Immunometabolic effects of oral testosterone for castration-resistant prostate cancer in the ACROBAT trial.

High-dose testosterone is an emerging treatment option for selected patients with castration-resistant prostate cancer (CRPC), but its efficacy is limited by frequent primary and acquired resistance. Preclinical studies suggest that high-dose testosterone induces tumor metabolic reprogramming that promotes resistance, however clinical validation is lacking. In the prospective ACROBAT trial, we performed longitudinal plasma metabolomic profiling and high-dimensional immune cell phenotyping of 10 patients with CRPC treated with high-dose oral testosterone undecanoate. Testosterone exposure increased circulating metabolites within the arginine-ornithine-polyamine axis, including guanidoacetic acid, creatine, homoarginine, and N1-acetylspermidine. Notably, non-responders exhibited elevated levels of circulating polyamines, including putrescine. Although we observed no significant changes in circulating immune cell subset frequencies, integrative analyses revealed positive associations between polyamine-related metabolites and immunosuppressive myeloid populations, including monocytic myeloid-derived suppressor cells. Collectively, these data provide clinical evidence that high-dose testosterone therapy increases polyamine synthesis from arginine, which is associated with therapy resistance and abundance of immunosuppressive myeloid cells. Implications: High-dose testosterone treatment of patients with castration-resistant prostate cancer enrolled on the ACROBAT trial increased circulating polyamines, which were associated with non-response to treatment and greater abundance of circulating immunosuppressive myeloid cells.