Evaluation of circulating tumor DNA kinetics as a prognostic biomarker for overall survival in metastatic castrate resistant prostate cancer using a novel methylation sequencing research assay

Abstract Introduction: IMbassador250 was a prospective phase III international multicenter trial enrolling 759 men with mCRPC who had prior progression on abiraterone, with or without prior taxane, randomizing to enzalutamide +/- atezolizumab. For this retrospective biomarker study, we hypothesized that decreases in ctDNA after 6 weeks of therapy, as measured from a novel low-pass, whole genome methylation sequencing assay from Foundation Medicine, will have greater discriminatory power to distinguish overall survival (OS) than PSA alone in a post-abiraterone mCRPC setting. Methods: Pre-treatment and C3D1 plasma samples from IMbassador250 were sequenced using a novel research assay that examines global copy number changes and methylation patterns through low pass, whole genome sequencing from Foundation Medicine. Kinetic changes in ctDNA were estimated between pre-treatment and C3D1 timepoints and patients were dichotomized into significant decreases vs. not using a predefined cutoff. PSA was examined as both 50% reduction from baseline to disease progression as well as a cutoff that matched the prevalence captured by the ctDNA reduction group at C3D1. Cox proportional hazards were calculated from Kaplan-Meier survival plots of overall survival between the reduction vs. no reduction groups. Results: Stratifying OS according to PSA 50% reduction from baseline to disease progression yielded an HR = 2.71 (95%CI:2.04-3.62). 370 patients (48%) had available ctDNA at both C1D1 and C3D1, and the median OS (mOS) in the reduction vs. non-reduction groups were 17.4 vs. 9.1 months, respectively (HR of 3.01; 95%CI:1.96-4.64). Evaluation of PSA reduction at C3D1 in the patients with available ctDNA yielded mOS of 16.3 and 9.5 months in the reduction vs. non-reduction groups, respectively (HR=2.70; 95%CI:1.77-4.12). Spearman’s correlation of ctDNA fold change between the research assay and an orthogonal FDA approved liquid biopsy assay was 0.95. Discussion: In this study, early ctDNA kinetic changes provided numerically superior estimation of overall survival compared to PSA in mCRPC patients receiving enzalutamide +/- atezolizumab in the post-abiraterone setting. Furthermore, ctDNA kinetic changes through C3D1 were apparent mostly prior to both PSA 50 and radiographic progression (6 weeks vs mean 3.3 months), providing a non-invasive strategy that is independent of PSA for monitoring therapy response when the disease is less AR dependent. Citation Format: Christopher Sweeney, Chang Xu, Jie He, Amanda Young, Alexander Robertson, Russell Petry, Daniel Zollinger, Alexander Fine, Neil Peterman, Eliana Polisecki, Tyler Warner, Kobe Yuen, Yanmei Huang, Zoe Assaf, Ryon Graf, Sanjeev Mariathasan, Priti Hegde, David Fabrizio, Thomas Powles. Evaluation of circulating tumor DNA kinetics as a prognostic biomarker for overall survival in metastatic castrate resistant prostate cancer using a novel methylation sequencing research assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3362.