11-Ketotestosterone and time to castration resistance in patients with recurrent non-metastatic prostate cancer receiving androgen deprivation therapy.

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209 Background: The contribution of 11-oxygenated androgens to disease progression in men receiving androgen deprivation therapy (ADT) for recurrent non-metastatic prostate cancer (PCa) remains unresolved. We hypothesized that evaluating circulating levels of 11-oxygenated androgens, such as the potent androgen receptor (AR) agonist 11-ketotestosterone (11KT), could serve as a potential predictor for the onset of castration resistance (CRPC). Methods: The multi-institutional prospective PROCURE cohort involves 2,026 patients who underwent radical prostatectomy for localized PCa. In this cohort, a subset of 145 patients who received ADT therapy for recurrent disease and had available plasma samples post-surgery were included in this study. The effect of therapy on steroid levels was assessed in paired samples obtained before and after the initiation of ADT (n=50), and samples from patients under combined ADT with AR pathway inhibitors, enzalutamide (n=10) and abiraterone (n =15). 11-oxygenated androgens (n=7) and canonical steroids, such as testosterone (T) and dihydrotestosterone (DHT), were quantified by mass spectrometry. Kaplan-Meier survival analyses were used to investigate relationships of androgen levels with the occurrence of CRPC. Results: 11-oxygenated androgens remained unaffected by ADT, which stands in contrast to the observed changes in T, DHT and other steroids. In men with castrated T levels, 11KT was the most abundant androgen. Elevated 11KT was associated with a sooner time to CRPC ( P=0.023). The 10-year CRPC event-free rate was 63% vs. 84% for 11KT levels above and below the median, respectively. The initiation of enzalutamide had no impact on 11-oxygenated androgen levels, whereas abiraterone significantly reduced 11KT levels owing to the adrenal origin of its precursor. Conclusions: Our findings indicate that 11KT is a significant component of the hormonal profile predictive of an earlier onset of CRPC and inhibition of its production by the CYP17A1 inhibitor abiraterone.

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