In a real‐world database of metastatic colorectal cancer (mCRC) in the United States, comprehensive genomic profiling (CGP) using plasma‐based next‐generation sequencing identified potentially actionable profiles for approximately one‐third of the patients with both the first test and again with a second test after disease progression, with around 60% of all patients tested receiving therapy consistent with the CGP results at each line of treatment. This suggests a role for CGP prior to more than one line of mCRC treatment.