SERENA-3 was an open-label, parallel-group, presurgical window-of-opportunity trial that explored the pharmacodynamic effects of camizestrant in postmenopausal women with newly diagnosed estrogen receptor-positive, human epidermal growth factor receptor 2-negative primary breast cancer. The trial randomly assigned 132 participants to receive camizestrant at doses of 75, 150, or 300 mg once daily for 5-7 days or 75 or 150 mg once daily for 12-15 days. The primary assessments were the effects on ER expression, activity, and tumor proliferation, measured in pre- and on-treatment tumor samples via immunohistochemical analysis of ER, progesterone receptor, and Ki67. Exploratory analyses using transcriptomics and mass spectrometry were also performed. Results showed that 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 the IHC H-score, indicating equivalent, maximal effects of all tested doses of camizestrant on ER expression and activity and Ki67 expression. Regarding safety, among participants receiving camizestrant 75 mg once daily, 90%-100% reported no treatment-emergent adverse events across all preferred terms. Of the adverse events reported, all were Grade 1 except for one participant who had a Grade 2 upper respiratory tract infection, which was not considered related to camizestrant. The study did not report specific p-values, hazard ratios, confidence intervals, or detailed sample sizes for subgroup analyses. The abstract presents findings from a presurgical, short-duration study designed to assess pharmacodynamic effects, not long-term clinical outcomes like progression-free survival or overall survival.
For women with the most common type of breast cancer, the cancer cells are often fueled by the hormone estrogen. A new drug called camizestrant is designed to block and break down the estrogen receptor, which is like cutting off the tumor's fuel supply. In this short study, women took the drug for either about a week or about two weeks before their scheduled surgery. The results were promising. The drug reduced levels of the estrogen receptor in the tumor by about 65% after just 5-7 days, and this happened with all three doses tested. The drug also slowed cancer cell growth, measured by a marker called Ki67, and this effect was stronger after taking the drug for 12-15 days. Importantly, the lowest dose (75 mg) worked just as well as the higher doses at reducing the estrogen receptor and slowing growth. At this lowest dose, most women reported no side effects from the drug, and any that did occur were mild. The study concludes that the 75 mg dose is well-tolerated and achieves the maximum effect on the tumor, supporting its use in larger, long-term trials to see if it helps patients live longer or better.
What this means for you: The lowest dose of a new breast cancer drug worked as well as higher doses to quickly reduce tumor fuel and slow growth, with few side effects.
View Original Abstract ↓
PURPOSE: 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.
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. 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.
RESULTS: 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.
CONCLUSION: 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.