Background: mCRPC is enriched for genomic aberrations in TP53, RB1, AR, PTEN and DNA damage repair (DDR) compared to localized prostate cancer. Here we pursued NGS of 470 primary prostate tumors from patients who all later developed mCRPC to evaluate this enrichment in this poor prognosis population. We also compared 49 pairs of same patient primary tumor and mCRPC biopsies. Methods: Libraries for targeted DNA NGS were built using a customized amplicon-based panel (Generead v2 DNAseq, Qiagen) and read in a MiSeq (Illumina). Copy number aberrations (CNA) were assessed using a previously described bioinformatics pipeline (Seed, CCR 2017) for 98 genes. We compared gene aberration frequencies with previously reported cohorts. Results: A total of 470 treatment naïve primary prostate biopsies were sequenced and passed QC filters for mutation and CNA calling. Frequencies for TP53 (27%) and RB1 (5%) aberrations were higher than previously reported for localized prostate cancer (TCGA, p<0.01 each) but lower than for mCRPC (SU2C/PCF, TP53 p = 0.001, RB1 p = 0.07). Conversely DDR gene defects were more common: BRCA2 5% (p = 0.004); CDK12 5% (including 7 cases with two mutations; p = 0.06); ATM 4% (p = 0.2), and PALB2, BRCA1, RAD50, FANCA 1% each. Overall, 2% of primary tumors had detectable mutations in MMR genes. PTEN genomic loss was detected in 12% of primary tumors; 5% had activating mutations of PIK3CA or AKT. Other genes recurrently mutated were SPOP (7%) and CTNNB1 (3%). Surprisingly, in 5 cases (1%) AR mutations at low allele frequencies were detectable prior to ADT. Among the 49 patient matched sample pairs, mutations detectable only in mCRPC were identified in AR (n = 4), TP53 (4), RB1 (3) and CTNNB1 (1). All 9 truncating mutations in BRCA2, ATM, CDK12, PALB2 were shared between treatment naïve and mCRPC samples. Conclusions:TP53 and RB1 aberrations are more common in poor prognosis primary prostate cancer than in localized, more curable, disease (TCGA) but lower than in mCRPC (SU2C/PCF). Aberrations detected only at mCRPC in patient-matched samples support the evolution of these mutations under treatment selection pressures. Poorer prognosis prostate cancers are enriched for BRCA2 aberrations.