The supplementary information section provides detailed supplementary tables and figures to support the main findings of the study. The figures include: 1. **Figure S1**: Kaplan-Meier analysis showing time on treatment with first-line ARSI for SPOP wild-type and SPOP-mutated tumors. 2. **Figure S2**: Kaplan-Meier analysis showing overall survival and time on treatment with first-line ARSI for diploid and aneuploid tumors. 3. **Figure S3**: AR-V7 levels in relation to prior treatment exposure, showing higher expression in tumors exposed to both ARSI and taxane. 4. **Figure S4**: Unsupervised gene expression clustering analysis of the study cohort, identifying a cluster of tumors with high NEPC expression score. 5. **Figure S5**: Associations between histopathology, NEPC expression score, and TP53/RB1 genomic status, as well as enrichment of genomic alterations in histopathologic NE tumors versus non-NE tumors. 6. **Figure S6**: Association between NEPC score and time on treatment with a first-line ARSI for mCRPC. 7. **Figure S7**: Association of RB1 loss score and cell cycle progression (CCP) expression score with overall survival and time on treatment with first-line ARSI. 8. **Figure S8**: Correlation between expression scores derived from PolyA RNA sequencing libraries and capture libraries for AR output scores and NEPC scores. The tables include: 1. **Table S1**: Summary clinical characteristics for 429 patients with metastatic CRPC who underwent successful tumor profiling. 2. **Table S2**: Pathway classifications of genes altered in mCRPC, including gene names, pathways, and potentially biologically relevant alterations. 3. **Table S3**: Genes that underwent secondary manual copy number assessment, including amplification (AMP) and homozygous deletion (HOMDEL).The supplementary information section provides detailed supplementary tables and figures to support the main findings of the study. The figures include: 1. **Figure S1**: Kaplan-Meier analysis showing time on treatment with first-line ARSI for SPOP wild-type and SPOP-mutated tumors. 2. **Figure S2**: Kaplan-Meier analysis showing overall survival and time on treatment with first-line ARSI for diploid and aneuploid tumors. 3. **Figure S3**: AR-V7 levels in relation to prior treatment exposure, showing higher expression in tumors exposed to both ARSI and taxane. 4. **Figure S4**: Unsupervised gene expression clustering analysis of the study cohort, identifying a cluster of tumors with high NEPC expression score. 5. **Figure S5**: Associations between histopathology, NEPC expression score, and TP53/RB1 genomic status, as well as enrichment of genomic alterations in histopathologic NE tumors versus non-NE tumors. 6. **Figure S6**: Association between NEPC score and time on treatment with a first-line ARSI for mCRPC. 7. **Figure S7**: Association of RB1 loss score and cell cycle progression (CCP) expression score with overall survival and time on treatment with first-line ARSI. 8. **Figure S8**: Correlation between expression scores derived from PolyA RNA sequencing libraries and capture libraries for AR output scores and NEPC scores. The tables include: 1. **Table S1**: Summary clinical characteristics for 429 patients with metastatic CRPC who underwent successful tumor profiling. 2. **Table S2**: Pathway classifications of genes altered in mCRPC, including gene names, pathways, and potentially biologically relevant alterations. 3. **Table S3**: Genes that underwent secondary manual copy number assessment, including amplification (AMP) and homozygous deletion (HOMDEL).