Prognostic Significance of Circulating Tumor DNA in Metastatic Prostate Cancer: A Systematic Review and Meta-Analysis.

Circulating tumor DNA (ctDNA) is a minimally invasive biomarker that enables molecular profiling and prognostic stratification in cancer. This meta-analysis evaluated the prognostic significance of ctDNA in metastatic prostate cancer (mPC). PubMed, Web of Science and Scopus were searched from inception to September 15, 2025 for studies assessing ctDNA and survival in prostate cancer. Hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were extracted; when unavailable, HRs were reconstructed from published survival curves. Meta-analyses were performed according to ctDNA detectability, ctDNA levels and ctDNA-detected gene mutations. About 13 studies including 18,575 patients were eligible. Across 9 studies, detectable ctDNA was associated with significantly worse PFS (HR = 1.65, 95% CI: 1.22-2.22) and OS (HR = 2.20, 95% CI: 1.92-2.51) versus undetectable ctDNA. In patients receiving androgen receptor pathway inhibitors and in mCRPC, ctDNA negativity consistently correlated with longer PFS and OS. Gene-level analyses showed that AR, CDK6/12, MYC, PIK3CA, and BRCA1/2 mutations in ctDNA were linked to inferior PFS, whereas BRCA1/2 mutations did not significantly worsen OS. About 5 studies examined ctDNA levels: higher ctDNA levels predicted poorer survival (PFS: HR = 1.68, 95% CI: 1.18-2.38; OS: HR = 2.43, 95% CI: 1.50-3.93), and lower levels were associated with better outcomes in ARPI-treated and mCRPC patients. In mPC, ctDNA detectability and elevated ctDNA levels are strongly associated with adverse survival. Quantitative ctDNA profiling, including assessment of key gene mutations, offers a clinically relevant tool to refine risk stratification and to support molecularly informed treatment selection and monitoring where clinically validated.