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BACKGROUNDContinued androgen receptor (AR) signaling constitutes a key target for treatment in metastatic castration-resistant prostate cancer (CRPC). Studies have identified 11-ketotestosterone (11KT) as a potent AR agonist, but it is unknown if 11KT is present at physiologically relevant concentrations in patients with CRPC to drive AR activation. The goal of this study was to investigate the circulating steroid metabolome including all active androgens in patients with CRPC.METHODSPatients with metastatic CRPC (n = 29) starting a new line of systemic therapy were included. Sequential plasma samples were obtained for measurement of circulating steroid concentrations by multisteroid profiling employing liquid chromatography-tandem mass spectrometry. Metastatic tumor biopsy samples were obtained at baseline and subjected to RNA sequencing.RESULTS11KT was the most abundant circulating active androgen in 97% of patients with CRPC (median 0.39 nmol/L, range: 0.03-2.39 nmol/L), constituting 60% (IQR 43%-79%) of the total active androgen (TA) pool. Treatment with glucocorticoids reduced 11KT by 84% (49%-89%) and testosterone by 68% (38%-79%). Circulating TA concentrations at baseline were associated with a distinct intratumor gene expression signature comprising AR-regulated genes.CONCLUSIONThe potent AR agonist 11KT is the predominant circulating active androgen in patients with CRPC and, therefore, one of the potential drivers of AR activation in CRPC. Assessment of androgen status should be extended to include 11KT, as current clinical approaches likely underestimate androgen abundance in patients with CRPC.TRIAL REGISTRATIONNetherlands Trial Register: NL5625 (NTR5732).FUNDINGDaniel den Hoed Foundation and Wellcome Trust (Investigator Award WT209492/Z/17/Z).

11-Ketotestosterone: the resilience of a potent androgen in prostate cancer patients after castration