This study investigates the divergent clonal evolution of castration-resistant neuroendocrine prostate cancer (CRPC-NE). By analyzing whole exome sequencing data from metastatic biopsies, the authors observed significant genomic overlap between CRPC-NE and castration-resistant adenocarcinoma (CRPC-Adeno). However, analysis of serial progression samples suggests that CRPC-NE may arise from a distinct clonal lineage within CRPC-Adeno, rather than from pre-existing neuroendocrine clones. Genome-wide DNA methylation analysis revealed marked epigenetic differences between CRPC-NE and CRPC-Adeno, with cases of CRPC-Adeno showing clinical features of AR-independence also classified as CRPC-NE. These findings support the emergence of an "AR-indifferent" cell state through divergent clonal evolution as a mechanism of treatment resistance in advanced prostate cancer. The study also developed a molecular classifier to improve the diagnosis and prediction of CRPC-NE, which demonstrated high precision and recall in identifying CRPC-NE in the discovery cohort.This study investigates the divergent clonal evolution of castration-resistant neuroendocrine prostate cancer (CRPC-NE). By analyzing whole exome sequencing data from metastatic biopsies, the authors observed significant genomic overlap between CRPC-NE and castration-resistant adenocarcinoma (CRPC-Adeno). However, analysis of serial progression samples suggests that CRPC-NE may arise from a distinct clonal lineage within CRPC-Adeno, rather than from pre-existing neuroendocrine clones. Genome-wide DNA methylation analysis revealed marked epigenetic differences between CRPC-NE and CRPC-Adeno, with cases of CRPC-Adeno showing clinical features of AR-independence also classified as CRPC-NE. These findings support the emergence of an "AR-indifferent" cell state through divergent clonal evolution as a mechanism of treatment resistance in advanced prostate cancer. The study also developed a molecular classifier to improve the diagnosis and prediction of CRPC-NE, which demonstrated high precision and recall in identifying CRPC-NE in the discovery cohort.