Circulating tumour DNA in mCRPC: bridging tumour biology and real-time treatment monitoring

Metastatic castration-resistant prostate cancer (mCRPC) is associated with poor prognosis. Currently, treatment selection and response assessment in mCRPC still rely largely on prostate-specific antigen (PSA) and imaging tools, which may be insensitive and biologically noninformative. Liquid biopsy (LB), particularly circulating tumor DNA (ctDNA), offers a minimally invasive and reproducible approach for real-time assessment of tumor burden and tumor genomics. Across major treatment classes, ctDNA tumor fraction has shown consistent prognostic value, while selected genomic alterations may provide therapy-specific predictive information. Early on-treatment ctDNA kinetics are also emerging as dynamic markers of response, although prospective validation is required before routine clinical implementation. In this narrative review, we synthesize current evidence on ctDNA biology, detection methods, and its clinical utility across key mCRPC treatment classes, including androgen receptor pathway inhibitors (ARPIs), taxane chemotherapy, PARP inhibitors, and PSMA-targeted radioligand therapy (RLT). We critically examine ctDNA tumor fraction as a pan-therapy prognostic biomarker, genomic alterations as potential predictors of treatment sensitivity or resistance, early kinetic changes as surrogate markers of response, and the biological and technical limitations that currently restrict clinical adoption. Overall, the current evidence base for ctDNA in mCRPC remains predominantly prognostic rather than definitively predictive. Its integration into routine clinical practice will require prospective biomarker-driven trials, assay standardization, and a clear demonstration of clinical utility. At present, ctDNA is best positioned as a complementary tool for risk stratification and disease monitoring, with the potential to evolve into a clinically actionable biomarker for treatment decision-making.