Abstract Purpose: The genomic underpinning of clinical phenotypes and outcomes in metastatic castration-sensitive prostate cancer is unclear. Experimental Design: In patients with metastatic castration-sensitive prostate cancer at a tertiary referral center, clinical-grade targeted tumor sequencing was performed to quantify tumor DNA copy number alterations and alterations in predefined oncogenic signaling pathways. Disease volume was classified as high volume (≥4 bone metastases or visceral metastases) versus low volume. Results: Among 424 patients (88% white), 213 (50%) had high-volume disease and 211 (50%) had low-volume disease, 275 (65%) had de novo metastatic disease, and 149 (35%) had metastatic recurrence of nonmetastatic disease. Rates of castration resistance [adjusted hazard ratio, 1.84; 95% confidence interval (CI), 1.40–2.41] and death (adjusted hazard ratio, 3.71; 95% CI, 2.28–6.02) were higher in high-volume disease. Tumors from high-volume disease had more copy number alterations. The NOTCH, cell cycle, and epigenetic modifier pathways were the highest-ranking pathways enriched in high-volume disease. De novo metastatic disease differed from metastatic recurrences in the prevalence of CDK12 alterations but had similar prognosis. Rates of castration resistance differed 1.5-fold to 5-fold according to alterations in AR, SPOP (inverse), and TP53, and the cell cycle, WNT (inverse), and MYC pathways, adjusting for disease volume and other genomic pathways. Overall survival rates differed 2-fold to 4-fold according to AR, SPOP (inverse), WNT (inverse), and cell-cycle alterations. PI3K pathway alterations were not associated with prognosis once adjusted for other factors. Conclusions: This study identified genomic features associated with prognosis in metastatic castration-sensitive disease that may aid in molecular classification and treatment selection.