尼拉帕利联合雄激素受体轴靶向治疗转移性去势抵抗性前列腺癌的安全性和药代动力学：来自 1b 期研究（BEDIVERE）的结果。
Niraparib with androgen receptor-axis-targeted therapy in patients with metastatic castration-resistant prostate cancer: safety and pharmacokinetic results from a phase 1b study (BEDIVERE).
机构信息
Centre Hospitalier de l'Université de Montréal, Montréal, Canada.
BC Cancer, Vancouver, Canada.
出版信息
Cancer Chemother Pharmacol. 2021 Jul;88(1):25-37. doi: 10.1007/s00280-021-04249-7. Epub 2021 Mar 22.
PURPOSE
To assess the safety and pharmacokinetics and determine the recommended phase 2 dose (RP2D) of niraparib with apalutamide or abiraterone acetate plus prednisone (AAP) in patients with metastatic castration-resistant prostate cancer (mCRPC).
METHODS
BEDIVERE was a multicenter, open-label, phase 1b study of niraparib 200 or 300 mg/day with apalutamide 240 mg or AAP (abiraterone acetate 1000 mg; prednisone 10 mg). Patients with mCRPC were previously treated with ≥ 2 lines of systemic therapy, including ≥ 1 androgen receptor-axis-targeted therapy for prostate cancer.
RESULTS
Thirty-three patients were enrolled (niraparib-apalutamide, 6; niraparib-AAP, 27). No dose-limiting toxicities (DLTs) were reported when combinations included niraparib 200 mg; five patients receiving niraparib 300 mg experienced DLTs [niraparib-apalutamide, 2/3 patients (66.7%); niraparib-AAP, 3/8 patients (37.5%)]. Although data are limited, niraparib exposures were lower when given with apalutamide compared with historical niraparib monotherapy exposures in patients with solid tumors. Because of the higher incidence of DLTs, the niraparib-apalutamide combination and niraparib 300 mg combination with AAP were not further evaluated. Niraparib 200 mg was selected as the RP2D with AAP. Of 19 patients receiving niraparib 200 mg with AAP, 12 (63.2%) had grade 3/4 treatment-emergent adverse events, the most common being thrombocytopenia (26.3%) and hypertension (21.1%). Five patients (26.3%) had adverse events leading to treatment discontinuation.
CONCLUSIONS
These results support the choice of niraparib 200 mg as the RP2D with AAP. The niraparib-AAP combination was tolerable in patients with mCRPC, with no new safety signals. An ongoing phase 3 study is further assessing this combination in patients with mCRPC.
TRIAL REGISTRATION NO
NCT02924766 (ClinicalTrials.gov).
目的
评估尼拉帕利联合阿帕鲁胺或醋酸阿比特龙联合泼尼松（AAP）用于转移性去势抵抗性前列腺癌（mCRPC）患者的安全性、药代动力学，并确定其推荐的 2 期剂量（RP2D）。
方法
BEDIVERE 是一项多中心、开放标签、1b 期研究，评估尼拉帕利 200 或 300mg/天联合阿帕鲁胺 240mg 或 AAP（醋酸阿比特龙 1000mg；泼尼松 10mg）的安全性和药代动力学。mCRPC 患者既往接受过≥2 线系统治疗，包括≥1 种用于前列腺癌的雄激素受体靶向治疗。
结果
共纳入 33 例患者（尼拉帕利-阿帕鲁胺组 6 例；尼拉帕利-AAP 组 27 例）。当联合方案包含尼拉帕利 200mg 时，未报告剂量限制毒性（DLT）；5 例接受尼拉帕利 300mg 的患者发生 DLT[尼拉帕利-阿帕鲁胺组 2/3 例（66.7%）；尼拉帕利-AAP 组 3/8 例（37.5%）]。尽管数据有限，但与接受过尼拉帕利单药治疗的实体瘤患者相比，阿帕鲁胺联合尼拉帕利治疗时尼拉帕利的暴露量较低。由于 DLT 发生率较高，未进一步评估尼拉帕利-阿帕鲁胺联合用药和尼拉帕利联合 AAP 300mg 方案。尼拉帕利 200mg 联合 AAP 被选为 RP2D。19 例接受尼拉帕利 200mg 联合 AAP 治疗的患者中，12 例（63.2%）发生 3/4 级治疗相关不良事件，最常见的是血小板减少症（26.3%）和高血压（21.1%）。5 例（26.3%）患者因不良事件而停止治疗。
结论
这些结果支持选择尼拉帕利 200mg 联合 AAP 作为 RP2D。尼拉帕利联合 AAP 在 mCRPC 患者中耐受性良好，无新的安全性信号。一项正在进行的 3 期研究正在进一步评估该联合方案在 mCRPC 患者中的应用。
临床试验注册
NCT02924766（ClinicalTrials.gov）。
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