Background: Men with intermediate-risk prostate cancer represent a clinically heterogeneous group with varying prognoses. High tumor copy number alteration as measured by percent genome aberration (PGA), intraductal carcinoma (IDC), and cribriform architecture (CA) are novel genomic and pathological indices that are associated with aggressive prostate cancer. Our primary endpoint was to test a combinatorial model integrating tumor genomics and pathology in predicting biochemical relapse in patients with intermediate-risk disease. Methods: IDC/CA, PGA, and clinical indices of T-category, PSA, and Gleason score (GS) were tested in a cohort of 531 men with NCCN-defined intermediate-risk prostate cancer, who were treated with radical prostatectomy (N = 173) or radiotherapy (N = 358). Pathological review was centrally performed by two expert pathologists. PGA was calculated using data from SNP array profiling (Affymetrix Oncoscan). Clinical end-points included biochemical relapse-free rate (bRFR), 18-month bRFR, and metastasis-free rate (mFR). Results: Biochemical relapse was independently associated with high PGA and presence of IDC/CA on univariable and multivariable analyses (HR high vs low PGA defined by median = 1.61 [95% CI = 1.04-2.49], Wald’s p = 0.033; HR IDC/CA present vs absent = 1.63 [1.04-2.54], p = 0.033). Early biochemical relapse and distant metastasis rates were higher in the patient subgroup of high PGA and IDC/CA present than in the low PGA and IDC/CA absent subgroup (HR 18-month bRFR = 2.55 [1.49-4.39], p < 0.001; mFR = 2.96 [0.83-10.63], p = 0.096), even for a sub-cohort with unfavorable clinical indices (PSA > 10 ng/ml, and T2b/c or GS 4+3). Inclusion of PGA to IDC/CA yielded the strongest model for predicting early biochemical relapse (AUC = 0.649 [0.476-0.776] for T-category, PSA, IDC/CA, with PGA vs 0.580 [0.456-0.675] without PGA). Conclusions: We developed a risk stratification model integrating novel pathological and genomic indices to identify patients with unfavorable intermediate-risk prostate cancer who are at risk of relapse. These patients may benefit from systemic intensification added to definitive local treatment.