Background: Androgen deprivation therapy (ADT) is one of the main treatment options for locally advanced, recurrent and metastatic prostate cancer. Neuroendocrine prostate cancer (NEPC) is inherently less sensitive to ADT. NEPC can be observed de novo (e.g., small cell prostate cancer) but more commonly arises after exposure to ADT. In some patients, even short exposure to ADT may ‘unmask’ a NEPC phenotype. We hypothesized that a gene expression signature of NEPC when measured in primary tumor specimens (RP) may be useful for predicting patients with innate resistance to ADT. Methods: Expression profiles of 786 PCa patients treated with RP were obtained from the Decipher GRID database. These were split into training (n=360) and validation (n=426) sets and stratified by the receipt of adjuvant ADT (n=222) or no adjuvant ADT (n=564). A literature review of ADT resistance and neuroendocrine genes identified 1,632 genes as candidates. This set was further filtered, using logistic regression and forward feature selection to select a genomic ADT resistance signature (ARS). ARS was trained using a generalized linear model with lasso regularization. Survival c-index, Kaplan Meier and Cox regression analysis was used to compare survival differences between treated and untreated patients with high and low ARS scores (defined by median split). Results: In validation cohorts, the ARS was predictive of metastasis in cohorts receiving adjuvant ADT (10-year metastasis free survival c-index of 0.64 (95% CI 0.55-0.71) as compared to 0.50 (95% CI 0.36-0.63) in patients not treated with ADT). Among ADT treated patients, those with low ARS scores had a 10 year MFS of 86%, versus 68% in those with high ARS scores (p=0.03). In multivariable analysis adjusting for confounding variableswith metastasis as an endpoint, ARS validated with a significant interaction with ADT treatment (p=0.02) which demonstrates ARS’s adjuvant ADT predictive capability. Conclusions: An ADT resistance signature validated as a predictive biomarker with a significant interaction term for predicting metastasis after hormonal treatment. ARS may allow for identification of patients that may be optimal candidates for trials of novel systemic agents