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.
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.
- Metabolite and immune cell abundance analysis: Code.R
Zipkowitz S, Redinger K, Jonnatan S, Vakkala V, Lu J, Schultz K, Rifkind I, Michalik A, King S, McIntyre K, Sinibaldi V, Markowski MC, Marshall CH, Paller CJ, Wang H, Mao SS, Denmeade SR, Sanin DE, Thompson EA, Sena LA. Immunometabolic effects of oral testosterone for castration-resistant prostate cancer in the ACROBAT trial. Molecular Cancer Research, In press (2026)
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