(UroToday.com) The 2026 American Society of Clinical Oncology (ASCO) Annual Meeting was host to a prostate, testicular, and penile cancers poster session. Dr. David Chen presented an analysis of cell-free DNA (cfDNA) nucleosome and genomic signatures as predictors of outcomes with radium-223 in metastatic castrate-resistant prostate cancer (mCRPC).
Radium-223 is a bone-targeted, alpha-emitting radiopharmaceutical that induces double-stranded DNA breaks and has demonstrated an overall survival benefit in men with symptomatic bone-predominant mCRPC without visceral metastases in the ALSYMPCA trial.1 However, clinical outcomes with Ra-223 remain heterogeneous, and reliable biomarkers to identify patients likely to derive benefit — or those at risk for progression with visceral disease — are lacking. Given increasing interest in precision treatment selection for radioligand and radionuclide therapies, the study investigators evaluated whether genomic and epigenetic features derived from plasma cfDNA could identify tumor characteristics prognostic of clinical outcomes following Ra-223 treatment.
Pretreatment plasma cfDNA samples were analyzed from 137 patients with mCRPC treated with Ra-223. Investigators performed ultra-low pass and deep whole genome sequencing, with tumor fraction and copy number alterations estimated using ichorCNA. Transcription factor (TF) activity was inferred through nucleosome profiling of cfDNA fragments surrounding transcription start sites and TF binding sites using the Griffin and TritonNP analytical platforms. Genomic and epigenomic features were then correlated with clinically relevant outcomes, including completion of six cycles of Ra-223, overall survival, and development of new nodal, visceral, or liver metastases.
To further evaluate predictive performance, the investigators developed a multimodal binary classifier integrating copy number variation and TF activity data. Feature selection was performed using LASSO methodology, followed by model development using XGBoost with repeated nested 5-fold cross-validation. External validation was subsequently conducted in independent cohorts of patients with mCRPC treated with docetaxel (n=46) or other systemic therapies (n=142) to evaluate the prediction of new metastatic involvement.
Several pretreatment cfDNA-derived features were associated with adverse clinical outcomes following Ra-223 therapy. Higher baseline tumor fraction and increased TF activity at specific loci, including HIF3A, ZNF770, and PRDM6, correlated with worse outcomes. In particular, these genomic and epigenomic signatures were associated with a lower likelihood of completing six cycles of Ra-223, inferior survival outcomes, and a greater risk of developing new metastatic disease involving visceral organs or the liver.
The multimodal classifier predicting completion of Ra-223 therapy demonstrated strong discriminatory performance during cross-validation and similarly performed well in predicting progression to liver metastases. Importantly, external validation across independent treatment cohorts demonstrated moderate discriminatory ability, suggesting that these cfDNA-derived biomarkers may capture broader biologic features associated with aggressive disease behavior rather than being specific to Ra-223 treatment alone.
The investigators concluded that cfDNA-derived genomic and epigenomic profiling can identify biologically relevant tumor characteristics associated with benefit from Ra-223 therapy in mCRPC. They further noted that ongoing analyses are integrating genomic alterations such as mutations, amplifications, and deletions in key disease-related genes to better define genotype-phenotype relationships associated with treatment outcomes.
Presented by: David D. Chen, PhD, Mayo Clinic, Rochester, MN, USA
Written by: Rashid K. Sayyid, MD, MSc, Assistant Professor, Urologic Oncologist, Department of Urology at The University of Arizona and Banner University Medical Center, Tucson, AZ – @rksayyid on X during the American Society of Clinical Oncology Genitourinary (ASCO) Annual Meeting held in Chicago, IL between May 29th and June 1st, 2026
References:
- Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013;369(3):213-223.