Phase I Clinical Trial of the CYP17 Inhibitor Abiraterone Acetate Demonstrating Clinical Activity in Patients With Castration-Resistant Prostate Cancer Who Received Prior Ketoconazole Therapy
Phase I Clinical Trial of the CYP17 Inhibitor Abiraterone Acetate Demonstrating Clinical Activity in Patients With Castration-Resistant Prostate Cancer Who Received Prior Ketoconazole Therapy
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DOI：
10.1200/jco.2009.24.1281
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发表时间：
2010-03-20
影响因子：
45.3
通讯作者：
Small, Eric J.
中科院分区：
文献类型：
--
作者：
Ryan, Charles J.;Smith, Matthew R.;Small, Eric J.
醋酸阿比特龙是阿比特龙的前体药物，阿比特龙是CYP 17的选择性抑制剂，CYP 17是雄激素生物合成中两个重要步骤的催化剂。在去势抵抗性前列腺癌（CRPC）中，性腺外雄激素来源可能维持肿瘤生长，尽管去势环境。醋酸阿比特龙的I期剂量递增研究评估了安全性，药代动力学和对类固醇生成和前列腺特异性抗原（PSA）水平的影响，在男性与CPRC有或没有以前的酮康唑therapy.Patients和MethodsThirty-three化疗初治进展CRPC男性入组。19例患者（58%）既往接受过酮康唑治疗CRPC。70%的患者存在骨转移，18%的患者存在内脏受累。3例患者（9%）患有局部晚期疾病，无远处转移。空腹或进食队列接受醋酸阿比特龙250、500、750或1，000 mg每日剂量。单剂量药代动力学分析之前，连续每日dose.ResultsAdverse事件主要是1级或2级。未观察到剂量限制性毒性。高血压（3级，12%）和低钾血症（3级，6%; 4级，3%）是最常见的严重毒性，对药物治疗有反应。33例患者中有18例（55%）在第12周时证实PSA下降>= 50%，包括19例既往接受过酮康唑治疗的患者中的9例（47%）和14例既往未接受过酮康唑治疗的患者中的9例（64%）。循环中的雄激素和盐皮质激素的增加大幅下降被认为与所有doses.ConclusionAbiraterone醋酸盐耐受性良好，并表现出活性CRPC，包括在以前用酮康唑治疗的患者。需要继续进行临床研究。
PurposeAbiraterone acetate is a prodrug of abiraterone, a selective inhibitor of CYP17, the enzyme catalyst for two essential steps in androgen biosynthesis. In castration-resistant prostate cancers (CRPCs), extragonadal androgen sources may sustain tumor growth despite a castrate environment. This phase I dose-escalation study of abiraterone acetate evaluated safety, pharmacokinetics, and effects on steroidogenesis and prostate-specific antigen (PSA) levels in men with CPRC with or without prior ketoconazole therapy.Patients and MethodsThirty-three men with chemotherapy-naive progressive CRPC were enrolled. Nineteen patients (58%) had previously received ketoconazole for CRPC. Bone metastases were present in 70% of patients, and visceral involvement was present in 18%. Three patients (9%) had locally advanced disease without distant metastases. Fasted or fed cohorts received abiraterone acetate doses of 250, 500, 750, or 1,000 mg daily. Single-dose pharmacokinetic analyses were performed before continuous daily dosing.ResultsAdverse events were predominantly grade 1 or 2. No dose-limiting toxicities were observed. Hypertension (grade 3, 12%) and hypokalemia (grade 3, 6%; grade 4, 3%) were the most frequent serious toxicities and responded to medical management. Confirmed >= 50% PSA declines at week 12 were seen in 18 (55%) of 33 patients, including nine (47%) of 19 patients with prior ketoconazole therapy and nine (64%) of 14 patients without prior ketoconazole therapy. Substantial declines in circulating androgens and increases in mineralocorticoids were seen with all doses.ConclusionAbiraterone acetate was well tolerated and demonstrated activity in CRPC, including in patients previously treated with ketoconazole. Continued clinical study is warranted.