Abstract 4755: Preclinical mechanistic PK/PD-efficacy modeling for AZD9750, a novel oral androgen receptor degrader (PROTAC), to support dose selection during early clinical development

Abstract Objectives: The androgen receptor (AR) is highly expressed in prostate cancers and is a clinically validated target in oncology. AZD9750 is a novel potent oral selective AR Proteolysis-targeting chimera (PROTAC) due to start clinical testing in 2025. We present here the preclinical PK/PD modeling work used to understand the required target modulation and concentration required to see anti-tumor efficacy and therefore help support the dose selection during the early clinical development of AZD9750. Methods: We developed a novel mechanistic mathematical model applied to in vivo preclinical mouse PDX models (MR041 and C901, primary prostatic adenocarcinoma, hormone sensitive and AR-wt) linking the compound pharmacokinetics with the magnitude of target modulation expressed as relative levels of AR measured by Western Blotting. These changes at the biomarker level were subsequently linked to inhibition of tumor cell proliferation resulting in macroscopic dynamic effects on tumor size. All model parameters were derived from internal studies; some were estimated using Non-Linear Mixed Effect modeling of individual longitudinal PK, PD biomarker and tumor size data taken from several studies. Results: The model described well the relationship between plasma concentration of AZD9750 and modulation of AR. In vivo AZD9750 concentration required to see 50% of the maximal target modulation in both animal models was on the region of 0.2-0.7 µM. Population tumor size patterns, for all treatment regimens ranging from 0 to tumour regressions across both tumor models were very well described with the model proposed. 55 - 80% reduction of AR levels was required to induce tumor regression in both models. Conclusions: This study provides quantitative mechanistic insights into the links between compound exposure, biomarker modulation (AR) and anti-tumor responses, supporting our understanding of the required target modulation needed for maximal anti-tumor effects in these two hormone sensitive patient-derived tumor models. This mechanistic understanding is valuable to contextualize compound-induced PD modulation in patients, for given doses and schedules. Citation Format: Pablo Morentin Gutierrez, Ana Quiroga Campano, Antonio Ramos Montoya, Claire Crafter, Chrysiis Michaloglou, Aaron Smith, Nuria Galeano Dalmau, Jamie Scott, Michael Niedbala. Preclinical mechanistic PK/PD-efficacy modeling for AZD9750, a novel oral androgen receptor degrader (PROTAC), to support dose selection during early clinical development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4755.