PARP and AR Inhibitor Regimen Improve Efficacy in mCRPC

Niraparib (Zejula) in combination with abiraterone acetate (Zytiga) and prednisone showed signs for promising efficacy and a manageable safety profile among patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations who had progressed on prior treatment with an androgen receptor (AR)–targeted therapy, according to findings from the phase 2 QUEST trial (NCT03431350).

In results presented in a poster at the 2022 American Urologic Association Annual Meeting, the triplet regimen resulted in a composite response in more than half of all patients (56.5%; 90% CI, 37.5%-74.2%).

The study authors, led by Kim N. Chi, MD, a senior research scientist at Vancouver Prostate Centre, a medical oncologist at BC Cancer in Vancouver, and a professor in the Department of Medicine at the University of British Columbia, explained in their paper that they expected that targeting both the PARP and AR oncogenic pathway may enhance efficacy in mCRPC, and the QUEST trial is part of a larger program to investigate the combination.

The QUEST trial began in March 2018 and enrolled adult patients with mCRPC and HRR gene alterations who received 1 line of therapy with a next-generation AR-targeted agent and an ECOG performance status of 0 or 1. Patients were divided between 3 cohorts based on their HRR gene alterations: biallelic BRCA1/2 alterations (n = 8), monoallelic BRCA1/2 alterations (n = 9), and other monoallelic alterations (n = 6). All participants received all-oral 200 mg niraparib plus 1000 mg abiraterone acetate and 10 mg prednisone daily.

Composite response rate (CRR) and the severity of adverse events (AEs) were the primary end points of the trial and secondary end points included objective response rate (ORR), circulating tumor cell (CTC) response rate, and radiographic progression-free survival (rPFS). CRR was defined as the quantity of patients with an objective response, overall CTC response, and/or prostate-specific antigen (PSA) decline of at least 50% (PSA50). CTC response was defined as CTC0 response at 8 weeks or CTC conversation.

A total of 24 patients were included in the safety population with a median age of 73 years (range, 58-88). Most patients were White (87.5%) and the remainder were Black or African American (12.5%). A large majority of patients (95.8%)were not Hispanic or Latino. Patients had an ECOG performance status of 0 (58.3%) or 1 (41.7%), and Gleason scores ranged from less than 7 (8.3%) to 8 or higher (62.5%), and scores were unknown in 8.3%. Disease was observed in the bone in 91.7% of patients or was bone only in 54.2%, visceral disease was reported in 4.2%, lymph node disease in 37.5%, or in other sites in 8.3%. Additionally, 42% had soft tissue or nodal metastases.

Seventeen patients had BRCA1/2 alterations, 2 had ATM, 2 had CHEK2, 1 had PALB2, and 1 had FANCA alterations.

In terms of prior treatments, 7 patients (29.2%) had received prior taxanes, and all patients had received prior AR-targeted therapy, prostate cancer–related radiotherapy, and surgery.

At a median follow-up of 18 patients, 8 patients were still receiving treatment and the median duration of treatment with the triplet regimen was 10.3 months (range, 0.7-22.0).

The intention-to-treat (ITT) efficacy population included 23 patients since 1 patient was HRR negative. Among these patients, the ORR was 21.7% (90% CI, 12.0%-45.1%), the overall CTC response rate was 26.1% (90% CI, 12.0%-45.1%), and the PSA50 response rate was 30.4% (90% CI, 15.2%-49.6%).

The median duration of response was 4.7 months (range, 3.7-8.2). The median rPFS was 11.0 months (90% CI, 9.7-not estimable). At 3 months, the rPFS rate was 85.1% (95% CI, 70.8%-100.0%), 74.1% (95% CI, 56.8%-96.7%) at 6 months, 74.1% (95% CI, 56.8%-96.7%) at 9 months, and 46.7% (95% CI, 25.3%-86.1%) at 12 months.

Among 10 patients with measurable disease, 50% had a partial response as their best overall response, 20% had stable disease, and 30% had progressive disease. Six of 10 patients had a maximum reduction in target lesions of at least 30%.

At 8 weeks, CTC0 response was achieved in 17.4% (90% CI, 6.2%-35.5%) and the CTC conversion rate was 21.7% (90% CI, 9.0%-40.4%).

The most common treatment-emergent AEs (TEAEs) observed with the combination of niraparib, abiraterone acetate, and prednisone were anemia, fatigue, constipation, thrombocytopenia, nausea, vomiting, and decreased appetite. Frequent grade 3 or higher TEAEs included anemia (41.7%), thrombocytopenia (20.8%), fatigue (16.7%), and neutropenia (12.5%). Serious drug-related events were reported in 3 patients due to lower gastrointestinal hemorrhage, asthenia and noncardiac chest pain, and anemia in 1 patient each. No deaths were observed in the study due to AEs.

Dose interruption/reduction was required in 58.3% of patients, most commonly due to anemia, thrombocytopenia, and neutropenia. Treatment discontinuation due to TEAEs was reported in 8.3% of patients.

“These findings are consistent with those of the GALAHAD [NCT02854436] and BEDIVERE [NCT02924766] studies and the recently reported outcomes in the phase 3 MAGNITUDE study [NCT03748641], supporting the continued development of the combination of polyadenosine diphosphate–ribose polymerase (PARP) and AR inhibitors in patients with mCRPC and HRR gene alterations,” Chi et al wrote in their poster.

_Reference

_{Chi K, Fleshner N, Chiuri VE, et al. Niraparib with abiraterone acetate and prednisone for metastatic castration-resistant prostate cancer: results from the phase 2 QUEST study. Presented at: 2022 AUA Annual Meeting; New Orleans, LA; May 13-16, 2022. Abstract MP27-17.}