Purpose: Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ER+ breast cancer, but it has administration and pharmacokinetic limitations. Pharmacodynamic data suggest complete ER degradation is not achieved at fulvestrant's clinically feasible dose. This presurgical study ([NCT03236974][1]) compared the pharmacodynamic effects of fulvestrant with AZD9496, a novel, orally bioavailable, nonsteroidal, potent SERD, in treatment-naïve patients with ER+ HER2− primary breast cancer awaiting curative intent surgery. Patients and Methods: Patients were randomized 1:1 to receive AZD9496 250 mg twice daily from day 1 for 5–14 days, or fulvestrant 500 mg on day 1. On-treatment imaging-guided core tumor biopsies were taken between day 5 and 14 and compared with pretreatment diagnostic biopsies. The primary objective was to compare the effects of AZD9496 and fulvestrant on ER expression. Secondary objectives included changes in progesterone receptor (PR) and Ki-67 pharmacokinetic/pharmacodynamic relationships and safety. Results: Forty-six women received treatment (AZD9496 n = 22; fulvestrant n = 24); 35 paired biopsies were evaluable (AZD9496 n = 15; fulvestrant n = 20). The least square mean estimate for ER H-score reduction was 24% after AZD9496 versus 36% after fulvestrant treatment ( P = 0.86). AZD9496 also reduced PR H-scores (−33.3%) and Ki-67 levels (−39.9%) from baseline, but was also not superior to fulvestrant (PR: −68.7%, P = 0.97; Ki-67: −75.4%, P = 0.98). No new safety findings were identified. Conclusions: This was the first presurgical study to demonstrate that an oral SERD affects its key biological targets. However, AZD9496 was not superior to fulvestrant at the dose tested. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03236974&atom=%2Fclincanres%2F26%2F16%2F4242.atom

中文翻译：

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一项随机、开放标签、术前、机会窗研究，比较新型口服 SERD AZD9496 与氟维司群在新诊断的 ER+ HER2-原发性乳腺癌患者中的药效学作用。

目的：氟维司群是一流的选择性雌激素受体 (ER) 降解剂 (SERD)，对 ER+ 乳腺癌患者具有临床疗效，但存在给药和药代动力学限制。药效学数据表明在氟维司群的临床可行剂量下无法实现完全的 ER 降解。这项术前研究 ([NCT03236974][1]) 比较了氟维司群与 AZD9496 的药效学作用，AZD9496 是一种新型的、口服生物可利用的、非甾体类、强效的 SERD，在等待根治性手术的初治 ER+ HER2− 原发性乳腺癌患者中。患者和方法：患者按 1:1 随机分配，从第 1 天开始每天两次 250 毫克 AZD9496，持续 5-14 天，或在第 1 天接受 500 毫克氟维司群。在第 5 天和第 14 天之间进行治疗中成像引导的核心肿瘤活检，并与治疗前诊断活检进行比较。主要目的是比较 AZD9496 和氟维司群对 ER 表达的影响。次要目标包括孕酮受体 (PR) 和 Ki-67 药代动力学/药效学关系和安全性的变化。结果：46 名女性接受了治疗（AZD9496 n = 22；氟维司群 n = 24）；35 个配对活检是可评估的（AZD9496 n = 15；氟维司群 n = 20）。AZD9496 后 ER H 评分降低的最小二乘平均估计值为 24%，而氟维司群治疗后为 36%（P = 0.86）。AZD9496 还从基线降低了 PR H 分数 (-33.3%) 和 Ki-67 水平 (-39.9%)，但也不优于氟维司群（PR：-68.7%，P = 0.97；Ki-67：-75.4% , P = 0.98)。没有发现新的安全性发现。结论：这是第一项证明口服 SERD 影响其关键生物学目标的术前研究。然而，AZD9496 在测试剂量上并不优于氟维司群。[1]：/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03236974&atom=%2Fclincanres%2F26%2F16%2F4242.atom