Darolutamide does not interfere with OATP-mediated uptake of docetaxel

SAJ Buck*, Z Talebi, T Drabison, Y Jin, AA Gibson, P Hu, P de Bruijn, CMA de Ridder, D Stuurman, SY Hu, WM van Weerden, SLW Koolen, R de Wit, A Sparreboom, RHJ Mathijssen, ED Eisenmann

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

The addition of darolutamide, an androgen receptor signalling inhibitor, to therapy with docetaxel has recently been approved as a strategy to treat metastatic prostate cancer. OATP1B3 is an SLC transporter that is highly expressed in prostate cancer and is responsible for the accumulation of substrates, including docetaxel, into tumours. Given that darolutamide inhibits OATP1B3 in vitro, we sought to characterise the impact of darolutamide on docetaxel pharmacokinetics. We investigated the influence of darolutamide on OATP1B3 transport using in vitro and in vivo models. We assessed the impact of darolutamide on the tumour accumulation of docetaxel in a patient-derived xenograft (PDX) model and on an OATP1B biomarker in patients. Darolutamide inhibited OATP1B3 in vitro at concentrations higher than the reported Cmax. Consistent with these findings, in vivo studies revealed that darolutamide does not influence the pharmacokinetics of Oatp1b substrates, including docetaxel. Docetaxel accumulation in PDX tumours was not decreased in the presence of darolutamide. Metastatic prostate cancer patients had similar levels of OATP1B biomarkers, regardless of treatment with darolutamide. Consistent with a low potential to inhibit OATP1B3-mediated transport in vitro, darolutamide does not significantly impede the transport of Oatp1b substrates in vivo or in patients. Our findings support combined treatment with docetaxel and darolutamide, as no OATP1B3 transporter based drug–drug interaction was identified.
Original languageEnglish
Pages (from-to)314-323
Number of pages10
JournalInternational Journal of Cancer
Volume155
Issue number2
Early online date16 Mar 2024
DOIs
Publication statusE-pub ahead of print - 16 Mar 2024

Bibliographical note

Publisher Copyright:
© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

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