4 148
Platinum Priority
–
Brief Correspondence
Editorial by Zoran Culig on pp. 9
–
10 of this issue
Moving Towards Precision Urologic Oncology: Targeting
Enzalutamide-resistant Prostate Cancer and Mutated Forms of the
Androgen Receptor Using the Novel Inhibitor Darolutamide
(ODM-201)
Hendrik Borgmann
a , b , Nada Lallous a , Deniz Ozistanbullu a , c , Eliana Beraldi a , Naman Paul a ,Kush Dalal
a , Ladan Fazli a , Axel Haferkamp b , Pascale Lejeune d , Artem Cherkasov a ,Martin E. Gleave
a , *a
Department of Urologic Sciences, The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada;
b
Department of Urology,
University Medicine Johannes Gutenberg-University Mainz, Mainz, Germany;
c
Department of Urology, University Hospital Frankfurt, Frankfurt, Germany;
d
Bayer AG, Berlin, Germany
E U R O P E A N U R O L O GY 7 3 ( 2 0 18 ) 4 – 8available at
www.scienced irect.comjournal homepage:
www.europeanurology.comArticle info
Article history:
Accepted August 11, 2017
Associate Editor:
James Catto
Keywords:
Castration-resistant prostate
cancer
Personalized medicine
Precision oncology
Treatment sequence
AR mutation
ctDNA
Abstract
Darolutamide (ODM-201) is a novel androgen receptor (AR) antagonist with a chemical
structure distinctly different from currently approved AR antagonists that targets both
wild-type and mutated ligand binding domain variants to inhibit AR nuclear transloca-
tion. Here, we evaluate the activity of darolutamide in enzalutamide-resistant castration
resistant prostate cancer (CRPC) as well as in AR mutants detected in patients after
treatment with enzalutamide, abiraterone, or bicalutamide. Darolutamide signi
fi
cantly
inhibited cell growth and AR transcriptional activity in enzalutamide-resistant MR49F
cells in vitro, and led to decreased tumor volume and serum prostate-speci
fi
c antigen
levels in vivo, prolonging survival in mice bearing enzalutamide-resistant MR49F
xenografts. Moreover, darolutamide inhibited the transcriptional activity of AR mutants
identi
fi
ed in the plasma of CRPC patients progressing on traditional therapies. In
particular, darolutamide signi
fi
cantly inhibited the transcriptional activity of the
F877L, H875Y/T878A, F877L/T878A, and the previously unreported T878G AR mutants,
that transform enzalutamide into a partial agonist. In silico cheminformatics computer
modeling provided atomic level insights con
fi
rming darolutamide antagonist effect in
F877L and T878G AR mutants. In conclusion, our results provide a rationale for further
clinical evaluation of darolutamide in enzalutamide-resistant CRPC, in particular in
combination with circulating tumor DNA assays that detect AR mutants sensitive to
darolutamide, in a precision oncology setting.
Patient summary:
In this study we evaluated the novel drug darolutamide in preclinical
models of prostate cancer. We found that darolutamide delays growth of enzalutamide-
resistant prostate cancer, in particular in cells with mutated forms of the androgen
receptor after previous treatment. Our data supports further evaluation of darolutamide
in clinical trials.
© 2017 Published by Elsevier B.V. on behalf of European Association of Urology.
* Corresponding author. Department of Urological Sciences, University of British Columbia,
The Vancouver Prostate Centre, 2775 Laurel Street, 6th Floor, Vancouver, BC V5Z 1M9, Canada.
Tel. +1 604 875 5006.
E-mail address:
m.gleave@ubc.ca(M.E. Gleave).
http://dx.doi.org/10.1016/j.eururo.2017.08.0120302-2838/© 2017 Published by Elsevier B.V. on behalf of European Association of Urology.