Dimitrios Voulgarelis1, Pablo Morentin Gutierrez1
1DMPK, Oncology R&D , AstraZeneca
Introduction/Objectives: The main objectives of this project are to establish a quantitative PK/PD-Efficacy relationship for the next generation oral selective estrogen receptor degrader (SERD) and complete ER antagonist camizestrant on the CTC-174 (ESR1 mutant) and MCF-7 (ESR1 WT) tumour mouse models and to evaluate the translatability of the PK/PD relationship of estrogen receptor (ER) degradation to human. One of the key modes of action of SERDs is to increase the basal degradation rate of ER, leading to a decrease in total protein levels. Methods: A 1-compartment model with first order absorption was used to describe the plasma PK. The mode of action of the drug was incorporated into two semi-mechanistic mathematical models for synthesis and degradation of ER and inhibition of progesterone receptor (PgR) for CTC-174 and MCF-7 respectively. An indirect response PKPD model was used to describe the biomarkers modulation as a function of the concentration in the plasma. Moreover, to account for the fact that PgR is a downstream marker of ER a single transit compartment was added to the indirect PD model for MCF-7. The PKPD models were then combined with an exponential growth tumour model in order to connect ER/PgR levels to tumour growth rate in the two cell lines. Additionally, the preclinical PD model was incorporated into the clinical population PK (popPK) [2] model for camizestrant to predict the level of ER degradation in patients’ tumours with different doses of camizestrant (SERENA-1 study) [1]. Clinical PD data are measured using immunohistochemistry (IHC) instead of the western blot (WB) method used in preclinical models. Therefore, to predict human PD modulation ER measured by WB preclinically, needs to be converted to IHC values. To that end ER levels were measured in CTC-174 preclinically using both IHC and WB, and an empirical power law relationship was established between the two to convert from one to the other. Results: The mathematical model was able to describe the effects of camizestrant on tumour ER and PgR levels. A clear correlation between the free concentration of camizestrant in plasma and levels of ER (and the downstream biomarker PgR) was observed. Additionally, a correlation between the degree of ER/PgR modulation and the anti-tumour effects of camizestrant was observed. The mathematical model provided key learnings indicating that in the CTC-174 model 60% ER degradation (by WB) leads to 50% tumour growth inhibition, and tumour stasis requires 90% ER degradation, while in the MCF-7 model 45% PgR modulation is required to achieve tumour stasis, with greater modulation driving tumour regression. Moreover, the observed effects of camizestrant on ER levels in tumours from the SERENA-1 clinical study were accurately predicted by the preclinical model. Conclusions: A semi-mechanistic PK/PD-Efficacy model has been built for camizestrant that successfully describes the antitumour effects in two different tumour models, CTC-174 and MCF-7, as a function of the compound exposure via the modulation of key biomarkers, ER for CTC-174 and PgR for MCF-7. In addition, the preclinical PK/PD model for camizestrant built from CTC-174 was able to predict the magnitude of ER degradation achieved by camizestrant in the SERENA-1 Phase I study, by taking into consideration differences in the bio-analytical methodologies for measuring ER degradation between preclinical and clinical samples.
1. Hamilton E, Oliveira M, Turner N, García-Corbacho J, Hernando C, Ciruelos EM, Kabos P, Ruiz-Borrego M, Armstrong A, Patel MR, Vaklavas C, Twelves C, Boni V, Incorvati J, Brier T, Gibbons L, Klinowska T, Lindemann JPO, Morrow CJ, Sykes A, Baird RD. A phase I dose escalation and expansion trial of the next-generation oral SERD camizestrant in women with ER-positive, HER2-negative advanced breast cancer: SERENA-1 monotherapy results. Ann Oncol. 2024 Aug;35(8):707-717. doi: 10.1016/j.annonc.2024.04.012. Epub 2024 May 8. PMID: 38729567. 2. Population PK modelling of camizestrant, a next-generation oral selective estrogen receptor degrader, as monotherapy and in combination with palbociclib in ER+/HER2- advanced breast cancer. Itziar Irurzun-Arana (1), Andy Sykes (1), Srinivas Bachina (2), Tim Brier (3), Justin PO Lindemann (3), Teresa Klinowska (4). PAGE 31 (2023) Abstr 10686 [www.page- meeting.org/?abstract=10686]
Reference: PAGE 33 (2025) Abstr 11737 [www.page-meeting.org/?abstract=11737]
Poster: Drug/Disease Modelling - Oncology