SAT-LB002 Steroid Metabolome Analysis Reveals 11-Ketotestosterone as the Most Abundant Androgen in Castration-Resistant Prostate Cancer Patients on Second-Line Therapies

Introduction Metastatic castration-resistant prostate cancer (CRPC) remains a clinical challenge despite antitumoral therapies such as taxane chemotherapeutics, enzalutamide, and abiraterone acetate. Clinical studies have highlighted the benefits of these therapies on overall and progression-free survival, but the changes these treatments impose on the steroid metabolome have not yet been fully mapped. In this study, we investigated the steroid metabolomes of CRPC patients on second-line therapies before and during treatment and after clinical progression was observed. Method Plasma samples from 30 patients from the ongoing CIRCUS trial were selected. Patients were included if progression on androgen-deprivation therapy was confirmed and patients were scheduled to receive additional secondary treatment with antiandrogens (enzalutamide (n=10) or apalutamide (n=1)), abiraterone + prednisone (n=2), docetaxel + prednisone (DP, n=10) or cabazitaxel + prednisone (CP, n=14). Seven patients completed two treatments during their enrollment in CIRCUS. Following liquid-liquid extraction of steroids from plasma, multi-steroid profiling by liquid chromatography-tandem mass spectrometry was carried out targeting 16 steroid hormones from classic and 11-oxygenated androgen pathways as well as mineralocorticoid and glucocorticoid biosynthetic pathways. Results Accurate quantification was achieved for all targeted steroids with the exception of dihydrotestosterone and androstenedione. The most abundant active androgen in CRPC patients was 11-ketotestosterone (11KT) with a median concentration of 0.46 nM (range 0.03 - 2.39 nM), whereas the median testosterone concentration was 0.14 nM (range 0.03 - 0.76 nM). 11KT and its precursors were suppressed by CP treatment. Analysis of all patients who started treatment with glucocorticoids revealed a potent suppression of 11KT by 88.5% (range 17.9 - 97.5%) and testosterone by 70.1% (range 24.1 - 95%), as well as suppression of 11-oxygenated androgen precursor steroids. Increased 11KT levels were observed in the DP-treated patients at the time of progressive disease. Discussion In this study, we present in-depth characterization of the previously unexplored steroid metabolomes in CRPC patients revealing 11KT as the most abundant androgen. 11KT has been shown to bind and activate the AR with similar potency to testosterone and our findings suggest that the 11-oxygenated androgens may be the dominant AR agonists in the CRPC setting. Routine quantification of testosterone alone may therefore underestimate the androgenic potential in CRPC patients. Suppression of adrenal androgens, including 11KT, was achieved by glucocorticoid treatment, which may explain the beneficial effects of glucocorticoids in CRPC patients. Funding This project was funded by the Daniel den Hoed foundation. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.