Enzalutamide after abiraterone progression is commonly used in metastatic castration resistant prostate cancer (mCRPC) despite a low rate of clinical benefit. Analyzing IMbassador250, a phase III trial assessing enzalutamide with or without atezolizumab after abiraterone, we hypothesized that baseline and early changes in circulating tumor DNA (ctDNA) tumor fraction (TF) may identify patients more likely to exhibit survival benefit from enzalutamide.
ctDNA was quantified from plasma samples using a tissue-agnostic assay without buffy coat sequencing. Baseline ctDNA TF, changes in ctDNA TF from baseline to cycle 3 day 1 (C3D1), and detection at C3D1 alone, were compared vs overall response rate (ORR), radiographic progression-free survival (rPFS), median OS (mOS), and 50% reduction in PSA.
ctDNA TF detection at baseline and/or C3D1 was associated with shorter rPFS and OS in 494 evaluable patients. Detection of ctDNA TF at C3D1, with or without detection at C1D1, was associated with worse rPFS and mOS than lack of detection. When ctDNA TF and PSA response at C3D1 were discordant, patients with [ctDNA TF undetected/PSA not reduced] had more favorable outcomes than [ctDNA TF detected/PSA reduced] (mOS 22.1 months vs. 16 months, p<0.001).
In a large cohort of mCRPC patients receiving enzalutamide after abiraterone, we demonstrate the utility of a new tissue-agnostic assay for monitoring molecular response based on ctDNA TF detection and dynamics. CtDNA TF provides a minimally-invasive, complementary biomarker to PSA testing and may refine personalized treatment approaches.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2024 Jul 11 [Epub ahead of print]
Christopher J Sweeney, Russell Petry, Chang Xu, Merrida Childress, Jie He, David Fabrizio, Ole Gjoerup, Samantha Morley, Timothy Catlett, Zoe June Assaf, Kobe Yuen, Matthew Wongchenko, Kalpit Shah, Pratyush Gupta, Priti Hegde, Lincoln W Pasquina, Sanjeev Mariathasan, Ryon P Graf, Thomas Powles
University of Adelaide, Adelaide, SA, Australia., Foundation Medicine, Boston, United States., Foundation Medicine, United States., Vanderbilt University, Nashville, TN, United States., Foundaion Medicine, Cambridge, MA, United States., Foundation Medicine Inc., Cambridge, MA, United States., Foundation Medicine, Inc., Cambridge, MA, United States., Roche/Genentech, United States., Genentech, south san francisco, CA, United States., Genentech Inc., South San Francisco, United States., Genentech, Inc., South San Francisco, United States., Genentech Foundation, South San Francisco, California, United States., Foundation Medicine, Boston, MA, United States., Genentech, United States., Foundation Medicine, San Diego, CA, United States., Barts Cancer Institute, Queen Mary University of London, Royal Free NHS Trust, London, United Kingdom.