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Cancer forms a local tumor that subsequently metastasizes to distant organs. In prostate cancer, the latter part of the trajectory is influenced by the inhibition of the androgen receptor (AR). The study of proteomic changes along disease progression may reveal insights into how prostate cancer evolves and open new therapeutic avenues. Here, we profile changes in protein abundance and post-translational modifications (PTMs) along the disease trajectory in patient-derived xenograft models. Our results suggest new therapeutic opportunities, such as USP1 inhibition and a key early involvement of the receptor tyrosine kinase (RTK)-RAS-mitogen-activated protein kinase (MAPK) pathway during disease progression. We highlight multiple alterations within the latter, including the tumor suppressors NF1 and ERF. Specific PTMs suggest changes in mitochondrial ATP synthesis, proteasomal activity, gene splicing, and transforming growth factor beta (TGF-β) signaling. Finally, we show how different transcription factors engage with disease progression. A web resource is provided, enabling the investigation of proteomic resources.