5008 Background: The combination of PARP inhibitors with standard AA-P may offer enhanced antitumor activity over AA-P. We conducted FUZUPRO, an international, randomized, double-blind, placebo-controlled phase 3 trial, to compare the efficacy of fuzuloparib, a novel PARP inhibitor, plus AA-P vs AA-P as 1L treatment for mCRPC. Methods: 1L mCRPC patients were randomized (1:1) to orally receive fuzuloparib 150 mg BID plus AA-P (abiraterone acetate 1000 mg QD; prednisone 5 mg BID) or placebo plus AA-P. Randomization was stratified by DNA-repair gene defect (DRD) status (positive vs negative/unknown) and other factors. Primary endpoint was blinded independent central review (BICR)-assessed radiographic progression-free survival (rPFS) per RECIST v1.1 and PCWG3. As of March 23, 2025, 259 (85% of total expected) BICR-assessed rPFS events occurred, and a prespecified interim analysis was conducted. Results: 496 patients were randomized to fuzuloparib-AA-P (n = 249) or AA-P (n = 247). Median follow-up was 33.3 mo. Fuzuloparib-AA-P significantly prolonged rPFS compared with AA-P (median, 24.8 mo vs 19.9 mo; HR 0.71, 95% CI 0.55-0.91; 1-sided p = 0.0034). rPFS benefit with fuzuloparib-AA-P was generally consistent across clinically relevant subgroups. Among DRD-positive patients (n = 116), median rPFS was 27.7 mo and 13.9 mo in the fuzuloparib-AA-P and AA-P groups, respectively (HR 0.51, 95% CI 0.31-0.85; 1-sided p = 0.0039). Subgroup analysis suggested improved rPFS among DRD-positive patients regardless of their BRCA1/2 mutation status. Among DRD-negative/unknown patients (n = 380), median rPFS was 22.8 and 21.2 mo, respectively. Overall survival showed a benefit trend in favor of fuzuloparib-AA-P (Table). Treatment-related adverse events (TRAEs) were reported by 81.9% and 76.0% of patients in the two groups, respectively. The most common grade ≥3 TRAEs were mainly hematological toxicities, including anemia (20.1%), decreased white blood cell count (5.6%), decreased platelet count, and decreased neutrophil count (5.2% for each). Conclusions: Fuzuloparib plus AA-P as 1L treatment significantly prolonged rPFS in patients with mCRPC. The combination showed acceptable safety and tolerability with no new safety signals identified. Clinical trial information: NCT04691804 . Overall DRD-positive DRD-negative/unknown Fuzuloparib-AA-P(N = 249) AA-P (N = 247) Fuzuloparib-AA-P (N = 60) AA-P (N = 56) Fuzuloparib-AA-P (N = 189) AA-P (N = 191) rPFS, mo, median (95% CI) 24.8 (20.4, 30.4) 19.9 (15.2, 22.2) 27.7 (17.7, NR) 13.9 (8.3, 24.9) 22.8 (19.9, 30.2) 21.2 (16.5, 24.6) HR (95% CI), vs. AA-P 0.71 (0.55, 0.91) 0.51 (0.31, 0.85) 0.81 (0.61, 1.08) Overall survival, mo, median (95% CI) 41.9 (31.1, NR) 36.8 (28.7, NR) NR (27.0, NR) 36.8 (24.7, 40.3) 37.3 (29.0, NR) 36.8 (28.7, NR) HR (95% CI), vs. AA-P 0.96 (0.73, 1.24) 0.76 (0.44, 1.32) 1.00 (0.74, 1.35) NR, not reached.
Ye et al. (Wed,) studied this question.