Ana Quiroga-Campano1, Pablo Morentin Gutierrez1, Antonio Ramos-Montoya2, Claire Crafter2, Chrysiis Michaloglou2, Gemma Hardman Fowler2, Nuria Galeano-Dalmau2, Aaron Smith1, James Scott3, Michael Niedbala4
1DMPK, Research and Early Development OTD, Oncology R&D, AstraZeneca, 2BioScience, Research and Early Development OTD, Oncology R&D, AstraZeneca, 3Chemistry, Research and Early Development OTD, Oncology R&D, AstraZeneca, 4Project Leadership, Research and Early Development OTD, Oncology R&D, AstraZeneca
Objectives: The androgen receptor (AR) plays a pivotal role in prostate cancer pathogenesis, where it is highly expressed, making it a well-established target for therapeutic intervention in oncology. AZD9750 represents a novel, potent oral AR-PROTAC due to start clinical evaluation in 2025. This study integrates pharmacokinetic (PK), pharmacodynamic (PD), and tumour volume in a mathematical model, which was used to determine the specific plasma concentration of AZD9750 necessary to achieve optimal AR modulation and substantial anti-tumour efficacy. This methodological framework was used to guide the dose selection during the early-stage clinical development phases of AZD9750. Methods: We developed a comprehensive mechanistic mathematical model based on internal in vivo preclinical studies. Two murine patient-derived xenograft (PDX) models, MR041 and C901, were assessed which represent primary, hormone sensitive prostate cancer (HSPC) and express wild type AR. The animals received AZD9750 doses of 0.3, 1, 3, 10 and 30 mg/kg, administered once per day for a total duration of 28 days. Throughout this period, extensive data collection took place, which included individual longitudinal PK data and PD biomarker levels (western blot analysis of the AR normalized to vinculin and a vehicle control). In addition, tumour size metrics were also recorded to assess the impact of AZD9750 on tumour progression or regression. This comprehensive dataset enabled the analysis of the correlation between the dosing regimen, biomarker changes, and alterations in tumour size. The PK module consists of a two-compartment model with first-order absorption. The indirect PKPD module assumes endogenous cellular synthesis and degradation rate constants of AR, which were determined using data from stable isotope labelling by amino acids in cell culture (SILAC) studies, and AR compound-induced degradation rate (non-linear correlation with plasma PK). These parameters were calculated and incorporated in the mathematical model to simulate AR levels in the tumour. Finally, the complete PK/PD/Efficacy model assumes tumour homogeneity and AR-dependent tumour growth rate. The model parameters were independently and sequentially determined by module (PK, PK/PD & PK/PD/Efficacy), taking into account interindividual variability at each step (bioavailability, clearance, initial AR levels, and tumour size). All parameters within the model were estimated through Non-Linear Mixed Effect modelling (Phoenix®, Certara). Results: The model accurately captured the relationship between plasma concentrations of AZD9750, modulation of AR levels and inhibition of tumour cell proliferation, leading to observable macroscopic changes in tumour volume. The in vivo concentration of AZD9750 required to achieve 50% of maximal target modulation was within the range of 0.2 µM (MR041) – 0.7 µM (C901). The population dynamics of tumour size, including all treatment regimens and outcomes—ranging from stable disease to tumour regressions—were effectively captured by the proposed model across both models. Importantly, a reduction in AR levels by 55–80% was identified as a critical threshold to induce tumour regression within these models. Conclusions: This study provides mechanistic, integrated and quantitative insights into the interplay between AZD9750 exposure, AR modulation, and anti-tumour responses, thereby enhancing our comprehension of the required target modulation levels needed to maximise antitumour effects in hormone-sensitive PDX tumour models. This understanding is valuable for contextualising AZD9750-induced PD modulation, for given doses and schedules in patients, facilitating informed dose selection decisions during initial clinical evaluation.
Guzzetti S and Morentin P. J. Pharmacokinet. Pharmacodyn., 50.5: 327-349, 2023
Reference: PAGE 33 (2025) Abstr 11638 [www.page-meeting.org/?abstract=11638]
Poster: Drug/Disease Modelling - Oncology