BackgroundKMT2 (lysine methyltransferase) family enzymes are epigenetic regulators that activate gene transcription.KMT2Cis mainly involved in enhancer-associated H3K4me1, and is also one of the top mutated genes in cancer (6.6% in pan-cancer). Currently, the clinical significance ofKMT2Cmutations in prostate cancer is understudied.MethodsWe included 221 prostate cancer patients diagnosed between 2014 and 2021 in West China Hospital of Sichuan University with cell-free DNA-based liquid biopsy test results in this study. We investigated the association betweenKMT2Cmutations, other mutations, and pathways. Furthermore, we evaluated the prognostic value ofKMT2Cmutations, measured by overall survival (OS) and castration resistance-free survival (CRFS). Also, we explored the prognostic value ofKMT2Cmutations in different patient subgroups. Lastly, we investigated the predictive value ofKMT2Cmutations in individuals receiving conventional combined anti-androgen blockade (CAB) and abiraterone (ABI) as measured by PSA progression-free survival (PSA-PFS).ResultsTheKMT2Cmutation rate in this cohort is 7.24% (16/221).KMT2C-mutated patients showed worse survival thanKMT2C-wild type (WT) patients regarding both CRFS and OS (CRFS: mutated: 9.9vs. WT: 22.0 months,p= 0.015; OS: mutated: 71.9vs. WT 137.4 months,p= 0.012).KMT2Cmutations were also an independent risk factor in OS [hazard ratio: 3.815 (1.461, 9.96),p= 0.006] in multivariate analyses. Additionally, we explored the association ofKMT2Cmutations with other genes. This showed thatKMT2Cmutations were associated with Serine/Threonine-Protein Kinase 11 (STK11,p= 0.004) and Catenin Beta 1 (CTNNB1,p= 0.008) mutations. In the CAB treatment,KMT2C-mutated patients had a significantly shorter PSA-PFS compared toKMT2C-WT patients. (PSA-PFS: mutated: 9.9vs. WT: 17.6 months,p= 0.014). Moreover,KMT2Cmutations could effectively predict shorter PSA-PFS in 10 out of 23 subgroups and exhibited a strong trend in the remaining subgroups.ConclusionsKMT2C-mutated patients showed worse survival compared toKMT2C-WT patients in terms of both CRFS and OS, andKMT2Cmutations were associated withSTK11andCTNNB1mutations. Furthermore,KMT2Cmutations indicated rapid progression during CAB therapy and could serve as a potential biomarker to predict therapeutic response in prostate cancer.