| Sumario: | Simple Summary: Metastatic castration-resistant prostate cancer (mCRPC) refers to prostate cancer that has spread to distant organs and no longer responds to androgen deprivation therapy. Despite the availability of treatments that can alleviate symptoms and modestly extend survival, it remains an incurable disease at this stage. The analysis of prostate cancer cells can now identify specific gene changes—called actionable mutations—that guide the selection of targeted therapies more likely to be effective for individual patients. However, obtaining tumor biopsies is often invasive and technically challenging, particularly in patients with metastatic disease. Recently, simple blood tests that analyze circulating tumor DNA (ctDNA), fragments of DNA shed by cancer cells into the bloodstream, have emerged as much less invasive and more practical alternatives. This review underscores the current utility and significance of ctDNA in detecting actionable genomic mutations to inform treatment strategies for patients with mCRPC. Circulating tumor DNA (ctDNA) analysis has emerged as a powerful and minimally invasive approach for genomic profiling of metastatic castration-resistant prostate cancer (mCRPC), enabling real-time detection of tumor-derived mutations that guide therapy. Approximately 20% of mCRPC patients harbor alterations in homologous recombination repair (HRR) genes, most commonly BRCA1/2 and ATM, which are actionable with different poly-(ADP-ribose) polymerase inhibitors (PARPIs) used as monotherapy or in combination with androgen receptor signaling inhibitors (ARSIs). A smaller subset of patients with mismatch repair deficiency (MMRd) or microsatellite instability-high (MSI-high) tumors may benefit from immune checkpoint blockade with pembrolizumab. Different FDA-approved liquid biopsy assays detect these actionable alterations when tissue biopsies are unavailable or insufficient. This review summarizes current evidence on ctDNA-based genotyping in mCRPC, highlighting clinically actionable mutations, corresponding targeted therapies, and technical and analytical considerations for clinical implementation. By capturing DNA shed from multiple metastatic sites, ctDNA profiling provides a comprehensive view of tumor heterogeneity and enables serial monitoring of molecular evolution. Overall, ctDNA analysis represents a transformative advance in precision oncology, supporting personalized treatment selection and ongoing assessment of therapeutic response in mCRPC.
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