Circulating Tumor DNA Genomic Profiling in <sup>223</sup>Ra-Treated Metastatic Castration-Resistant Prostate Cancer: The KYUCOG-1901 Study.

Abstract

Circulating tumor DNA (ctDNA) testing has emerged as a cancer precision medicine approach. We investigated the genomic landscape and clinical utility of ctDNA in patients receiving 223Ra dichloride for bone metastatic castration-resistant prostate cancer (mCRPC). Methods: This prospective, observational, multicenter study enrolled patients treated with 223Ra for bone mCRPC. Targeted sequencing of cell-free DNA from plasma at baseline and end of treatment (EOT), along with paired leukocyte DNA, was performed using an 88-gene panel. Associations between ctDNA profiles and clinical outcomes, including biomarker response, radiographic progression-free survival (rPFS), and overall survival (OS), were analyzed. Results: Of 93 patients analyzed, ctDNA was successfully profiled in 84 baseline and 74 EOT samples, with matched data available for 68 patients. A ctDNA fraction of at least 5%, as well as TP53 alteration, PTEN alteration, and cell cycle pathway alterations at baseline were significantly associated with shorter rPFS and OS. Dynamic changes in ctDNA fraction and PTEN alteration between baseline and EOT correlated with distinct rPFS and OS. Conclusion: This study suggests the clinical utility of ctDNA profiling as both a prognostic and a monitoring tool in patients with bone mCRPC treated with 223Ra. The findings obtained in this study raise the possibility that ctDNA could contribute to future strategies for risk stratification or treatment monitoring during 223Ra therapy.