BACKGROUND. Continued 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. METHODS. Patients 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. RESULTS. 11KT 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. CONCLUSION. The 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.
Bibliographical noteFunding Information:
being on an advisory board of Astellas. RDW reported receiving speaker fees from Merck and Sanofi; advisory fees from Sanofi, Merck, Janssen, Astellas, Roche, and Bayer; and institutional research grants from Sanofi and Bayer. MPL reported receiving institutional research grants from Dutch Cancer Society, during the conduct of the study; institutional research grants and personal fees from Sanofi; institutional research grants and personal fees from Johnson & Johnson; institutional research grants from Merck; institutional research grants and personal fees from Astellas; and personal fees from Incyte, Amgen, Janssen Cilag, Bayer, Servier, and Pfizer.
FUNDING. Daniel den Hoed Foundation and Wellcome Trust (Investigator Award WT209492/ Z/17/Z).
This study was funded by the Daniel den Hoed Foundation (to JH) and the Wellcome Trust (Investigator Award WT209492/Z/17/Z, to WA). The sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of data; or in the preparation, review, or approval of the manuscript.
© 2021, Snaterse et al.
- Prostate cancer
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