To obtain mechanistic insights about the treatment failures for metastatic castration-resistant prostate cancer (mCRPC), plasma cell-free DNA (cfDNA) was harvested from patients at baseline, after two months of treatment, and upon disease progression. Whole-genome sequencing identified oncogenic mutations capable of predicting therapy response or failures. To infer epigenetic regulation from cfDNA, researchers used duet evoC to gain insights from the 6-base genome (A, C, G, T, 5mC and 5hmC). Global loss of DNA methylation, which was often prominent in cancers, was observed in cfDNA. More importantly, AR signaling genes, which mark the presence of prostate cancer, were enriched for 5hmCs. Similarly, AR-associated transcription factor binding sites were enriched for 5hmCs and depleted for 5mCs. Notably, genes regulating immune activities and cell adhesion were progressively decorated with 5hmCs from a patient with CDK12 deficiency after treatment. Genetic activities suggestive of distinct tumour phenotypes and treatment failures were also discovered and will be discussed during the presentation.