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.

Abstract

SERENA-3 is a presurgical window-of-opportunity (WOO) trial exploring the pharmacodynamic effects of camizestrant in postmenopausal women with newly diagnosed estrogen receptor (ER)-positive, human epidermal growth factor receptor 2-negative breast cancer. 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. 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. Exploratory analyses using transcriptomics and mass spectrometry were also performed. ER expression was reduced by approximately 65% for all camizestrant doses, regardless of treatment duration. Reduction in Ki67 expression was greater after 12-15 days of camizestrant treatment, compared with 5-7 days. 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. 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. 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. 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.