274P - A multiomic approach for camizestrant-induced estrogen receptor (ER) degradation, antagonism and anti-proliferation: Exploratory analysis from SERENA-3

Background

Camizestrant, a next-generation oral selective ER degrader and pure antagonist, at 75 mg dose, caused maximal ER degradation and Ki67 suppression by IHC analysis in the SERENA-3 trial (NCT04588298).

Methods

Post-menopausal women with ER+ primary breast cancer scheduled for curative intent surgery were randomly assigned to pre-surgical treatment with camizestrant 75, 150, or 300 mg for 5–7 days, or camizestrant 75 or 150 mg for 12–15 days. Paired pre- and on-treatment biopsies were analyzed using targeted proteomics by mass spectrometry of macrodissected tissue, computationally guided immunohistochemistry (IHC) image analysis, and assessment of a 38 estrogen–regulated gene expression signature by bulk RNAseq.

Results

The trends observed with the exploratory analysis were concordant with one another and the primary analysis, although the magnitude of the effect differed between techniques (Table). Despite molecular analyses confirming comparable ER degradation and transcriptional output at 5-7 days of treatment, after 5–7 days camizestrant 75 mg reduced Ki67 less than 150 and 300 mg. However, after 12–15 days there was no difference in Ki67 between 75 and 150 mg. Table: 274P

Mass spectrometry and Ki67 image analysis: geometric mean [n] RNAseq and ER image analysis: arithmetic mean [n] a % change b Absolute change, arbitrary units c Excluded if baseline Ki67 index

Conclusions

Complementary multiomic assessment of SERENA-3 showed that camizestrant 75 mg achieved maximal levels of ER degradation and antagonism at 5-7 days, and proliferation suppression by 12–15 days, affirming the conclusion from IHC analysis and its selection as the primary endpoint, allowing comparison with prior pre-surgical studies. These results highlight the different temporal nature of the PD effects and suggest the utility of the endpoints as primary readouts for PD assessment in future trials. Together with SERENA-2, this evidence supports 75 mg as the optimal camizestrant dose, including in early disease, and highlights the value of a specific multi-dose pre-surgical pharmacodynamic study for dose selection.

Clinical trial identification

NCT04588298.

Editorial acknowledgement

Editorial support was proivided by Neville Pitts of InterComm International, UK.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

C. Morrow: Financial Interests, Personal, Stocks/Shares: AstraZeneca. Z.S. Katashvili: Financial Interests, Personal, Full or part-time Employment: Todua Clinicl, S. Khechinashvili Klinik. J.E. Bargallo Rocha: Financial Interests, Personal, Speaker, Consultant, Advisor: MSD, Gilead; Financial Interests, Personal, Speaker’s Bureau: Roche, MSD, Gilead, Exact Science. I. Moppett: Financial Interests, Personal, Full or part-time Employment, Of family member, not of author themselves: Barnsley Hospital; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca. K. Cheung: Financial Interests, Personal, Speaker, Consultant, Advisor: Roche; Financial Interests, Personal, Other, travel/accomodation support: Cancers. G. Nemsadze: Financial Interests, Institutional, Other, Payments made to institution: AstraZeneca. M. Ajimi; K. Andreou; A. Chambers; J. Lindemann; R. Mcewen; J. Robertson; D. Whitston: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca.D. Chain: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca; Financial Interests, Personal, Research Funding: AstraZeneca. R. Kim: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca; Financial Interests, Personal, Research Funding: AstraZeneca. M. Nikolaou: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. All other authors have declared no conflicts of interest.