Globally, colorectal cancer (CRC) ranks as the third most common cancer. Advanced metastatic malignancy (metCRC) often indicates a poor prognosis with declining 5-year survival rates. Despite numerous available systemic therapies, treatment resistance due to tumor heterogeneity limits long-term efficacy. Many therapies lack biomarkers for accurate patient response prediction. A functional personalized oncology (FPO) approach using CRC patient-derived organoids (PDOs) was implemented to identify patient-specific vulnerabilities and effective treatment combinations. Three pairs of matched metCRC PDOs from primary and metastatic sites were characterized, preserving histopathological and genetic features. The Quadratic Phenotypic Optimisation Platform identified patient-specific drug sensitivity profiles, emphasizing the limitations of genomic-driven precision medicine in metCRC. The study suggests that epigenomic profiling and FPO may uncover novel vulnerabilities for synchronous ptCRC and mCRC treatment.