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.

Abstract

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* 2.04 0.73–5.69 0.17  BRCA2 12 4.5 1.71 0.89–3.29 0.11 1.28 0.62–2.66 0.51  MSH6 9 6.2 1.06 0.48–2.33 0.88 1.07 0.48–2.34 0.87  CHD1 9 3.5 2.10 1.03–4.25 0.040* 1.47 0.64–3.37 0.37  APC 13 6.2 1.49 0.79–2.79 0.21 1.22 0.62–2.38 0.56  SPOP 9 5.5 2.45 1.19–5.08 0.015* 1.76 0.75–4.16 0.20  ZFHX3 10 5.6 2.07 1.01–4.26 0.047* 1.17 0.43–3.20 0.76  TP53/RB1/PTEN 20 3.4 3.57 2.04–6.25 <0.0001* 3.60 1.80–7.21 0.0003* Altered pathway  AR–associated 9 3.1 2.70 1.32–5.55 0.0067* 1.94 0.82–4.63 0.13  Cell cycle 22 3.5 3.47 2.00–6.03 <0.0001* 3.50 1.79–6.85 0.0003*  PI3K 16 3.5 2.26 1.26–4.06 0.0063* 1.86 0.96–3.61 0.066  DNA repair 23 5.7 1.53 0.89–2.62 0.12 1.21 0.65–2.25 0.54  Chromatin modifier 18 6.0 1.73 0.99–3.02 0.055 1.46 0.80–2.68 0.22  WNT 15 6.2 1.50 0.83–2.72 0.18 1.28 0.69–2.40 0.44