A phase 1 trial of fuzuloparib in combination with apatinib for advanced ovarian and triple-negative breast cancer: efficacy, safety, pharmacokinetics and germline BRCA mutation analysis

作者：Yaxin Liu, Weimin Wang, Rutie Yin, Youzhong Zhang, Yu Zhang, Keqiang Zhang, Hongming Pan, Ke Wang, Ge Lou, Guiling Li, Ruyan Zhang, Kun Li, Jing Rao, Ben Zhang, Yuting Wang, Quanren Wang, Yunong Gao, Huiping Li · 发表于：BMC Medicine · 年份：2023 · DOI：10.1186/s12916-023-03046-8 · 被引用次数：15 · 研究领域：PARP inhibition in cancer therapy、Ovarian cancer diagnosis and treatment、Advanced Breast Cancer Therapies

Abstract Background The effect of the combination of an anti-angiogenic agent with a poly (ADP-ribose) polymerase (PARP) inhibitor in cancer treatment is unclear. We assessed the oral combination of fuzuloparib, a PARP inhibitor, and apatinib, a VEGFR2 inhibitor for treating advanced ovarian cancer (OC) or triple-negative breast cancer (TNBC). Methods This dose-escalation and pharmacokinetics-expansion phase 1 trial was conducted in China. We used a standard 3 + 3 dose-escalation design, with 7 dose levels tested. Patients received fuzuloparib orally twice daily, and apatinib orally once daily. The study objectives were to determine the safety profile, recommended phase 2 dose (RP2D), pharmacokinetics, preliminary efficacy, and efficacy in relation to germline BRCA mutation (g BRCA mut ). Results Fifty-two pre-treated patients were enrolled (30 OC/22 TNBC). 5 (9.6%) patients had complete response, 14 (26.9%) had partial response, and 15 (28.8%) had stable disease. Objective response rate (ORR) and disease control rate were 36.5% (95% CI 23.6–51.0) and 65.4% (95% CI 50.9–78.0), respectively. At the highest dose level of fuzuloparib 100 mg plus apatinib 500 mg, the ORR was 50.0% (4/8; 95% CI 15.7–84.3); this dose was determined to be the RP2D. Patients with g BRCA mut had higher ORR and longer median progression-free survival (PFS) than those with g BRCA wt , both in OC (ORR, 62.5% [5/8] vs 40.9% [9/22]; PFS, 9.4 vs 6.7 months) and TNBC (ORR, 66.7% [2/3] vs 15.8% [3/19]; PFS, 5...