Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor (<i>AR</i>) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only <i>RB1</i> alteration was significantly associated with poor survival, whereas alterations in <i>RB1</i>, <i>AR</i>, and <i>TP53</i> were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies <i>RB1</i> genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.