Impact of Abiraterone Therapeutic Drug Monitoring on Cortisol as a Surrogate Biomarker of CYP17 Inhibition in Metastatic Prostate Cancer Treatment

BACKGROUND: Prostate cancer is driven by androgen receptor activation caused by (dihydro)testosterone. Abiraterone, which is used against metastatic castration-resistant prostate cancer (mCRPC), improves survival by irreversibly inhibiting CYP17 to reduce androgen and cortisol synthesis. As such, cortisol is a potential biomarker for androgen suppression. This study assessed the impact of pharmacokinetically (PK)-guided interventions after therapeutic drug monitoring (TDM) of abiraterone on cortisol plasma concentrations as a biomarker for CYP17 inhibition in patients with mCRPC.

METHODS: In this retrospective cohort study, patients with mCRPC receiving abiraterone with TDM based on abiraterone plasma concentrations were compared with a historical cohort receiving standard care. The primary end point was adequate CYP17 inhibition, defined as cortisol plasma concentration <6.18 nmol/L. Secondary end points included the time course of cortisol plasma concentrations and the impact of PK-guided interventions.

RESULTS: A total of 103 patients were included in the TDM population, and 99 were included in the historical cohort. Median cortisol plasma concentrations were lower in the TDM population [1.9 (95% confidence interval 1.1-5.8) versus 3.9 (95% confidence interval 1.4-12.4] nmol/L, P = 0.01), with more patients achieving adequate CYP17 inhibition (75.7% versus 62.6%, P = 0.06). Of the 32 patients with evaluable data before and after PK-guided intervention, 96.9% reached adequate abiraterone concentrations; however, no significant improvement in adequate CYP17 inhibition was observed when comparing cortisol before and after PK-guided intervention (81.3% versus 71.9%, P = 0.45).

CONCLUSIONS: In the TDM population, lower cortisol plasma concentrations were observed. However, it is unclear whether increasing abiraterone exposure through PK-guided interventions decreased cortisol plasma concentrations.