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BackgroundEnzalutamide, as a second-generation endocrine therapy drug for prostate cancer (PCa), is prominent representative among the synthetic androgen receptor antagonists. Currently, there is lack of enzalutamide-induced signature (ENZ-sig) for predicting progression and relapse-free survival (RFS) in PCa.MethodsEnzalutamide-induced candidate markers were derived from single-cell RNA sequencing analysis integrating three enzalutamide-stimulated models (0-, 48-, and 168-h enzalutamide stimulation). ENZ-sig was constructed on the basis of candidate genes that were associated with RFS in The Cancer Genome Atlas leveraging least absolute shrinkage and selection operator method. The ENZ-sig was further validated in GSE70768, GSE94767, E-MTAB-6128, DFKZ, GSE21034, and GSE70769 datasets. Biological enrichment analysis was used to discover the underlying mechanism between high ENZ-sig and low ENZ-sig in single-cell RNA sequencing and bulk RNA sequencing.ResultsWe identified a heterogenous subgroup that induced by enzalutamide stimulation and found 53 enzalutamide-induced candidate markers that are related to trajectory progression and enzalutamide-stimulated. The candidate genes were further narrowed down into 10 genes that are related to RFS in PCa. A 10-gene prognostic model (ENZ-sig)—IFRD1, COL5A2, TUBA1A, CFAP69, TMEM388, ACPP, MANEA, FOSB, SH3BGRL, and ST7—was constructed for the prediction of RFS in PCa. The effective and robust predictability of ENZ-sig was verified in six independent datasets. Biological enrichment analysis revealed that differentially expressed genes in high ENZ-sig were more activated in cell cycle–related pathway. High–ENZ-sig patients were more sensitive to cell cycle–targeted drugs (MK-1775, AZD7762, and MK-8776) than low–ENZ-sig patients in PCa.ConclusionsOur results provided evidence and insight on the potential utility of ENZ-sig in PCa prognosis and combination therapy strategy of enzalutamide and cell cycle–targeted compounds in treating PCa.