Pharmacodynamics of Camizestrant Treatment in Postmenopausal Women With Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Primary Breast Cancer: Results From the Randomized, Presurgical SERENA-3 Study.

Methods

This open-label, parallel-group trial randomly assigned 132 participants to receive camizestrant 75, 150, or 300 mg once daily for 5-7 days or 75 or 150 mg once daily for 12-15 days.

这项开放标签、平行组试验随机分配了132名参与者，分别接受卡米塞斯特兰 75、150 或 300 毫克，每日一次，连续 5-7 天，或 75 或 150 毫克，每日一次，连续 12-15 天。

The effects of camizestrant on ER expression, activity, and tumor proliferation were assessed in pre- and on-treatment tumor samples by immunohistochemical (IHC) analysis of ER, progesterone receptor (PgR), and Ki67.

通过免疫组化（IHC）分析雌激素受体（ER）、孕激素受体（PgR）和Ki67，评估了camizestrant对肿瘤样本中ER表达、活性和肿瘤增殖的影响，这些样本分别取自治疗前后。

Exploratory analyses using transcriptomics and mass spectrometry were also performed.

还进行了使用转录组学和质谱分析的探索性分析。

Results

ER expression was reduced by approximately 65% for all camizestrant doses, regardless of treatment duration.

所有剂量的卡米塞斯特兰均可使雌激素受体表达减少约65%，无论治疗持续时间长短。

Reduction in Ki67 expression was greater after 12-15 days of camizestrant treatment, compared with 5-7 days.

与5-7天的治疗相比，经过12-15天的卡米塞斯特兰治疗后，Ki67表达的减少更为显著。

Exploratory analyses including mass spectrometry and IHC image analysis aligned with IHC H-score, indicating equivalent, maximal effects of all tested doses of camizestrant on ER expression and activity and Ki67 expression.

通过质谱分析和IHC图像分析，包括IHC H评分，发现所有测试剂量的camizestrant对ER表达和活性以及Ki67表达均有等效、最大效应。

Of those participants receiving camizestrant 75 mg once daily, 90%-100% reported no treatment-emergent adverse events across all preferred terms; of those reported, all were Grade 1 except one participant with Grade 2 upper respiratory tract infection, not considered related to camizestrant.

在每天一次接受75毫克camizestrant的参与者中，90%-100%报告没有治疗后出现的不良事件；在报告的不良事件中，除了一名参与者出现与camizestrant无关的2级上呼吸道感染外，其余均为1级。

Conclusions

SERENA-3 demonstrates that camizestrant 75 mg once daily (Phase III dose) is well-tolerated and achieves maximal reduction in ER through known mechanisms, that is, antagonism and degradation, by 5-7 days, and proliferation suppression determined by Ki67 expression, by 12-15 days.

SERENA-3研究表明，每日一次75毫克的camizestrant（III期剂量）耐受性良好，并通过已知机制达到最大雌激素受体(ER)降低，即拮抗和降解，5-7天内实现，通过Ki67表达确定的增殖抑制，12-15天内实现。

These data support camizestrant 75 mg once daily as the preferred dose for ongoing clinical development and highlight the importance of presurgical WOO studies in guiding dose selection.

这些数据支持每日一次75毫克的camizestrant作为正在进行的临床开发的首选剂量，并强调了术前WOO研究在指导剂量选择中的重要性。