Plasma Exosomal RNA Signature for Prostate Cancer Bone Metastasis

Brief Summary: This prospective, multicenter study aims to discover, develop, and validate a plasma exosomal RNA-based signature as a rule-out test for predicting bone metastasis in prostate cancer, using baseline treatment-naïve PSMA PET as the gold standard. The study is designed in four sequential phases: Phase 1 (Discovery, n=250): High-throughput sequencing of plasma exosomal RNAs to identify differentially expressed candidate RNAs. Phase 2 (Model Development, n=300): Digital droplet PCR (ddPCR) analysis of candidates in an independent cohort to construct and lock the final multi-RNA predictive signature using appropriate machine learning methods. Phase 3 (Internal Validation, n=300): Independent validation of the locked signature in a consecutive cohort reflecting natural disease prevalence. Phase 4 (External Validation, n=150): Final independent validation in a multi-center cohort enriched for bone metastasis. Primary Outcome: To evaluate the diagnostic performance of the signature as a rule-out test for PSMA PET-defined bone metastasis. The primary performance metrics are: Sensitivity, with a prespecified target of ≥95% (to ensure minimal false negatives). Specificity at the threshold that achieves the ≥95% sensitivity. A specificity of ≥30% will be considered supportive of clinical utility. A specificity of ≥30% (or a lower bound of the 95% confidence interval exceeding 20%) will be considered supportive of clinical utility. Need: Current biomarkers lack sensitivity and specificity for early detection of bone metastasis. More importantly, existing tools lack adequate negative predictive value to safely rule out bone metastasis in low-risk patients, leading to over-imaging or delayed detection. There is an urgent need for a non-invasive rule-out test to safely defer PSMA PET/CT in very-low-risk patients. Plasma exosomal RNAs offer a promising liquid biopsy approach, but prospective multicenter studies with rigorous validation are lacking. Seconda