Metastatic castration-resistant prostate cancer (CRPC) remains a major clinical challenge despite the recent introduction of novel therapies such as taxane chemotherapeutics, enzalutamide, and abiraterone. Clinical studies have highlighted the efficacy of these therapies, but the changes these treatments impose on the steroid metabolome have not yet been fully mapped. In this study, we investigated the steroid hormone metabolomes of CRPC patients on second-line therapies before and during treatment and after clinical progression.

Plasma samples from 37 patients  were included if progression on androgen-deprivation therapy was confirmed and patients were scheduled for additional secondary treatment with antiandrogens (AA), abiraterone + prednisone (ABIP), docetaxel + prednisone (DP) or cabazitaxel + prednisone (CP). Steroids were extracted from plasma by liquid-liquid extraction method, followed by multi-steroid profiling liquid chromatography-tandem mass spectrometry targeting 16 steroids from various steroidogenic pathways.

AA treatment increased the levels of 11-deoxycortisol, the active 11-oxygenated androgen 11-ketotestosterone (11KT) and its precursor 11-hydroxyandrostenedione (11OHA4). In contrast, 11KT and 11OHA4 levels were suppressed by CP treatment. Increased 11KT levels were observed in the DP-treated patients at the time of progressive disease. Several other steroid hormones including testosterone, corticosterone, cortisone and cortisol were suppressed by CP treatment. Sample size was too small to perform statistical analysis in the ABIP group. Prednisone administration and withdrawal confounded the steroid metabolomes of patients.

In this study, we present an in-depth characterization of previously unexplored steroid hormone metabolomes in CRPC patients. The second-line treatments imposed various changes on the steroid hormone levels in CRPC patients, including stimulation of adrenal-derived steroids by antiandrogens, suppression of adrenal steroids by DP and CP and increased levels of 11KT at the time of progression in DP-treated patients.