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

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Abstract

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 (Cmin) of 10.2 ng/ml (range: 0.58 – 92.1). In the survival analyses, abiraterone Cmin ≥ 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.

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Data Availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Author notes

  1. M. A. C. Bruin, M. I. Mohmaed Ali, and M. van Nuland have contributed equally and thus share first authorship.

Authors and Affiliations

  1. Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Maaike A. C. Bruin, Ma Ida Mohmaed Ali, Merel van Nuland, Bart A. W. Jacobs, Luc Lucas, Hilde Rosing, Jos H. Beijnen & Alwin D. R. Huitema

  2. Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Maaike A. C. Bruin, Ma Ida Mohmaed Ali, Merel van Nuland, Bart A. W. Jacobs, Jos H. Beijnen & Alwin D. R. Huitema

  3. Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Vincent O. Dezentje, Jeantine M. de Feijter & Andries M. Bergman

  4. Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

    Jos H. Beijnen

  5. Department of Pharmacology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

    Alwin D. R. Huitema

  6. Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands

    Alwin D. R. Huitema

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  1. Maaike A. C. Bruin
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Contributions

M.A.C Bruin: conceptualization, investigation, formal analysis, writing: Review & Editing. M.I. Mohmaed Ali: investigation, formal analysis, writing: original draft. M. van Nuland: conceptualization, investigation, formal analysis, writing: Review & Editing. B.A.W. Jacobs: writing: Review & Editing. L. Lucas: writing: Review & Editing. V.O. Dezentje: writing: Review & Editing. J.M. de Feijter: writing: Review & Editing. H. Rosing: writing: Review & Editing. A.M. Bergman: writing: Review & Editing. J.H. Beijnen: writing: Review & Editing. A.D.R. Huitema: conceptualization, writing: Review & Editing, supervision.

Corresponding author

Correspondence to Ma Ida Mohmaed Ali.

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Conflict of Interest

M.A.C. Bruin, M.I. Mohmaed Ali, M. van Nuland, B.A.W. Jacobs, L. Lucas, H. Rosing and A.D.R. Huitema: declare they have no conflict of interest to report.

V.O. Dezentje attended advisory boards for Novartis, Astra Zeneca / Daiichy Sankyo. This all is not related to the submitted manuscript.

J.M. de Feijter attended advisory boards for Janssen and Bayer. Received reimbursement of travel expenses from Merkc / Pzizer. This all is not related to the submitted manuscript.

A.M. Bergman received grants, contracts, or consulting fees from Bayer, Sanofi, Astellas. This all is not related to the submitted manuscript.

J.H. Beijnen is a part-time employee and (indirect) stock holder of Modra Pharmaceuticals BV (Amsterdam), a small spin out company of the Netherlands Cancer Institute developing oral taxane treatments. He is also a co-inventor on a patent of oral taxane formulations. This all is not related to the submitted manuscript.

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Bruin, M.A.C., Mohmaed Ali, M.I., van Nuland, M. et al. Cortisol as Biomarker for CYP17-Inhibition is Associated with Therapy Outcome of Abiraterone Acetate. Pharm Res 40, 3001–3010 (2023). https://doi.org/10.1007/s11095-023-03615-9

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