Phase I Study of ARN-509, a Novel Antiandrogen, in the Treatment of Castration-Resistant Prostate Cancer
Phase I Study of ARN-509, a Novel Antiandrogen, in the Treatment of Castration-Resistant Prostate Cancer
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DOI：
10.1200/jco.2013.50.1684
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发表时间：
2013-10-01
影响因子：
45.3
通讯作者：
Scher, Howard I.
中科院分区：
文献类型：
--
作者：
Rathkopf, Dana E.;Morris, Michael J.;Scher, Howard I.
目的ARN-509是一种新型雄激素受体(AR)拮抗剂，用于治疗去势抵抗型前列腺癌(CRPC)。ARN-509抑制AR核转位和AR与雄激素反应元件的结合，并且与比卡鲁胺不同，在AR过度表达的情况下不表现出激动剂特性。这项人类第一阶段I期研究评估了ARN-509在男性转移性CRPC患者中的安全性、耐受性、药代动力学、药效学和抗肿瘤活性。患者和方法30名进展期CRPC患者连续每天口服ARN-509，剂量在30至480 mg之间，然后单次给药，然后进行为期一周的观察期和药代动力学采样。用正电子发射断层扫描/计算机断层扫描技术监测治疗前和治疗期间肿瘤组织中[F-18]氟-α-二氢睾酮(FDHT)与AR的结合情况。主要目的是确定药物动力学、安全性和推荐的第二阶段剂量。46.7%的患者在12周时观察到前列腺特异性抗原下降(>；=较基线下降50%)。在所有剂量下都观察到FDHT摄取的减少，当>；=120 mg剂量时，反应平台期，与AR结合的饱和一致。最常见的不良事件是1/2级疲劳(47%)。在300毫克剂量时，发生了一个剂量限制性毒性事件(3级腹痛)。剂量增加到480 mg并不能确定最大耐受量。结论ARN-509是安全的，耐受性良好，表现出剂量比例的药代动力学，并在所测试的所有剂量水平显示出药效学和抗肿瘤活性。根据临床前和临床数据的整合，选择每天240毫克的最大有效剂量进行II期探索。
PurposeARN-509 is a novel androgen receptor (AR) antagonist for the treatment of castration-resistant prostate cancer (CRPC). ARN-509 inhibits AR nuclear translocation and AR binding to androgen response elements and, unlike bicalutamide, does not exhibit agonist properties in the context of AR overexpression. This first-in-human phase I study assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ARN-509 in men with metastatic CRPC.Patients and MethodsThirty patients with progressive CRPC received continuous daily oral ARN-509 at doses between 30 and 480 mg, preceded by administration of a single dose followed by a 1-week observation period with pharmacokinetic sampling. Positron emission tomography/computed tomography imaging was conducted to monitor [F-18]fluoro-alpha-dihydrotestosterone (FDHT) binding to AR in tumors before and during treatment. Primary objective was to determine pharmacokinetics, safety, and recommended phase II dose.ResultsPharmacokinetics were linear and dose proportional. Prostate-specific antigen declines at 12 weeks (>= 50% reduction from baseline) were observed in 46.7% of patients. Reduction in FDHT uptake was observed at all doses, with a plateau in response at >= 120-mg dose, consistent with saturation of AR binding. The most frequently reported adverse event was grade 1/2 fatigue (47%). One dose-limiting toxicity event (grade 3 abdominal pain) occurred at the 300-mg dose. Dose escalation to 480 mg did not identify a maximum-tolerated dose.ConclusionARN-509 was safe and well tolerated, displayed dose-proportional pharmacokinetics, and demonstrated pharmacodynamic and antitumor activity across all dose levels tested. A maximum efficacious dose of 240 mg daily was selected for phase II exploration based on integration of preclinical and clinical data.