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Background: Intrinsic resistance to androgen receptor signalling inhibitors (ARSI) such as enzalutamide and abiraterone occurs in 20-30% of men with metastatic castration-resistant prostate cancer (mCRPC), and responders will eventually develop resistance. Epidemiological, lipidomic and molecular studies suggest a role of ceramide metabolism in ARSI resistance. Our study aims to investigate the association of the ceramide-S1P (ceramide-S1P) signalling axis with ARSI resistance in mCRPC. Method(s): Lipidomic analysis (>700 lipids) was performed on plasma samples collected from 132 men with mCRPC before starting enzalutamide or abiraterone. AR gene aberrations were identified by deep sequencing of circulating tumour DNA on a subset of the cohort (n=77). Associations between circulating lipids, AR aberrations, radiological progression-free survival (rPFS) and overall survival (OS) were examined. The effect of inhibiting ceramide-S1P signalling with sphingosine kinase (SPHK) inhibitors (PF-543 & ABC294640) on enzalutamide efficacy was investigated with in vitro assays, and transcriptomic and lipidomic analyses of prostate cancer (PC) cell lines (LNCaP, C42B, 22Rv1). Result(s): Men with a plasma lipidomic profile of elevated levels of ceramides had shorter rPFS (HR 2.3, 95% CI 1.5-3.6, P = 0.0004), shorter OS (HR 2.3, 95% CI 1.4-3.6, P = 0.0005) and a higher frequency of AR aberrations (58% vs 33%, P = 0.04) than those with the opposite profile. The presence of an AR aberration combined with a lipidomic profile of elevated ceramides was associated with a shorter rPFS and OS, than the presence of only one of these characteristics, or none (median rPFS time = 3.9 vs 8.3 vs 17.7 months; median OS time = 8.9 vs 19.8 vs 34.4 months). SPHK inhibitors decreased the IC50 of enzalutamide in PC cell lines by 1.8 to 15 fold (P<0.0008). Transcriptomic and lipidomic analyses indicated that enzalutamide combined with SPHK inhibition enhanced PC cell death by SREBP-induced lipotoxicity