Abstract 677: A precision dosing application for prostate cancer chemotherapy
Authors: Claire Villettte, Hitesh Mistry, Fernando G. Ortega, David Orrell, Frances A. Brightman, Jim Millen, Christophe Chassagnole
Journal: Cancer Research (2019)

Abstract The therapeutic window of chemotherapy drugs is commonly established at a population level and patient dose selection is often simply scaled with Body Surface Area. Due to large inter-individual physiological variability, this leads to a significant number of patients being under or over-dosed. While a limited number of precision dosing techniques exist to tailor patient-specific treatment, they typically require costly additonal tests which severly restrict their use in clinical practice. Focusing on the use of docetaxel in metastatic castrate-resistant prostate cancer, we have developed a demonstrator for precision dosing which relies only on routine blood tests that are already universally available in most health systems and could thus fit within the current clinical practice to improve patient outcome at a low cost. This tool was developed using publicly available data from Project Datasphere for the comparator arm of a phase III clinical trial for metastatic hormone-resistant prostate cancer (NCT00617669). This cohort includes 412 patients who were treated with Docetaxel between 2008 and 2011 in cycles of 21 days with weekly blood tests in the first cycle. A population PK/PD model for Docetaxel and leukocyte population was assembled based on literature [1,2]. Individual patient parameters including Docetaxel AUC were estimated by calibrating this model with weekly measured blood count using a Bayesian approach. Survival and toxicity Cox models were developed using estimated PK/PD parameters as well as biomarker levels. They allowed estimations of gains in prognostic as well as toxicity risks associated with modifying patient dose after the first chemotherapy cycle. These models will be made available through a web application to support clinicians in their decision to refine patient doses. Concordance levels of the order of 0.7 were obtained for the survival and toxicity models, with significant predictive variables including Docetaxel AUC, patient liver markers as well as PSA. Patients with low estimated hematologic toxicity (neutrophil count not dropping under 1 billion/L for more than 5 days) presented a median overall survival time of 461 days, against 563 days for patients with higher hematologic toxicity. Patients with low estimated Docetaxel AUC (&amp;lt;1.5 µg.h/mL) presented a median overall survival time of 455 days, against 587 days for patients with higher estimated Docetaxel AUC. For some patients, the models predicted gains in prognosis without severe toxicity when increasing the dose. We have developed a precision dosing app for Docetaxel in prostate cancer which requires a single weekly classical blood test in the first chemotherapy cycle. This app has the potential to significantly improve patient outcome at low cost without disrupting current clinical practice. References [1]: McLeod, H.L. et al (1998). Cancer chemotherapy and pharmacology [2]: Friberg, L.E. et al (2002). Journal of clinical oncology Citation Format: Claire Villettte, Hitesh Mistry, Fernando G. Ortega, David Orrell, Frances A. Brightman, Jim Millen, Christophe Chassagnole. A precision dosing application for prostate cancer chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 677.