Giredestrant 是一种在研的下一代口服选择性雌激素受体拮抗剂和降解剂，用于治疗雌激素受体阳性 (ER) 乳腺癌。我们介绍 Ia/b 期 GO39932 研究 (NCT03332797) 的主要分析结果。既往接受内分泌治疗的 ER、HER2 阴性局部晚期/转移性乳腺癌患者接受单药吉瑞德群（10、30、90 或 250） mg），或吉瑞地群（100 mg）±palbociclib 125 mg±黄体生成素释放激素（LHRH）激动剂。使用 giredestrant 100 mg 进行详细的心血管评估。终点包括安全性（主要）、药代动力学、药效学和疗效。 截至 2021 年 1 月 28 日，入组 175 名患者，未观察到剂量限制性毒性，且未达到最大耐受剂量。在单药 ±LHRH 激动剂和吉瑞德群 Palbociclib ±LHRH 激动剂队列中，与吉瑞德群相关的不良事件 (AE) 发生率分别为 64.9% 和 59.4%（仅吉瑞德群相关的 3/4 级 AE 发生率为 4.5%）。单一药物队列中的患者和 3.1% 接受 giredestrant Palbociclib 治疗的患者）。观察到剂量依赖性无症状心动过缓，但心脏相关结果（心率、血压或运动持续时间）没有临床显着变化。在所有队列中均观察到临床获益（单药队列中 48.6% 的患者和 giredestrant palbociclib ±LHRH 激动剂队列中 81.3% 的患者），但没有明确的剂量关系，包括 ESR1 突变肿瘤患者。 Giredestrant 耐受性良好且在既往 ET 中进展的患者中具有临床活性。结果值得在早期和晚期 ER 乳腺癌随机试验中进一步评估吉瑞德群。

Giredestrant is an investigational next-generation oral selective estrogen receptor antagonist and degrader for the treatment of estrogen receptor-positive (ER+) breast cancer. We present the primary analysis results of the phase Ia/b GO39932 study (NCT03332797).Patients with ER+, HER2-negative locally advanced/metastatic breast cancer previously treated with endocrine therapy received single-agent giredestrant (10, 30, 90, or 250 mg), or giredestrant (100 mg) ±palbociclib 125 mg ±luteinizing hormone-releasing hormone (LHRH) agonist. Detailed cardiovascular assessment was conducted with giredestrant 100 mg. Endpoints included safety (primary), pharmacokinetics, pharmacodynamics, and efficacy.As of January 28, 2021, with 175 patients enrolled, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. Adverse events (AEs) related to giredestrant occurred in 64.9% and 59.4% of patients in the single-agent ±LHRH agonist and giredestrant +palbociclib ±LHRH agonist cohorts, respectively (giredestrant-only related grade 3/4 AEs were reported in 4.5% of patients across the single-agent cohorts and 3.1% of those with giredestrant +palbociclib). Dose-dependent asymptomatic bradycardia was observed, but no clinically significant changes in cardiac-related outcomes: heart rate, blood pressure, or exercise duration. Clinical benefit was observed in all cohorts (48.6% of patients in the single-agent cohort and 81.3% in the giredestrant +palbociclib ±LHRH agonist cohort), with no clear dose relationship, including in patients with ESR1-mutated tumors.Giredestrant was well tolerated and clinically active in patients who progressed on prior ET. Results warrant further evaluation of giredestrant in randomized trials in early- and late-stage ER+ breast cancer.