Research Spotlight: Circulating Tumor DNA Assessment for Treatment Monitoring Adds Value to PSA in Metastatic Castration Resistant Prostate Cancer
Sweeney CJ, Petry R, Xu C, et al. Circulating tumor DNA assessment for treatment monitoring adds value to PSA in metastatic castration resistant prostate cancer. Clin Cancer Res. 2024. https://doi.org/10.1158/1078-0432.CCR-24-1096
Background:
While enzalutamide following abiraterone progression is still used in the treatment of metastatic castration resistant prostate cancer (mCRPC), many patients see limited clinical benefits due to primary or acquired resistance. Quickly identifying patients who may benefit from enzalutamide can help inform treatment decisions and prevent those with resistance from receiving ineffective therapy. However, the current standards of measuring treatment response through radiographic assessments and changes in PSA levels have limitations in identifying non-responders early during treatment. Longitudinal circulating tumor DNA (ctDNA) monitoring has emerged as a powerful new tool for assessing treatment response in advanced cancers.
Study details:
In this study, researchers leveraged data from IMbassador250, a randomized phase III trial assessing enzalutamide with or without atezolizumab after abiraterone in patients with mCRPC, to analyze changes in ctDNA tumor fraction, a determination of the amount of tumor DNA circulating in each blood sample. To assess ctDNA tumor fraction at pre-enzalutamide (baseline) and at cycle 3 day 1 (C3D1), banked plasma samples were analyzed with the research use version of FoundationOne®Monitor, a tissue-naïve ctDNA monitoring assay using next-generation sequencing. Baseline ctDNA tumor fraction detection, changes in ctDNA tumor fraction from baseline to C3D1 and ctDNA tumor fraction detection at C3D1 alone were then compared to the overall response rate (ORR), radiographic progression-free survival (rPFS), median overall survival (mOS) and 50% reduction in PSA.
Researchers found that ctDNA tumor fraction detection at baseline and/or C3D1 was associated with shorter rPFS and overall survival in 494 evaluable patients. Additionally, the detection of ctDNA tumor fraction at C3D1, with or without detection at baseline, was associated with worse rPFS and mOS compared to patients where ctDNA tumor fraction was undetected. When ctDNA tumor fraction and PSA response at C3D1 were discordant, patients with ctDNA undetected/PSA not reduced had more favorable outcomes than patients with ctDNA tumor fraction detected/PSA reduced.
Why this matters:
The use of a tissue-naïve assay to monitor ctDNA tumor fraction detection and changes represents an additional approach to evaluating the clinical response to enzalutamide after abiraterone in patients with mCRPC. The study indicates that ctDNA tumor fraction can complement PSA testing and conventional radiographic assessments while also serving as a strong prognostic factor across time points of treatment and providing additional risk stratification for patients with clinically ambiguous results.
Additionally, the research suggests that the serial measurement of ctDNA tumor fraction through minimally invasive liquid biopsies presents as a valuable tool in assessing and predicting the response to therapy in advanced cancers, particularly those with a high rate of bone metastasis where imaging may be inconclusive. With comprehensive genomic profiling, serial liquid biopsies can identify novel alterations that may confer resistance to various therapies at different time points, allowing oncologists to make better-informed, personalized treatment decisions.
View the full publication in Clinical Cancer Research.