Metastatic castration-resistant prostate cancer (CRPC) remains a clinical challenge despite antitumoral therapies such as taxane chemotherapeutics, enzalutamide, and abiraterone acetate. Recent studies have identified 11-ketotestosterone (11KT) as a potent androgen receptor (AR) agonist present in humans. AR signaling continues to play an important role after castration resistance. However, it is unknown if 11KT 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 was observed.

Plasma samples of 30 CRPC patients starting treatment with antiandrogens (n=11), abiraterone with prednisone (n=2), docetaxel + prednisone (n=10) or cabazitaxel + prednisone (n=14) were selected. Seven 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.

11KT was the most abundant androgen in CRPC patients at baseline, with a median concentration of 0.39 nM (0.03 – 2.39 nM) which constituted 68% (IQR: 53.5 – 79.8%) of the total circulating androgen pool. Testosterone (0.14 nM; 0.03 – 0.64 nM) constituted 23.8% (IQR: 16.8 – 33.9%) of the total androgen pool. Treatment with glucocorticoids reduced circulating 11KT by 83.6% (IQR: 38.6 – 89.3%) and testosterone by 70.1% (IQR: 38.3 – 79.3%), as well 11-oxygenated androgen precursors steroids by >80%.

This study has identified 11-ketotestosterone, a potent AR agonist, as the major circulating androgen in CRPC patients. The androgen abundance in CRPC may have been underestimated and routine quantification of testosterone alone may not accurately reflect the total androgen pool. Suppression of 11KT and testosterone was achieved by glucocorticoid treatment, which may explain the beneficial effects of glucocorticoids in CRPC patients.