Pharmacokinetics, safety, and efficacy of fuzuloparib in combination with abiraterone acetate and prednisone in patients with metastatic castration-resistant prostate cancer: a phase 1 dose escalation and expansion study

Studies have shown that poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors can potentiate the antitumor effect of abiraterone acetate plus prednisone (AA-P) in metastatic castration-resistant prostate cancer (mCRPC). This study evaluated the pharmacokinetics, safety, and efficacy of fuzuloparib, a PARP inhibitor, in combination with AA-P in mCRPC patients who had not received prior novel hormonal agents. This was a dose escalation and expansion study. In dose escalation, eligible patients received fuzuloparib at 100 or 150 mg BID for 5 days, followed by fuzuloparib plus AA-P (abiraterone acetate 1000 mg QD, prednisone 5 mg BID) in 28-day treatment cycles. The higher tolerated dose of fuzuloparib was selected for dose expansion. In dose expansion, two treatment groups were planned. The fuzuloparib group received fuzuloparib for 5 days, and the abiraterone group received AA-P for 5 days. Both groups were then treated with the combination therapy. A total of 39 patients were enrolled and treated. As of July 12, 2023, the median follow-up time was 23.2 months (range, 3.9−44.3). No obvious drug-drug interaction was observed between 150 mg fuzuloparib and AA-P, and no dose-limiting toxicities were identified. Treatment-related adverse events (TRAEs) occurred in 36 (92.3%) patients, of which 20 (51.3%) reported grade ≥ 3 TRAEs. At the end of Week 12, prostate-specific antigen (PSA) response rate was 71.8% (95% CI, 55.1−85.0). The median time to PSA progression was 19.4 months (95% CI, 11.3−27.8). Objective response rate was 60% and disease control rate was 90% among patients with evaluable target lesions. The median duration of response was 8.1 months (95% CI, 4.6−31.5), and the median time to radiographic progression was 27.9 months (95% CI, 14.0−not reached). Time to disease progression was generally longer in patients with homologous recombination repair gene mutations, including those with BRCA mutations. Fuzuloparib plus AA-P had an acceptable safety profile and showed promising efficacy among mCRPC patients. ClinicalTrials.gov, NCT04108247 (Registered on September 26, 2019).