类固醇合成抑制剂ODM-209治疗转移性去势抵抗性前列腺癌和晚期乳腺癌：首次人体STESIDES研究结果
Steroidogenesis inhibitor ODM-209 for metastatic castration-resistant prostate cancer and advanced breast cancer: Results from the first-in-human STESIDES study
转移性去势抵抗性前列腺癌（mCRPC）和晚期乳腺癌患者标准治疗预后差。STESIDES（NCT03878823）是ODM-209的1期剂量探索研究，ODM-209是一种口服选择性CYP11A1抑制剂，可阻断所有类固醇激素合成，需同时补充糖皮质激素和盐皮质激素。研究采用3+3设计，入组38人（mCRPC 34例、晚期乳腺癌4例），剂量10-20 mg/天。所有受试者出现不良事件，最常见为疲乏（53%）和外周水肿（34%），9人（24%）出现≥3级相关不良事件，3人（8%）发生严重肾上腺功能不全事件，其中1例为剂量限制性毒性。治疗期间类固醇激素浓度大多检测不到。34例mCRPC中10人（29%）PSA下降≥50%，包括携带雄激素受体配体结合域（AR-LBD）突变者（该亚组应答率9/19[47%]）。晚期乳腺癌未见应答。ODM-209在重度经治mCRPC中显示活性，安全性符合预期。
为什么推荐给您：全新CYP11A1抑制剂首次人体试验，在重度经治前列腺癌中显示活性。
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摘要Abstract
PURPOSE: Patients with metastatic castration-resistant prostate cancer (mCRPC) and advanced breast cancer (aBC) have poor outcomes with standard treatments. We report phase 1 results from the STESIDES (NCT03878823) study of ODM-209, an oral selective CYP11A1 inhibitor that blocks all synthesis of steroid hormones.
METHODS: STESIDES was a dose-finding study (3 +3 design) in adults with progressive mCRPC, with or without activating androgen receptor ligand-binding domain (AR-LBD) mutations, who received ≥ 1 prior AR pathway inhibitor and ≥ 1 taxane-based regimen. Participants with aBC were also enrolled. ODM-209 was administered with glucocorticoid and mineralocorticoid replacement therapy. Primary endpoints included dose-limiting toxicities (DLTs) and adverse events (AEs); secondary endpoints included pharmacodynamics and clinical response.
RESULTS: Thirty-eight participants received ODM-209 (mCRPC: 34; aBC: 4); dose range: 10-20 mg/day. All experienced AEs; fatigue (53%) and peripheral edema (34%) were most common. Nine (24%) experienced grade ≥ 3 AEs related to ODM-209. Three (8%) had serious adrenal insufficiency events (including terms adrenal insufficiency, glucocorticoid deficiency and adrenocortical insufficiency acute); one was a DLT (participant with aBC). Steroid hormone concentrations were mostly undetectable upon treatment. Ten (29%) participants with mCRPC had prostate-specific antigen decline ≥ 50% (PSA50), including patients with AR-LBD mutations (PSA50 response rate: 9/19 [47%]; 5.6-month median treatment duration for this group). Three of 16 (19%) evaluable participants with mCRPC had partial clinical response. No responses were seen in participants with aBC.
CONCLUSIONS: ODM-209 showed activity in heavily pretreated participants with mCRPC, particularly those with activating AR-LBD mutations, with an expected AE profile.