Abstract 5019: Preclinical mechanistic PK/PD/Efficacy modeling for AZD4241, a novel oral estrogen receptor (ER) degrader (PROTAC), to support dose selection during early clinical development

Abstract The high prevalence of ER-positive breast cancer and the emergence of resistance to current endocrine therapies highlight the need for more effective ER degraders. AZD4241 is a novel, potent, orally bioavailable, and selective ER proteolysis-targeting chimera (PROTAC) scheduled to enter clinical evaluation in 2026. We describe preclinical pharmacokinetic/pharmacodynamic (PK/PD) and efficacy modeling that quantifies the relationships among drug exposure, ERα degradation, and antitumor activity, thereby defining the extent of compound plasma exposure and target modulation required to achieve efficacy. These translational analyses are intended to inform dose selection and guide early clinical development of AZD4241.We developed a mechanistic mathematical model to quantify the exposure-target-response profile of AZD4241 in in-vivo patient-derived xenograft (PDX) models harboring either wild-type or mutated ESR1. The PK module characterized plasma concentrations across a range of doses. An indirect-response PK/PD module incorporated AZD4241 mechanism of action, whereby the compound accelerates ERα degradation yielding reductions in total ER protein measured by Western blot. The integrated PK/PD/Efficacy model linked plasma exposure, ERα levels, and tumor growth kinetics in the PDX models. Model parameters were estimated via nonlinear mixed-effects (NLME) modeling using individual longitudinal PK, PD biomarker, and tumor volume data aggregated across multiple studies. The mathematical model captured the dose-dependent reduction of ERα and the associated inhibition of tumor growth observed in the PDX models. The level of ER degradation required to induce tumor regressions on the PDX models was also quantified and will be presented. This work provides quantitative, mechanistic insight into how exposure drives biomarker modulation and antitumor responses, delineating the level of ERα degradation required for robust efficacy in endocrine-sensitive PDX models. The framework supports interpretation of compound-induced PD effects in patients under defined dosing regimens and supplies translational evidence to enable dose selection in early clinical development. Citation Format: Ana Quiroga, Pablo Morentin Gutierrez, Lynet Nyoni, Natalie Cureton, Mandy Lawson, Aaron Smith, Thomas Hayhow, Neil Gibson. Preclinical mechanistic PK/PD/Efficacy modeling for AZD4241, a novel oral estrogen receptor (ER) degrader (PROTAC), to support dose selection during early clinical development abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5019.