Abstract PS1-12-11: Giredestrant immobilizes the Estrogen Receptor to potently suppress ER-active breast cancers

Abstract Estrogen Receptor α (ER) is one of the most successfully prosecuted therapeutic targets in oncology, with multiple ER-targeted therapies approved for the treatment of breast cancer. Understanding the limitations of approved agents re-energized the breast cancer community towards the development of next-generation endocrine therapies to further benefit patients. In particular, orally bioavailable selective ER antagonists and degraders (SERDs) were designed to overcome exposure limitations of fulvestrant and achieve deep and sustained ER inhibition, to both treat and delay resistance. Results from randomized clinical trials in women with pre-treated advanced metastatic breast cancer (mBC) support potential superiority of latest-generation SERDs in patients harboring ESR1-mutant tumor cells, while the gains for patients with no mutations detected appears more limited. It was hypothesized that ER degraders with a distinct mechanism of action i.e. proteolysis-targeting chimeras (PROTACs) that are engineered to directly recruit the CRBN E3 ligase to ER, would drive more robust depletion of ER protein and thus extend benefit to ER wildtype tumors. Recent data from the VERITAC-2 trial do not support that hypothesis, likewise demonstrating a more prominent advance for patients harboring ESR1 mutations versus those with no mutations detected. We evaluated the activity of investigational and approved endocrine therapies in 22 ER-expressing breast cancer models in vitro, and observed a broad range of anti-proliferative activity spanning complete arrest to no measurable impact. Leveraging a previously curated ER activity signature we discovered that a key determinant of SERD, in particular giredestrant, sensitivity is the extent of ER activation prior to treatment. Most critically, differentiation of endocrine therapies with distinct modes of action occurs most clearly in cell lines with high ER activity; ER activity-low cell lines are less sensitive to endocrine therapies and fail to discriminate between agents. This finding is important given the extensive heterogeneity in ER activity in 2/3L mBC, observed by leveraging the same ER activity signature in biopsies from patients participating in giredestrant trials. We next explored differentiating attributes of SERDs and PROTACs. Transcription factors, including ER, move dynamically within the nucleus to engage DNA and trigger gene expression. In prior studies, we proposed that a major mechanism through which SERDs achieve full ER antagonism is via profound reduction of ER mobility. We show that giredestrant, like other full ER antagonists, immobilizes ER, while ER PROTACs do not; we thus uncouple ER immobilization and ER degradation as distinct pharmacological features. PROTACs can promote greater degradation of ER protein than is achieved by giredestrant, however, increased ER depletion does not result in superior anti-proliferative potential. We propose that ER immobilization by SERDs is a key pharmacological attribute driving ER inhibition even in the absence of ER elimination. Thus, sub-maximal ER degradation by SERDs likely does not, in this context, represent a limitation to be overcome by direct E3 ligase recruitment. Rather, the limited gains observed for novel SERDs in 2/3L ESR1 wildtype mBC is more likely a function of tumor biology, whereby those tumors tend to be ER activity-low, a context in which differentiation of endocrine therapies is challenging. Advances delivered by latest-generation SERDs may be more apparent where ER activity is more consistently high; a number of ongoing clinical trials, including those in earlier treatment lines, will test this hypothesis. Citation Format: J. Guan, W. Zhou, J. Liang, A. Collier, P. Perez-Moreno, M. Hafner, C. Metcalfe. Giredestrant immobilizes the Estrogen Receptor to potently suppress ER-active breast cancers abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-12-11.