Enzalutamide significantly improves overall survival (OS) of patients with metastatic hormone- sensitive prostate cancer (mHSPC). However, ∼10% of patients will die within 2 years. PCPro is a plasma lipid panel associated with decreased OS in metastatic castration-resistant prostate cancer. In this study, we assessed the association between PCPro and clinical outcomes in mHSPC by performing a post-hoc analysis of ENZAMET, the landmark phase 3 trial comparing enzalutamide to non-steroidal anti-androgen (NSAA). PCPro status was determined by liquid chromatography-mass spectrometry analysis of plasma samples from 866 participants (77% of ENZAMET trial cohort), before treatment (n=866) and at first progression (n=282). Outcomes examined were OS and clinical progression-free survival (clinPFS). Participants with a positive PCPro status at baseline (13.4%), had significantly shorter OS and clinPFS compared to those with a negative PCPro status (OS HR=1.81; clinPFS HR=1.65; p<0.0001). PCPro is an independent prognostic factor when modelled with key clinical prognostic factors (p<0.001). Enzalutamide (compared to NSAA) improved the OS of PCPro-negative participants (HR = 0.61, p<0.0001), but not the survival of PCPro-positive participants (HR=1.10, p=0.69; interaction p=0.024). Participants, who were PCPro-positive at progression, have shorter OS than those who were negative, irrespective of baseline status (median OS 24-28 months versus 42-45 months). PCPro status is a prognostic biomarker and predictive of the lack of OS benefit from enzalutamide compared to NSAA in mHSPC. These findings provide a rationale for testing therapeutic agents that can modify circulating lipid profiles in mHSPC.