Circulating tumor DNA levels in blood plasma accurately predicted survival outcomes in 97 men with metastatic castration-resistant prostate cancer receiving cabazitaxel chemotherapy. Patients with undetectable ctDNA lived a median 26.8 months versus only 8.2 months for those with high ctDNA levels, while those showing ctDNA increases by the third treatment cycle had dramatically shortened survival compared to patients maintaining undetectable levels. This liquid biopsy approach represents a significant advance in precision oncology for advanced prostate cancer, potentially allowing clinicians to identify treatment futility early and switch therapies before disease progression becomes irreversible. The blood-based monitoring could spare patients unnecessary toxicity from ineffective treatments while preserving quality of life. However, the findings require validation in larger cohorts before clinical implementation. The research also revealed distinct resistance patterns: androgen receptor mutations emerged after hormone therapy failure, while chromosome 3 amplifications containing DNA repair genes appeared after taxane exposure, suggesting different evolutionary pressures shape tumor adaptation. This mechanistic insight could inform sequential treatment strategies and combination approaches targeting these specific resistance pathways in future clinical trials.