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 CRPC patients to drive AR activation. The goal of this study was to investigate the circulating steroid metabolome including all active androgens in CRPC patients.
Metastatic CRPC patients (n=29) starting a new line of systemic therapy were included. Sequential plasma samples were obtained for measurement of circulating steroid concentrations by multi-steroid profiling employing liquid chromatography-tandem mass spectrometry. Metastatic tumor biopsy samples were obtained at baseline and subjected to RNA sequencing.
11KT was the most abundant circulating active androgen in 97% of CRPC patients (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 (T) by 68% (38-79%). Circulating TA concentrations at baseline were associated with a distinct intratumoral gene expression signature comprising AR-regulated genes.
The potent AR agonist 11KT is the predominant circulating active androgen in CRPC patients 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 CRPC patients. Trial registrationNetherlandsTRIAL REGISTRATION. NL5625(NTR5732)FUNDING. Daniel den Hoed foundation (Hofland) and Wellcome Trust (Investigator Award WT209492/Z/17/Z, Arlt).
JCI insight. 2021 May 11 [Epub ahead of print]
Gido Snaterse, Lisanne F van Dessel, Job van Riet, Angela E Taylor, Michelle van der Vlugt-Daane, Paul Hamberg, Ronald de Wit, Jenny A Visser, Wiebke Arlt, Martijn P Lolkema, Johannes Hofland
Department of Internal Medicine, Erasmus MC, Rotterdam, Netherlands., Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands., Centre for Diabetes, Endocrinology, and Metabolism, University of Birmingham, Birmingham, United Kingdom., Department of Internal Medicine, Franciscus Gasthuis & Vlietland Hospital Rotterdam, Rotterdam, Netherlands.