18 months. ORR was 50.0% (90% CI, 9.0-40.4), and the median duration of response (DOR) was 4.7 months (range, 3.7-8.2).³
• Results from other niraparib combination therapies in the QUEST study have not been published.

CLINICAL DATA

QUEST Study

Chi et al (2023)³ reported the safety, tolerability, and efficacy of niraparib/AAP (combination 2) in patients with mCRPC and HRR gene alterations who had progressed on 1 prior line of ART therapy.

Study Design/Methods

• Ongoing, phase 1b-2, multicenter, open-label study.^1,3
• In this study, designed as a master protocol, patients were assigned to receive one of three combination therapies, with oral niraparib as a backbone therapy:
  • Combination 1: niraparib 200 mg orally (PO) once daily + cetrelimab 480 mg intravenously (IV) every 4 weeks.^1,2
  • Combination 2: niraparib 200 mg (2 x 100 mg) PO once daily + abiraterone acetate 1000 mg (4 x 250 mg) PO once daily + prednisone 5 mg PO twice daily.^1-3
  • Combination 3: niraparib with abiraterone acetate for pharmacokinetics assessment.¹
• Part 1 of the study established the recommended phase 2 dose (RP2D) for combination 1 and determined the incidence of specified toxicities.^1,2
• Part 2 of the study evaluated the antitumor activity and safety of combination 1 and combination 2.
  • Combination 1 patients were assigned to cohort 1A or cohort 1B if they were DNA repair gene defect (DRD) positive or DRD negative, respectively.²
  • Combination 2 patients were divided into 3 cohorts depending on if they had biallelic BRCA1/2 HRR alterations, monoallelic BRCA1/2 HRR alterations, or monoallelic other HRR alterations.
• The study will also determine the relative bioavailability of combination 3.¹
• The study design for combination 2 is presented in Figure: QUEST Study Design (Combination 2).

Results

Patient Characteristics

• A total of 24 patients with mCRPC were enrolled to receive combination 2 of niraparib/AAP. Select patient baseline characteristics are described in Table: Select Baseline Characteristics: Combination 2 Safety Population.
• Of the 24 enrolled patients, 8 patients had biallelic BRCA1/2 alterations, 9 patients had monoallelic BRCA1/2 alterations, and 6 patients had monoallelic other alterations.⁴
  • Initially, 1 HRR negative patient was assigned to the monoallelic BRCA1/2 cohort in error. This patient was excluded from the ITT population but was included in the safety population.
• In the safety population, 42% of patients had soft tissue or nodal metastasis and 29% of patients received prior docetaxel therapy.⁴

Safety

• In the safety population (n=24), the most common TEAEs of any grade reported by ≥15% of patients were anemia, fatigue, constipation, thrombocytopenia, nausea, vomiting, decreased appetite, neutropenia, back pain, dyspnea, dizziness, and weight decreased.³
  • The most common grade ≥3 AEs were anemia (41.7%), thrombocytopenia (20.8%), fatigue (16.7%), and neutropenia (12.5%).
• TEAEs led to dose interruption in 11 patients and dose reduction in 9 patients. Anemia (n=7), thrombocytopenia (n=5), and neutropenia (n=3) were the most cited reasons for dose interruptions/reductions.
• Discontinuation of niraparib/AAP therapy due to a TEAE occurred in 2 patients (thrombocytopenia [n = 1]; thrombocytopenia and anemia [n = 1]).
• A total of 3 patients in the combination 2 group experienced serious TRAEs, which consisted of lower GI hemorrhage (n=1), asthenia and noncardiac chest pain (n=1), and anemia (n=1).
  • No deaths due to AEs were observed.

Efficacy

• The median treatment duration for patients receiving niraparib/AAP was 10.3 months (range, 0.7-22.0).
• CRR was 56.5% (90% CI, 37.5-74.2) in the ITT population (n=13) at a median followup of 18 months.³ Primary and secondary efficacy endpoints are described in Table: Primary and Secondary Efficacy Endpoints: Combination 2 ITT Population.
  • A total of 8 patients remained on treatment at the analysis cutoff.
• Of 10 patients with measurable disease at baseline, 5 (50%) patients reached partial response. Best response of stable disease and progressive disease were experienced by 2 (20%) patients and 3 (30%) patients, respectively. No patient experienced a complete response.
• ORR was 50.0% (90% CI, 9.0-40.4), and the median DOR was 4.7 months (range, 3.78.2).
• The median rPFS was 11.0 months (9.7-not estimable). At 3, 6, 9, and 12 months, event-free survival rates were 85.1%, 74.1%, 74.1%, and 46.7%, respectively.⁴

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 09 August 2024.