Plasma extracellular vesicle proteomics nominates candidate biomarkers of 177Lu-PSMA-617 outcomes in metastatic prostate cancer patients.

177Lu-PSMA-617 represents a transformative treatment for metastatic castration-resistant prostate cancer (mCRPC), yet biomarkers of benefit beyond prostate-specific membrane antigen positron emission tomography (PSMA-PET) imaging remain lacking. Here, we present findings from a prospective study of 100 mCRPC patients receiving 177Lu-PSMA-617, using shotgun proteomics to profile plasma-derived extracellular vesicle (EV) proteins alongside PSMA-positive circulating tumor cell (CTC) enumeration. We identify 5,137 EV-derived proteins, including the cell-surface targets PSMA, B7-H3, Trop-2, and STEAP1, with high levels of these proteins associating with worse overall survival (OS). All four EV proteins positively correlate with molecular tumor volume on PSMA-PET imaging, serum PSA, and serum alkaline phosphatase. CTC subpopulations, including PSMA+/EpCAM+ and PSMA-/EpCAM+ cells, associate with worse progression-free survival (PFS) and OS. Pathway analysis reveals that p53 upregulation associates with poor PFS and OS, while an activated E2F pathway unexpectedly portends better PFS and OS. These findings support the integration of liquid biopsy proteomics into biomarker-driven mCRPC trials to improve patient stratification.