EURURO Vol. 73 No. 1

9 148

Platinum Priority – Editorial
Referring to the article published on pp. 4– 8 of this issue
Innovative Therapies to Overcome Resistance to Enzalutamide:
Perspective on the Use of Darolutamide
Zoran Culig
Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria
Therapy with nonsteroidal antiandrogens has been histor-
ically associated with different adaptive responses ob-
served after chronic treatment with hydroxyflutamide,
bicalutamide, and, more recently, enzalutamide. As in the
case of “older” antiandrogens, research on enzalutamide
resistance has been focused on alterations in the expres-
sion or function of the androgen receptor (AR). In this issue
of European Urology, Borgmann and associates present
an investigation of the role of darolutamide (ODM-201), a
new AR antagonist, in inhibition of mutated AR associated
with enzalutamide resistance. The authors have addressed
the effects of darolutamide with the AR F877L, H875Y/
T878A, and F877/T878Amutants. For all these mutations, it
was demonstrated that enzalutamide could act as a partial
agonist. Darolutamide could also bind to the pocket
of the T878G mutant, but did not cause partial activation
of the receptor. For that receptor, it was previously
documented that flutamide and bicalutamide could act
as partial agonists . In vitro and in vivo studies have been
performed with the MR49F cell line, which expresses the
AR F877Lmutant . On the basis of a favorable response in
culture, the authors tested the effect of darolutamide on
xenograft growth. Those studies revealed that daroluta-
mide inhibited tumor growth primarily by slowing
proliferation.
It is obvious that the results reported by Borgmann and
associates have importance for future clinical trials.
However, some issues need to be discussed before the
design of appropriate clinical studies with darolutamide.
First, how is the duration of darolutamide response
determined? It seems that treatment with any antiandrogen
may lead to an increase in the appearance of AR mutations.
In light of this, an “antiandrogen switch” may be a strategy
that will provide a time-limited response to a drug used for
second-line therapy. However, it is likely that the duration
of the response will depend on the epithelial-to-mesenchy-
mal transition (EMT). EMT is frequently described in
response to chemotherapy in prostate and other cancers,
but is also observed in various models representing
androgen ablation/AR blockade therapy . A switch in
cadherin expression involving a reduction in E-cadherin and
higher expression of N-cadherin characterizes the EMT in
vitro. Other molecules such as fibronectin and vimentin are
also frequently upregulated in EMT. It may be difficult to
precisely quantitate the extent of EMT in clinical specimens.
Features of EMT are frequently associated with increased
expression of markers of cellular stemness. Thus, the
possible success of darolutamide in endocrine therapy for
prostate cancer may depend on its direct or indirect effects
on factors that critically influence the development of
tumor metastasis.
With regard to discussion on enzalutamide resistance,
one has to keep in mind that AR variants that show
constitutive activity are upregulated during prolonged
treatment with antiandrogens. The relationship between
darolutamide and the appearance of AR variants may
therefore be a subject of interesting studies in the future. AR
coactivators that interact with the AR N- or C-terminus may
also be increasingly expressed in patients receiving therapy
with any antiandrogen including darolutamide . Such
coactivators are probably important factors that prevent the
antagonistic role of compounds that target the AR. On
the basis of the various mechanisms discussed above,
several other models developed in research laboratories
ava ilable at
journal homepage:
DOI of original article: .
* Experimental Urology, Department of Urology, Medical University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria. Tel. +43 512 50424717;
Fax: +43 512 50424817.
E-mail address: .
0302-2838/© 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.