Genomic profiling in circulating tumor DNA from a multicenter prospective study of radium-223 in bone-metastatic castration-resistant prostate cancer: The KYUCOG-1901 study.

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211 Background: Circulating tumor DNA (ctDNA) testing has emerged as a novel approach in cancer precision medicine. We investigated the genomic landscape and clinical utility of ctDNA in patients receiving radium-223 (Ra-223) for bone-metastatic castration-resistant prostate cancer (mCRPC). Methods: This prospective observational multicenter study enrolled patients treated with Ra-223 for bone-mCRPC. Targeted sequencing of cell-free DNA from plasma at baseline (BL) 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 BL and 74 EOT samples, with matched data available for 68 patients. A ctDNA fraction ≥5% (rPFS; hazard ratio [HR], 95% confidence interval [CI]; 2.44, 1.47-4.08), as well as TP53 alteration (rPFS; HR, 95% CI; 2.65, 1.30-5.42), alterations in TP53 , RB1 or PTEN (rPFS; HR, 95% CI; 3.57, 2.04-6.25), and cell cycle pathway alterations (rPFS; HR, 95% CI; 3.47, 2.00-6.25) at BL, were significantly associated with shorter rPFS and OS. Dynamic changes in ctDNA between BL and EOT correlated with distinct PSA-PFS, ALP-PFS, rPFS, and OS although PSA and ALP declines were not associated. Conclusions: ctDNA profiling outperformed PSA and ALP in monitoring disease trajectory and predicting outcomes. These findings highlight ctDNA as a promising biomarker to guide and optimize Ra-223 therapy in mCRPC. Clinical trial information: UMIN000040358 . Association between ctDNA profile at baseline and radiographic progression-free survival. Median, 8.8 months Univariate analysis Adjusted with ctDNA fraction n=84 HR 95% CI P–values HR 95% CI P–values DNA amount cfDNA amount, ≥20 ng/ml 18 3.4 1.56 0.89–2.75 0.12 ctDNA fraction, ≥5% 32 5.6 2.44 1.47–4.08 0.0006* Altered gene AR 13 5.7 2.18 1.18–4.03 0.013* 1.80 0.92–3.52 0.087 TP53 9 3.4 2.65 1.30–5.42 0.0077* 2.46 1.19–5.09 0.016* RB1 9 3.3 2.94 1.42–6.10 0.0037*

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