Matsubara Nobuaki, Mukai Hirofumi, Hosono Ako, Onomura Mai, Sasaki Masaoki, Yajima Yoko, Hashizume Kensei, Yasuda Masanobu, Uemura Miho, Zurth Christian
Division of Breast and Medical Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, Japan.
Clinical Development, Bayer Yakuhin, Osaka, Japan.
Cancer Chemother Pharmacol. 2017 Dec;80(6):1063-1072. doi: 10.1007/s00280-017-3417-3. Epub 2017 Aug 11.
This trial assessed the safety, pharmacokinetics, and efficacy of darolutamide (ODM-201), a new-generation nonsteroidal androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer (mCRPC).
In this open-label, nonrandomized, two-cohort, dose-escalating phase 1 study, Japanese patients with mCRPC were enrolled after a screening period. In the single-dose period (≈1 week), darolutamide was administered at 300 mg (Cohort 1) or 600 mg (Cohort 2) on day -5 (fasting state) and day -2 (fed condition). In the subsequent multiple-dose period (fed condition), patients received darolutamide 300 mg twice daily (Cohort 1) or 600 mg twice daily (Cohort 2) for 12 weeks. Primary endpoints: evaluate safety and pharmacokinetics of darolutamide.
Of 12 patients enrolled, 9 received darolutamide (Cohort 1, n = 3; Cohort 2, n = 6). All 9 patients experienced ≥1 treatment-emergent adverse event (TEAE; majority Grade 1/2). Incidence of drug-related TEAEs (DR-TEAEs) was 44% (all grades; n = 4); most common DR-TEAE was decreased appetite (22%), and 1 serious DR-TEAE (Grade 3 nausea) was observed. No Grade ≥4 DR-TEAEs or new safety signals were observed. C and AUC (0-t ) were dose-dependent; pharmacokinetics of each dose appeared to be linear over time. Prostate-specific antigen response was observed in 11% (1/9) of patients. Compared with fasting status, geometric mean C increased 2.5-fold after 300 mg and 2.8-fold after 600 mg; geometric mean AUC (0-t ) increased 2.5-fold after both doses under fed conditions.
Darolutamide was well tolerated at the examined doses in Japanese patients with mCRPC, without differences in safety and pharmacokinetics relative to Western patients.
本试验评估了新一代非甾体雄激素受体拮抗剂达洛鲁胺（ODM-201）在日本转移性去势抵抗性前列腺癌（mCRPC）患者中的安全性、药代动力学和疗效。
在这项开放标签、非随机、双队列、剂量递增的1期研究中，日本mCRPC患者在经过筛选期后入组。在单剂量期（约1周），达洛鲁胺于第-5天（空腹状态）和第-2天（进食状态）分别以300mg（队列1）或600mg（队列2）给药。在随后的多剂量期（进食状态），患者接受达洛鲁胺300mg每日两次（队列1）或600mg每日两次（队列2），持续12周。主要终点：评估达洛鲁胺的安全性和药代动力学。
入组的12例患者中，9例接受了达洛鲁胺治疗（队列1，n = 3；队列2，n = 6）。所有9例患者均经历了≥1次治疗期间出现的不良事件（TEAE；大多数为1/2级）。药物相关TEAE（DR-TEAE）的发生率为44%（所有级别；n = 4）；最常见的DR-TEAE是食欲下降（22%），观察到1例严重DR-TEAE（3级恶心）。未观察到≥4级DR-TEAE或新的安全信号。Cmax和AUC(0-t)呈剂量依赖性；各剂量的药代动力学随时间似乎呈线性。11%（1/9）的患者观察到前列腺特异性抗原反应。与空腹状态相比，300mg后几何平均Cmax增加2.5倍，600mg后增加2.8倍；进食条件下两种剂量后的几何平均AUC(0-t)均增加2.5倍。
在日本mCRPC患者中，达洛鲁胺在所研究的剂量下耐受性良好，与西方患者相比，安全性和药代动力学无差异。
