Targeted cancer therapies can prolong the lives of men with metastatic castration resistant prostate cancer (mCRPC). However, these treatments also selectively favor the growth of tumor cells that harbor therapy resistance, and mCRPC is currently lethal. It has been challenging to study factors influencing how therapy resistance develops in this setting because few autopsy studies of have been performed in the settings of DNA-repair deficient mCRPC. Here, we assessed how resistance to targeted cancer therapies evolved in an autopsy cohort of 53 mCRPC tumors from six such men using deep whole genome and transcriptome analysis, validating our observations in an independent cohort of 135 mCRPC tumors. We identified intra-patient heterogeneity in clinically actionable DNA repair deficiencies and transcriptionally-defined tumor subtypes. Identical polygenic DNA repair resistance mutations were present in physically distinct tumors within the same individual, suggesting that these mutations pre-exist selection by later targeted therapy. Extra-chromosomal DNA (ecDNA) was present in more than half of mCRPC biopsies and frequently amplified the androgen receptor (AR) and enhancers of AR and MYC. Individual ecDNA amplicons included multiple driver genes on different chromosomes, and arose multiple times within distinct tumors in a single patient. The presence of ecDNA was significantly associated with whole genome doubling, chromothripsis, and with inactivating TP53 alterations. We conclude that ecDNA amplification is a major contributor to therapy resistance in mCRPC and that late-stage mCRPC develops intra-patient heterogeneity in response to targeted therapy.