Cortisol as Biomarker for CYP17-Inhibition is Associated with Therapy Outcome of Abiraterone Acetate

• Published in: Pharmaceutical research Vol. 40; no. 12; pp. 3001 - 3010
• Main Authors: Bruin, Maaike A. C., Mohmaed Ali, Ma Ida, van Nuland, Merel, Jacobs, Bart A. W., Lucas, Luc, Dezentje, Vincent O., de Feijter, Jeantine M., Rosing, Hilde, Bergman, Andries M., Beijnen, Jos H., Huitema, Alwin D. R.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-12-2023; Springer; Springer Nature B.V
• Subjects: Acetates; Acetic acid; Analysis; Biochemistry; Biomarkers; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Blood levels; Cancer patients; Care and treatment; Castration; Corticosteroids; Cortisol; Enzymes; Hormones; Liquid chromatography; Mass spectrometry; Mass spectroscopy; Medical Law; Metastases; Metastasis; Original Research Article; Patients; Pharmacology/Toxicology; Pharmacy; Prostate cancer; Prostate-specific antigen; Survival; Testosterone; pharmacokinetics; cortisol; prostate cancer; abiraterone acetate; therapeutic drug monitoring
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-023-03615-9

Background
Abiraterone acetate is an irreversible 17α-hydroxylase/C17, 20-lyase (CYP17) inhibitor approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients. Inhibition of this enzyme leads to low testosterone and cortisol levels in blood. There is growing evidence that clinical efficacy of abiraterone is related to the rate of suppression of serum testosterone. However, quantification of very low levels of circulating testosterone is challenging. We therefore aimed to investigate whether circulating cortisol levels could be used as a surrogate biomarker for CYP17 inhibition in patients with mCRPC treated with abiraterone acetate.
Patients and methods
mCRPC patients treated with abiraterone acetate were included. Abiraterone and cortisol levels were measured with a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). On treatment cortisol and abiraterone concentrations were related to treatment response and progression free survival.
Results
In total 117 patients were included with a median cortisol concentration of 1.13 ng/ml (range: 0.03 – 82.2) and median abiraterone trough concentration (C
min
) of 10.2 ng/ml (range: 0.58 – 92.1). In the survival analyses, abiraterone C
min
 ≥ 8.4 ng/mL and cortisol  < 2.24 ng/mL were associated with a longer prostate-specific antigen (PSA) independent progression-free survival than patients with an abiraterone concentration  ≥ 8.4 ng/mL and a cortisol concentration ≥ 2.24 ng/mL (13.8 months
vs
. 3.7 months).
Conclusion
Our study shows that cortisol is not an independent predictor of abiraterone response in patients with mCRPC, but it is of added value in combination with abiraterone levels, to predict a response on abiraterone.