Metastatic castration-resistant prostate cancer (mCRPC) is the lethal form of the disease. Several recent studies have identified genomic alterations in mCRPC, but the clinical implications of these genomic alterations have not been fully elucidated. To use whole-genome sequencing (WGS) to assess the association between key driver gene alterations and overall survival (OS), and to use whole-transcriptome RNA sequencing to identify genomic drivers of enzalutamide resistance. We performed survival analyses and gene set enrichment analysis (GSEA) on WGS and RNA sequencing results for a cohort of 101 mCRPC patients. OS was the clinical endpoint for all univariate and multivariable survival analyses. Candidate drivers of enzalutamide resistance were identified in an unbiased manner, and mutations of the top candidate were further assessed for enrichment among enzalutamide-resistant patients using Fisher's exact test. Harboring two DNA alterations in RB1 was independently predictive of poor OS (median 14.1 vs 42.0mo; p=0.007) for men with mCRPC. GSEA identified the Wnt/β-catenin pathway as the top differentially modulated pathway among enzalutamide-resistant patients. Furthermore, β-catenin mutations were exclusive to enzalutamide-resistant patients (p=0.01) and independently predictive of poor OS (median 13.6 vs 41.7mo; p=0.025). The presence of two RB1 DNA alterations identified in our WGS analysis was independently associated with poor OS among men with mCRPC. The Wnt/β-catenin pathway plays an important role in enzalutamide resistance, with differential pathway expression and enrichment of β-catenin mutations in enzalutamide-resistant patients. Moreover, β-catenin mutations were predictive of poor OS in our cohort. We observed a correlation between genomic findings for biopsy samples from metastases from men with metastatic castration-resistant prostate cancer (mCRPC) and clinical outcomes. This work sheds new light on clinically relevant genomic alterations in mCRPC and provides a roadmap for the development of new personalized treatment regimens in mCRPC. The presence of two DNA alterations in RB1 is associated with poor overall survival independently of other clinicopathologic factors in metastatic castration-resistant prostate cancer. In addition, Wnt/β-catenin pathway activation and β-catenin mutations are associated with enzalutamide resistance and poor overall survival.