Endocrine Abstracts

Background: The treatment of metastatic castration-resistant prostate cancer (CRPC) remains dependent on Androgen Receptor (AR) mediated signalling, thus understanding all components involved in testosterone signalling in these men is of utmost importance. Recent studies have identified 11-ketotestosterone (11 KT) as a potent androgen receptor (AR) agonist present in humans. However, it is unknown if 11 KT is present at physiologically relevant concentrations in CRPC patients. In this study, we investigated the steroid hormone metabolomes of CRPC patients at baseline, during treatment with second-line therapies and after clinical progression.

Method: Plasma samples of 29 CRPC patients starting treatment with antiandrogens (n = 10) docetaxel + prednisone (n = 10) or cabazitaxel + prednisone (n = 14) were selected. Five patients completed two treatments. Steroids were extracted from plasma by liquid-liquid extraction method, followed by multi-steroid profiling liquid chromatography-tandem mass spectrometry (LC-MS/MS) targeting 16 steroid hormones as well as prednisone, prednisolone and dexamethasone. Next-generation sequencing and RNAseq were performed on the tumour biopsy samples of these patients obtained at baseline (n = 20).

Results: 11 KT was the most abundant androgen in CRPC patients at baseline, with a median concentration of 0.33 nM (0.03–2.39 nM) which constituted 65.5% (43–79.1%) of the total androgen (TA) pool. Testosterone (0.13 nM; 0.03–0.64 nM) constituted 23.8% (IQR 15.0–32.3%) of the TA pool. Treatment with glucocorticoids reduced circulating 11 KT by 83.6% (IQR: 38.6–89.3%) and testosterone by 67.9% (IQR: 38.3%–79.3%) as well as 11-oxygenated androgen precursor steroids by >80%. Differential gene expression was observed between tumour biopsy samples of patients with high (>median) versus low (<median) TA concentrations. High TA concentrations at baseline were associated with longer progression-free survival (P < 0.05).

Conclusions: This study has identified 11-ketotestosterone, a potent AR agonist, as the major circulating androgen in CRPC patients and its abundance correlates with gene expression in the tumour tissue. Thus androgen abundance in CRPC haspreviously been underestimated and routine quantification of testosterone alone may not accurately reflect the TA abundance in patients. Suppression of 11 KT and testosterone was achieved by glucocorticoid treatment, which may explain the beneficial effects of glucocorticoid treatment in CRPC patients.