Background: Despite the use of clinical prognostic factors, 20 to 40% of patients with intermediate-risk prostate cancer (IR-PCa) fail local treatment for unexplained reasons. Given that an accurate DNA damage response (DDR) may be associated with genetic instability and radioresponse, we investigated whether copy number alterations (CNAs) in DDR genes are predictive or prognostic following local treatment. Methods: Using array comparative genomic hybridization (aCGH), we characterized CNAs in biopsies derived from 126 IR-PCa pts. who underwent image-guided radiotherapy (IGRT). We studied the DDR-sensing genes: MRE11A, RAD50, NBN, ATM, and ATR. The IGRT cohort (median dose: 76.4Gy; median follow-up: 7.8yrs) was compared to a radical prostatectomy (RP) cohort (154 pts. from Memorial Sloan-Kettering Cancer Center database; median follow-up: 4.8yrs). CNAs were then tested for their independent prognostic capability using Kaplan-Meir method and Cox proportional hazard models. Results: In our IGRT cohort, m,ost frequent DDR gene CNAs were: NBN 20 of 126 (15.9%), ATR 11of 126 (8.7%), and ATM 7 of 126 (5.5%). NBN CNAs were mainly gains (19/20) and strongly correlated with increased NBN-mRNA abundance compared to NBN-neutral cases (p=0.016). CNAs in DDR genes were not associated with GS, prostate-specific antigen, or T-stage. Importantly, NBN gain ranked among the top 3.3% of all genes in terms of its strength of association with the percent of the genome altered (PGA). After adjusting for clinical factors in a multivariate model, NBN gain was a significant independent predictor of 5 years-biochemical relapse-free rate (bRFR) following IGRT (48.6% versus 78.8%; HR = 3.14, 95% CI: 1.42-6.94, p=0.004). No DDR CNA was prognostic in the RP cohort. Increased NBN mRNA expression correlated to radioresistance in vitro (i.e. clonogenic surviving fraction after 3Gy) in five prostate cancer cell lines (R²= 0.665). This relationship was not observed for any of the other DDR genes. Conclusions: NBN copy number gain or increased expression correlates with tumor genomic instability, decreased bRFR (IGRT- but not surgery-treated pts.) and intrinsic prostate cancer cell radioresistance. If validated in independent IGRT cohorts, NBN gain could be the first PCa predictive biomarker to facilitate local treatment decisions using precision medicine approaches.