The molecular determinants of the heterogenic course of prostate cancer (PC) remain elusive. We aimed to determine the drivers predisposing to unfavorable PC outcomes anticipated by BCR events among patients of similar preoperative characteristics. The TCGA transcriptomic and clinical data of 497 PC individuals were used, stratified according to the risk of BCR by EAU-EANM-ESTRO-ESUR-SIOG. The relevance of the functional markers regarding BCR-free survival was examined by the cutp algorithm. Through UpSetR, subgroups of PC patients bearing an unfavorable signature were identified, followed by the hierarchical clustering of the major markers of the epithelial-to-mesenchymal transition (EMT). BCR-free survival was estimated with the Cox proportional hazards regression model.ESR1significantly differentiated BCR-free survival, whereasARdid not. An elevation inKLK3correlated with better prognosis, althoughPGR,KLK3,CDH1, andMMP3predicted BCR better than the preoperative PSA level. Patients sharing an unfavorable profile ofESR1andMMP3together with lymph node status, Gleason score, T, and EAU risk groups were at a higher risk of BCR originating from mesenchymal features of PC cells. To conclude, we revealed anESR1-driven unfavorable profile of EMT underpinning a worse PC trajectory.ESR1may have a major role in PC progression; therefore, it could become a major focus for further investigations.