Abstract B115: Vepdegestrant, a PROteolysis Targeting Chimera (PROTAC) estrogen receptor (ER) degrader, induces greater ER degradation and antitumor activity relative to selective ER degraders (SERDs) in preclinical ER+ breast cancer models

Abstract Purpose: Vepdegestrant is an oral PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader that contains an ER-binding domain and an E3 ubiquitin ligase-binding domain joined by a linker. Unlike selective ER degraders (SERDs), which are competitive ER antagonists that induce conformational changes in the ER and indirectly induce ER degradation, vepdegestrant forms a trimer complex with an E3 ligase and ER, leading to direct ubiquitination and proteasomal degradation of wild-type (WT) ER and clinically relevant ER mutants. Here, we report preclinical ER degradation and antitumor activity of vepdegestrant compared with FDA-approved (fulvestrant and elacestrant) and investigational oral SERDs (giredestrant, camizestrant, amcenestrant, and imlunestrant). Methods: We compared dose-dependent in vitro ER protein degradation with vepdegestrant, fulvestrant, elacestrant, and investigational oral SERDs (giredestrant, camizestrant, amcenestrant, and imlunestrant) at a minimal concentration of 0.16 nM and a maximal concentration of 100 nM in two WT ER+ breast cancer cell lines, MCF7 and T47D, after 4 hours of treatment. Additionally, we compared the antitumor activity and ER degradation of vepdegestrant 30 mg/kg versus fulvestrant 200 mg/kg in the MCF7 cell line-derived xenograft (CDX) model. Results: As analyzed by immunoblot in MCF-7 and T47D cell lines in vitro, vepdegestrant treatment leads to greater maximal degradation of ER (79%–86%) compared with the investigational oral SERDs (55%–74.5%), elacestrant (8%–19.5%), or fulvestrant (73%–74%) after 4 hours of treatment. In the MCF7 CDX model, vepdegestrant displayed greater antitumor activity (103% tumor growth inhibition [TGI]) than fulvestrant (54% TGI) at day 28 of treatment. Mean ER protein levels decreased by 93% with vepdegestrant vs 71% with fulvestrant in tumor lysates collected at day 28 relative to vehicle-treated tumors. Conclusions: Our results indicate that vepdegestrant induces greater maximal ER degradation than investigational oral SERDs, elacestrant, or fulvestrant in WT ER+ breast cancer cell lines. Vepdegestrant also demonstrated greater TGI and ER degradation in vivo compared with fulvestrant in a WT ER+ breast cancer CDX model. Citation Format: Madeline Dorso, Christopher Kuhlberg, XiaoZhe (Janet) Wang, Jessica Teh. Vepdegestrant, a PROteolysis Targeting Chimera (PROTAC) estrogen receptor (ER) degrader, induces greater ER degradation and antitumor activity relative to selective ER degraders (SERDs) in preclinical ER+ breast cancer models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B115.