Endocrine-RelatedCancer

Thematic ReviewC Helsen et al. Role of AR antagonists in

treatment of PCa21 :4 T105–T118

Androgen receptor antagonists forprostate cancer therapy

Christine Helsen1, Thomas Van den Broeck1,2, Arnout Voet3, Stefan Prekovic1,

Hendrik Van Poppel2, Steven Joniau2 and Frank Claessens1

1Laboratory of Molecular Endocrinology, Department of Cellular and Molecular Medicine,

Katholieke Universiteit Leuven, Herestraat 49, B-3000 Leuven, Belgium2Urology, Department of Development and Regeneration, University Hospitals Leuven, Herestraat 49,

3000 Leuven, Belgium3Laboratory for Structural Bioinformatics, Center for Life Science Technologies, RIKEN, Yokohama, Japan

http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Published by Bioscientifica Ltd.

Printed in Great Britain

This paper is one of 12 papers that form paAndrogens and the AR in Breast and Prostatewere Wayne Tilley and Frank Claessens. F Clof this paper, on which he is listed as an au

Downloa

Correspondence

should be addressed

to F Claessens

Email

frank.claessens@med.

kuleuven.be

Abstract

Androgen deprivation is the mainstay therapy for metastatic prostate cancer (PCa).

Another way of suppressing androgen receptor (AR) signaling is via AR antagonists or

antiandrogens. Despite being frequently prescribed in clinical practice, there is conflicting

evidence concerning the role of AR antagonists in the management of PCa. In the

castration-resistant settings of PCa, docetaxel has been the only treatment option for

decades. With recent evidence that castration-resistant PCa is far from AR-independent,

there has been an increasing interest in developing new AR antagonists. This review gives

a concise overview of the clinically available antiandrogens and the experimental AR

antagonists that tackle androgen action with a different approach.

Key Words

" androgen receptorantagonist

" antiandrogen

" enzalutamide

" bicalutamide

" abiraterone

" prostate cancer

rt oCa

aesthoded

Endocrine-Related Cancer

(2014) 21, T105–T118

Introduction

Prostate cancer (PCa) remains a major healthcare problem

and it is expected that the prevalence will only increase

due to aging of the population. In 2013, it is estimated that

PCa will account for 28% of all cancers in the USA with

29 720 expected PCa-related deaths (Siegel et al. 2013).

Epidemiological studies from Europe show comparable

data with an estimated incidence of 416 700 new PCa cases

in 2012, representing 22.8% of cancer diagnoses in men.

In total, 92 200 PCa-specific deaths are expected, making

it one of the three cancers men are most likely to die

from, with a mortality rate of 9.5% (Ferlay et al. 2013).

Due to its heterogeneity, the treatment of PCa has

been shown to be an important challenge, for which

careful selection of the most suitable treatment regimen

is required (Fig. 1).

Currently, therapy selection is based on clinical

staging (including TNM staging, Gleason scoring, and

prostate specific antigen (PSA) levels) and patients’ overall

health status. Low-risk, localized PCa is generally managed

by active surveillance. For intermediate- and especially

high-risk disease, more invasive therapy is required, for

which surgery or radiotherapy are currently the standard

treatment options whether or not within the context of a

multimodal approach. In the metastatic setting, androgen

deprivation therapy (ADT) is the mainstay treatment,

targeting androgen receptor (AR) signaling. The first

therapies, aimed at blocking AR activity, were already

being used in the 1940s by Huggins (1942). He proposed

castration and high doses of estrogens to create an

androgen-deprived state of the tumor. This revolutionary

method was refined during the years and has led to the use

of luteinizing hormone-releasing hormone (LHRH) ago-

nists that interfere with the hypothalamic–pituitary–testis

axis, leading to androgen deprivation. This initially leads

f a thematic review section onncer. The Guest Editors for this sectionsens was not involved in the handlingr. from Bioscientifica.com at 08/01/2021 08:15:59AM

via free access

LHRH-antagonists

Localized

Completeandrogenblockade

Radiotherapy+

HT

Metastatic prostate cancer

Dis

ease

pro

gres

sion

Organ-confined

Extra-capsular

Metastases

Activesurveillance

Radicalprostatectomy

Radiotherapy

Radicalprostatectomy

Castration-resistant

LHRH-agonists

Addition of a non-steroidalanti-androgen (NSAA)

Docetaxel-resistant

Orchiectomy

Withdrawal of NSAA

Abiraterone Sipuleucel T Docetaxel

AbirateroneEnz

(MDV3100) Cabazitaxel Alpharadin

Castration-resistant

Docetaxel-resistant

Locally advanced

Figure 1

Overview of prostate cancer therapy. This scheme gives the therapeutic

options assigned to each stage of prostate cancer disease. Based on

tumor characteristics, patients’ health status, biological age, and

personal preference, the optimal therapeutic regimen can be chosen.

Treatments with a dotted frame are not considered as standard

therapy according to the EAU guidelines. HT, hormone therapy; NSAA,

non-steroidal antiandrogen. Adapted from Higano & Crawford (2011)

and Massard & Fizazi (2011).

Endocrine-RelatedCancer

Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa

21 :4 T106

to tumor regression, but eventually the tumor adapts to

the low androgen levels by developing an alternative way

of activating AR or by bypassing AR (Higano & Crawford

2011, Massard & Fizazi 2011). This stage of the disease is

referred to as castration-resistant PCa (CRPC).

In the castration-resistant setting, docetaxel has been

the only treatment option that could prolong life for

decades. The recent understanding that the AR remains an

important target, even in the castration-resistant setting,

has led to the development of a plethora of treatment

options targeting the AR.

The goal of this review is to give an insight into

the available therapeutic options for the treatment of

metastatic PCa, directly or indirectly targeting the AR.

Secondly, we will review the preclinical development of

http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain

a number of novel AR antagonists. Other promising non-

AR-targeted therapies such as cabazitaxel (de Bono et al.

2010), sipuleucel-T (Higano et al. 2009), alpharadin

(Harrison et al. 2013), and tasquinimod (Armstrong et al.

2013) are currently under development but are not within

the scope of this review.

AR-targeted therapies

As androgens have a pivotal role in the development of the

prostate gland and prostate carcinogenesis, the AR is the

fundamental target of systemic therapy for PCa (Taplin &

Balk 2004). The AR is a ligand-dependent transcription

factor that is activated when androgens are present (Helsen

et al. 2012a). In response to androgen binding, it can initiate

expression of genes that contain response elements, which

are recognized by the AR (Denayer et al. 2010). Indeed, in

prostate cells, the AR controls the balance between cell

differentiation and proliferation. In normal prostate tissue,

the scale is tipped toward differentiation, while during

progression of PCa from early to advanced cancer the scale

gradually tips in favor of proliferation. This shift is

accompanied by a downregulation of genes that support

differentiation and upregulation of genes that promote

proliferation (Hendriksen et al. 2006, Marques et al. 2011).

Thus, the uncontrolled cell growth that is associated with

PCa is reflected by a shift of the transcriptional program of

AR toward a proliferative gene set (Wang et al. 2009). It is

therefore crucial to inhibit androgen signaling either by

depriving the tumor from androgens or by blocking the

receptor activity. AR activity can be enhanced not only by

steroids produced in the testis and adrenal glands but

also by androgens that were synthesized by the tumor itself

(Montgomery et al. 2008). In that way, the tumor supports

its own uncontrolled AR activity leading to CRPC.

Androgen deprivation therapy

Inhibition of testicular androgen synthesis ADT

leads to a systemic decrease in the level of circulating

androgens resulting in an androgen-depleted environ-

ment that prevents activation of the AR (Fig. 2). ADT,

achieved by chemical or surgical castration, still is the

mainstay of treatment for patients with metastatic PCa.

Due to convincing evidence showing comparable efficacy,

surgical castration is generally replaced by chemical

castration in the Western world (Soloway et al. 1991,

Vogelzang et al. 1995, Seidenfeld et al. 2000).

Chemical castration is achieved by blocking the

hypothalamic–pituitary–testis feedback system with

Published by Bioscientifica Ltd.

Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access

CYP17A1 inhibitor

AR

Inactive AR

Function

DHT

CoR

AF1

Prostate

TestosteroneDHEA

Pituitary gland

Adrenal glands Testis

ACTH FSHLH

Hypothalamus

LHRH

CYP17A1 inhibitor

Neg

ativ

e fe

edba

ck LHRH

antagonistLHRH agonist

Figure 2

Androgen deprivation therapy. Depriving the tumor from androgens is one

strategy to tackle uncontrolled androgen signaling by the AR. LHRH

analogues, both agonists and antagonists, are able to inhibit the synthesis

of testosterone in the testis and of DHEA in the adrenal glands by affecting

the hypothalamic–pituitary–gonadal/adrenal axis. CYP17A1 inhibitors

cause androgen deprivation by inhibiting the intracellular biosynthesis of

androgens in the testis and adrenals starting from cholesterol. Besides

reduced testosterone, DHT, and DHEA levels, some CYP17A1 inhibitors

(e.g., abiraterone and TOK-001) are also able to directly bind to the

androgen receptor (AR) and block its activity as a ligand-dependent

transcription factor. LHRH, luteinizing hormone-releasing hormone; FSH,

follicle-stimulating hormone; LH, luteinizing hormone; ACTH, adrenocor-

ticotropic hormone; DHEA, dehydroepiandrosterone; DHT, dihydrotestos-

terone; AF1, activation function 1; CoR, corepressor complexes.

Endocrine-RelatedCancer

Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa

21 :4 T107

LHRH analogues (Fig. 2). Currently, the available LHRH

agonists are leuprolide, goserelin, triptorelin, and histre-

lin, which need to be administered, monthly to yearly, by

injection or implantation. There is an initial release of

luteinizing hormone, causing a downregulation of LHRH

receptors at the hypothalamus, disrupting the hypo-

thalamic–pituitary–testicular axis and therefore reducing

http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain

testosterone production (Schally et al. 1992). Due to the

initial release of luteinizing hormone (increase by up to

tenfold), there is an initial rise in testosterone levels

(approximately twofold), occurring during the initial 72 h

of treatment, which leads to a transient increase in PSA

levels (Thompson 2001). Testosterone levels are being

suppressed at 10–20 days from administration, however,

at a lower efficacy compared with orchidectomy, as a

significant number of patients treated with the LHRH

agonists fail to reach castrate levels of testosterone (Wex

et al. 2013).

It has been suggested that this ‘biochemical flare’,

occurring in 4–63% of patients, could cause clinical ‘flares

of disease’, with reports of increased pain from bone

metastases, spinal cord compression, pathological frac-

tures, bladder outlet obstruction, and even death (Bubley

2001, Heidenreich et al. 2011). Besides the initial flare,

miniflares are observed within 12 h after the second or

subsequent administration of the LHRH agonist (Sarosdy

et al. 1999, Sharifi & Browneller 2002). To prevent these

flares, antiandrogens (see below) are being combined with

LHRH agonistic treatment, before and during the first

weeks, to reach a total androgen blockade. While the

antiandrogens will block the action of testosterone and

adrenal androgens on the AR, they will not inhibit the

hormonal surge and some of the potentially harmful

effects that it produces (Brawer 2001).

To circumvent the flares, LHRH antagonists have been

developed, resulting in an equally effective, but more

rapid chemical castration as LHRH agonists (Van Poppel

et al. 2008, Crawford et al. 2011, Garnick & Mottet 2012,

Ozono et al. 2012). Moreover, the LHRH antagonists do

not have increased risk for cardiovascular diseases as is the

case for LHRH agonists (Levine et al. 2010).

Despite the lack of evidence on the contribution of

antiandrogens, the current EAU Guidelines recommend

ADT therapy in all (symptomatic and asymptomatic)

metastatic patients combined with short-term adminis-

tration of antiandrogen therapy to reduce the risk of the

‘flare’ phenomenon in patients receiving LHRH agonists.

They emphasize that, especially in patients at high risk of

‘clinical flare’, LHRH agonists should not be administered

as monotherapy, even though there is no evidence of

long-term effects (Heidenreich et al. 2011).

Inhibition of adrenal and intracellular androgen

synthesis Despite the initial good response to ADT, PCa

progresses toward a castration-resistant stage after a median

time of 2–3 years (Knudsen & Kelly 2012). This means that

the tumor has adapted to survive the castrate levels of

Published by Bioscientifica Ltd.

Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access

Endocrine-RelatedCancer

Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa

21 :4 T108

androgens or the presence of antiandrogens. Frequently,

AR signaling has been restored not only by an upregulation

of the AR, by mutation of the AR, by an imbalance of

AR co-regulatory proteins but also by the synthesis of

androgens in the tumor cells itself (Taplin & Balk 2004).

Several compounds, such as ketoconazole and abir-

aterone, are able to inhibit the intracellular biosynthesis

of androgens (CYP17A1) and thereby prevent activation

of the AR (Attard et al. 2009; Fig. 2). Compared with

ketoconazole, abiraterone acetate is a potent, selective,

and safe drug. It inhibits the androgen synthesis not only

in the testis but also in the adrenal glands and the prostate

(Attard et al. 2009). Ketoconazole and abiraterone have

to be administered together with prednisone to avoid

symptoms of mineralocorticoid excess, caused by an

excess of ACTH secretion (Danila et al. 2010).

Abiraterone acetate Abiraterone acetate was developed to

manage metastatic PCa, progressing after chemotherapy.

One of the observed adaptive mechanisms in PCa cells

CPA

Abirat

DHT

TAK700

H

H H

H

OH

O

CYP17A1 inhibitor

NH

N

N

O

OH

CI

H

H

H

O

H

OH

Figure 3

Steroidal antiandrogens and CYP17 inhibitors. The CYP17 inhibitors with a stero

AR. DHT, dihydrotestosterone; CPA, cyproterone acetate; MPA, medroxyproges

http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain

resulting in castration resistance is an increase of the

intracellular androgen levels (Montgomery et al. 2008).

CYP17A1, which is an enzyme involved in the androgen

biosynthesis pathway, is specifically inhibited by abirater-

one. By suppressing testosterone synthesis in the adrenals

and intratumorally, administration of abiraterone results

in decreased intraprostatic testosterone levels.

After the efficacy had been proved in clinical trials

on both chemotreated and chemonaive mCRPC patients

(de Bono et al. 2011, Ryan et al. 2013), the drug was

approved by the FDA and EMA for use in patients with

mCRPC. Recently, Richards et al. (2012) demonstrated that

part of the mechanism of action of abiraterone (steroidal)

can be attributed to AR binding and inhibition (Fig. 2).

Novel CYP17A1 inhibitors Other CYP17A1 inhibitors are under

development (Vasaitis et al. 2008, Yamaoka et al. 2012;

Fig. 3). Indeed, abiraterone is an inhibitor of both the

C17,20-lyase activity and the 17a-hydroxylase activity of

CYP17A1 and inhibition of the latter causes symptoms

Steroidal antiandrogens

erone

MPA

TOK-001

H

O

O

O

H

H

N

H

H H

O OO

H

O

H H

N

N

H

OH

idal structure also display antiandrogenic effects by binding directly to the

terone acetate.

Published by Bioscientifica Ltd.

Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access

DHT

AR

Active AR

CoA

FunctionAF1

Bic

AR

DHT

Endocrine-RelatedCancer

Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa

21 :4 T109

of mineralocorticoid excess. Therefore, compounds with

higher specificity against the C17,20-lyase activity of

CYP17A1 have been developed to prevent the need for

prednisone. TAK700, a non-steroidal CYP17A1 inhibitor,

is an example of more selective CYP17A1 inhibitor;

however, the phase 3 clinical trial with TAK700 has

ended preliminary because of the observation that

TAK700 plus prednisone would not likely meet the

primary endpoint of improved overall survival compared

with placebo plus prednisone. For TOK-001, it is known

that it is not only a CYP17 inhibitor, but also a competitive

AR antagonist that results in the downregulation of the

AR (Vasaitis et al. 2008, Bruno et al. 2011).

Inactive AR

Function

CoR

AF1

Enz

AR

Inactive AR

Function

DHT

CoR

AF1

Figure 4

Mechanism of action of AR antagonists. After binding to the ligand-

binding pocket of AR and nuclear translocation of AR, dihydrotestosterone

(DHT) is able to induce the formation of a coactivator-binding platform,

called AF1, which leads to the recruitment of coactivators (CoA). These

coactivators will induce the formation of an active transcriptional complex

containing RNA polymerase that leads to transcription of androgen-

regulated genes. AR antagonists can interfere with all of these required

events for activation of AR gene expression by an androgen. Bicalutamide

(bic) binds to the ligand-binding pocket of AR but fails to induce the correct

conformational change. The platform that is formed cannot recruit

coactivators, but corepressors (CoR) leading to an inactive AR–DNA

complex. Enzalutamide (Enz) has a similar mechanism of action as bic,

but can prevent nuclear translocation of the AR and the binding of AR

to DNA as well, making it a stronger AR antagonist.

Antiandrogens

AR antagonists or antiandrogens prevent androgens from

carrying out their biological activity by directly binding

and blocking the AR LBD, and by inducing repressive

activity (Fig. 4).

The current roles of antiandrogen therapy are limited

to preventing the flare-up of LHRH-agonistic therapies

(see above) and usage in combination with LHRH-

agonistic or -antagonistic therapy to achieve complete

androgen blockade (Fig. 1).

Despite the fact that chemical or surgical castration

reduces 95% of testosterone levels, an intraprostatic

androgen stimulus is still present as a result of circulating

androgens and androgen precursors of adrenal origin.

Adding an antiandrogen to castration blocks the action of

these adrenal androgens, resulting in complete androgen

blockade. However, as the clinical advantage of this

combined treatment is still questionable, the current

EAU guidelines do not recommend this as standard

treatment (Heidenreich et al. 2011).

In the next section, we will discuss the current

evidence on the role of (steroidal and non-steroidal)

antiandrogens in treating advanced PCa.

Steroidal antiandrogens In analogy with the

structure of androgens, the first antiandrogens contained

a steroidal skeleton to ensure binding to the receptor

(Fig. 3). Several steroidal antiandrogens (cyproterone

acetate (CPA), megestrol acetate, and medroxyprogesterone

acetate) were initially used for obtaining maximal

androgen blockade in patients; however, severe

drawbacks such as hepatotoxicity, interference with libido

and potency, cardiovascular side effects, and low efficacy

have limited their clinical use (Jacobi et al. 1980,

http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain

Pavone-Macaluso et al. 1986, 1989, Moffat 1990, Patel

et al. 1990, Dawson et al. 2000, Schroder et al. 2004).

The side effects that occur for these drugs are related

to their effects on other steroid receptors such as the

progesterone receptor and the glucocorticoid receptor, for

Published by Bioscientifica Ltd.

Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access

Endocrine-RelatedCancer

Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa

21 :4 T110

which they are (weak/partial) agonists (Pridjian et al. 1987,

Schroder 1993). Interference with libido and potency is the

result of their antigonadotropic effects leading to reduced

secretion of LH and follicle-stimulating hormone (FSH) and

as a consequence decreased plasma levels of T and E. Unlike

the steroidal antiandrogens, flutamide (flut) increases T

and E levels which could lead to gynecomastia (Schroder

1993). In concert with LHRH treatment, the steroidal

antiandrogens seem to reduce gynecomastia and hot

flushes. The effectiveness of the LHRH therapy, however,

cannot be increased as was shown in a prospective,

randomized study comparing goserelin acetate vs CPA vs

a combination of the two, and this study concluded that

CPA as monotherapy was inferior and the combined

treatment was not superior to goserelin acetate alone

(Thorpe et al. 1996). With regard to reducing hot flushes,

Irani et al. (2010) performed a randomized double-blind

trial, comparing efficacies of these drugs, concluding that

medroxyprogesterone acetate could be considered as the

standard treatment for hot flushes.

Non-steroidal antiandrogens Non-steroidal antian-

drogens (NSAAs) were first introduced in 1989 in clinical

practice as treatment for advanced and metastatic PCa.

Currently, they are mainly used in combination with

LHRH agonists in preventing clinical ‘flare-up’ and in

combination with LHRH agonists/antagonists to achieve

‘complete androgen blockade’ (see above). Available drugs

are the first-generation antiandrogens flut, bicalutamide

(bic), and nilutamide (nil), and the second-generation

compound enzalutamide (enz) (previously known as

MDV3100) (Fig. 5). They antagonize the actions of

androgens at the receptor level and thereby inhibit

tumor growth. The first-generation antiandrogens bic

and nil were derived from flut and thus have a similar

non-steroidal, chemical structure (Fig. 5). The non-

steroidal structure avoids the typical constraints associ-

ated with the previous steroidal antiandrogens. Of them,

bic is the best tolerated and most stable antiandrogen

currently used in clinical practice. It has a half-life of seven

days compared with 6–8 h for flut and 2 days for nil which

allows once-a-day dosing (McLeod 1997). The efficacy of

bic in clinical trials was reported to be at least equivalent

to the efficacy of flut (Schellhammer et al. 1996) and it is

better tolerated in terms of diarrhea, a common adverse

effect in flut-treated patients (Sarosdy 1999). No beneficial

effects were observed for nil over flut and nil has

the least favorable safety profile (Sarosdy 1999). While

peripheral selectivity was observed in intact rats due to a

low passage across the blood–brain barrier (Furr 1996), this

http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain

was not the case in men with advanced PCa. Their serum

LH and serum T levels were significantly increased due to

bic therapy (Mahler & Denis 1990).

Enzalutamide was first introduced in 2009 as a

second-generation antiandrogen with several advantages

over bic (Tran et al. 2009). In contrast to the ‘classical

antiandrogens’, enz does not only block androgen

binding, but it also inhibits translocation of the AR to

the nucleus and impairs AR binding to DNA (Tran et al.

2009). It has been approved by the FDA and EMA for

treating patients with chemo-resistant CRPC (Ning et al.

2013). Further structural optimization for inhibition of

proliferation, pharmacokinetics, and in vivo efficacy

resulted in the development of a compound called ARN-

509 (Fig. 5). It has a higher efficacy than enz, as 30 mg/kg

per day has the same therapeutic effect as 100 mg/kg per

day enz (Clegg et al. 2012). Moreover, due to the lower

required dosage of ARN-509, it has a lower tendency to

induce seizures, a typical side effect of antiandrogens from

the bic class (Foster et al. 2011).

Clinical use Several studies have been conducted to

determine the efficacy and to assess whether NSAAs in

monotherapy have an advantage over LHRH analogues

regarding side effects such as erectile dysfunction, loss of

libido, fatigue, etc. Both the first- and second-generation

NSAAs demonstrate an identical off-target on GABAA

receptors in the brain, leading to seizures (Foster et al.

2011). In light of this, ARN-509 has been developed, which

has a reduced passage through the blood–brain barrier.

We will briefly discuss the clinical use of the first- and

second-generation antiandrogens.

Flutamide Flut was the first NSAA available for clinical use,

approved by the FDA in 1989. It is indicated to use in

combination with LHRH agonists for the management

of locally confined/advanced and metastatic PCa.

Its role as a monotherapeutic agent is still unclear, with

only one randomized controlled trial (RCT) published,

comparing the therapeutic efficacy of flut with surgical

castration in patients with metastatic PCa. However, the

results remained inconclusive on its efficacy (Boccon-

Gibod et al. 1997). Furthermore, the EORTC group could

not show a difference in outcome between flut and CPA

either (Schroder et al. 2004). The same EORTC trial 30892

showed that only 20% of men treated with flut remained

sexually active for 7 years (Schroder et al. 2004). Due to

the poor evidence for its efficacy and its side effects on

sexual activity in men, flut is currently not indicated as

a monotherapeutic drug in patients with metastatic PCa.

Published by Bioscientifica Ltd.

Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access

N

O

N

NH

S O

F

NN

F

F F

Non-steroidal antiandrogens

First-generation

HN

O2N

F

F F

Nilutamide

Second-generation

Flutamide Enzalutamide

Bicalutamide ARN-509

N NH

O

OCH3

CH3

O2N

F

F F

HN

O

OHO O

S

FN

F

F F

O

N

O

N

NH

S O

F

N

F

F F

Figure 5

Non-steroidal antiandrogens. Both the first- and second-generation

antiandrogens that are currently being used in clinical practice share a

structural motif consisting of an anilide substituted with a trifluoromethyl

group in meta-position and a nitro- or cyano-group in para-position. In

nilutamide, enzalutamide, and ARN-509, the amide of the anilide is a part

of (thio)hydantoin.

Endocrine-RelatedCancer

Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa

21 :4 T111

Bicalutamide Bic is currently the most investigated and most

widespread NSAA in clinical practice, with recommended

doses of 50 mg/day in complete androgen blockage and

150 mg/day for monotherapy. The latter has been inves-

tigated most extensively, with several prospective RCTs

being performed. When comparing bic in monotherapy

with castration, bic was associated with worse survival

rates, although the difference in median survival was only

6 weeks (Tyrrell et al. 1998). Two small RCTs, comparing

bic with complete androgen blockade, remained incon-

clusive, although Boccardo et al. showed an increased risk

of death in poorly differentiated tumors (Fourcade et al.

1998, Boccardo et al. 2002).

Despite these inconclusive results, the American

Society of Clinical Oncology (ASCO) has suggested bic

http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain

monotherapy as an alternative for the gold standard (ADT)

in well-informed patients with favorable clinical para-

meters (Loblaw et al. 2007).

NilutamideThere are nocomparative trials ofnil monotherapy

with castration or with other antiandrogens, because of

which nil is currently not licensed for monotherapy.

Enzalutamide In patients who progressed during docetaxel

therapy, enz has been shown to increase overall survival

in comparison with placebo in mCRPC patients in the

AFFIRM trial, leading to its FDA approval (Scher et al. 2012,

Ning et al. 2013). A recent report from the AFFIRM trial

showed comparable efficacy, safety, and tolerability in

patients aged O75 years as well, suggesting its possible

future widespread use (Sternberg et al. 2014). Two small

Published by Bioscientifica Ltd.

Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access

Endocrine-RelatedCancer

Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa

21 :4 T112

retrospective studies demonstrated only a limited activity

of enz in the post-docetaxel and post-abiraterone patient

population, suggesting the existence of cross-resistance

(Bianchini et al. 2013a, Schrader et al. 2013). These studies

are not RCTs and lack power with only 35–39 patients

being investigated, limiting its clinical value. However,

the molecular basis of such cross-resistance should be

further investigated because it will provide information on

the sequence in which these treatments should be used.

To test its efficacy in the pre-chemotherapy setting,

the PREVAIL trial was started (NCT01212991). However,

it has recently been stopped early after meeting its

co-primary endpoints of overall survival and radiographic

progression-free survival, making it possible for patients

from the placebo group to switch treatment arms.

Mechanismof action of antiandrogens Antiandro-

gens bind to the ligand-binding pocket of the AR and

thereby prevent its activation. When androgens such as

dihydrotestosterone (DHT) bind to the AR, a very specific

conformational change occurs in the ligand-binding

domain, leading to an active receptor (Pereira de Jesus-Tran

et al. 2006; Fig. 4). Crystal structures of steroid receptor

ligand binding domains (LBDs) with an agonist have shown

that after binding, helix 12 closes off the pocket and forms a

platform for the binding of coactivators, called activation

function 1 (AF1; Shiau et al. 1998, Williams & Sigler 1998).

This specific position of helix 12 is required and can only be

induced by agonists. When antagonists bind, they induce

a distinct inactive LBD conformation in which helix 12 is

repositioned from its active position or helix 12 is forced

into a flexible position (Kauppi et al. 2003, Hodgson et al.

2008, Lusher et al. 2011). This disables the binding

of coactivators and/or enables the formation of another

platform to which corepressors can bind. Moreover,

antiandrogens can recruit corepressors via other domains

such as the amino terminal domain (NTD), which was

demonstrated for CPA (Dotzlaw et al. 2002). For the AR,

the carboxy-terminal end of helix 12 is anchored by the

formation of a b-sheet leading to a less flexible helix 12.

In absence of antagonist-bound AR crystals, molecular

modeling techniques have predicted that, for the AR, a

displacement of helix 12 could occur in the presence of

antiandrogens, although involvement of residues in helix 5

and helix 11 cannot be excluded (Georget et al. 2002, Bohl

et al. 2005a, Bisson et al. 2008, Osguthorpe & Hagler 2011).

The conformation of the receptor induced by antagonists

results in the inhibition of many required actions of the AR,

such as inhibition of entry to the cell nucleus, binding to

DNA response elements, recruitment of coactivators, etc.

http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain

Each step is important for the execution of the normal

function of AR, and each step is therefore a potential target

for antiandrogen therapy. The precise mechanism of action

of bic and enz is described below (Fig. 4).

Bicalutamide When bic binds to the ligand-binding pocket

of the AR, a displacement of helix 12 and consequently

a distortion of the coactivator platform were suggested

by molecular dynamics-based simulations (Osguthorpe &

Hagler 2011). Furthermore, it leads to the assembly of

a transcriptionally inactive complex due to the inability

of the bic-bound AR to recruit coactivators and/or the

preferential recruitment of corepressors, NCoR and SMRT

(Masiello et al. 2002). By fluorescence recovery after

photobleaching (FRAP) analysis with a GFP-tagged AR,

the immobile fraction of nuclear AR disappeared when bic

was present, meaning that the receptor was unable to bind

DNA (Farla et al. 2005). Moreover, the AR was shown to

be destabilized in the presence of bic (Waller et al. 2000).

All these observations explain why bic can decrease

androgen-induced gene expression and reduce the weight

of rat ventral prostate and seminal vesicles after oral

administration (Furr & Tucker 1996).

Enzalutamide As mentioned earlier, enz is considered as a

more effective inhibitor of AR compared with bic due to

a higher binding affinity, the inhibition of AR nuclear

translocation and DNA binding by AR (Tran et al. 2009,

Guerrero et al. 2013). FoxA1 is a PCa-involved pioneering

factor that makes DNA more accessible for binding by the

AR. Enz prevented the AR from binding to DNA response

elements in presence of FoxA1, while bic could not (Belikov

et al. 2012). Further optimization of enz is ongoing and has

led to the development of ARN-509, a compound with

optimized pharmacokinetics, phase 1 and 2 clinical studies

of which are currently running (Clegg et al. 2012, Rathkopf

et al. 2013). Due to its structural similarities (Fig. 5), a

similar binding mode to AR and thus a similar working

mechanism are attributed to ARN-509 (Clegg et al. 2012,

Balbas et al. 2013). Unfortunately, so far no antagonist-

containing WT AR LBD crystal structures are available

(Balbas et al. 2013, Joseph et al. 2013, Korpal et al. 2013).

The discovery of the AR W741C/L mutation in bic-resistant

cells, AR T877A mutation in flut-resistant cells, and AR

F876L mutation in enz-resistant cells has given some

insights. A model for the binding of enz to the ligand-

binding pocket of WT AR has been proposed (Fig. 6; Balbas

et al. 2013). A focused chemical screen, based on this in silico

model, has led to a compound that circumvents this escape

mutation and remains antagonistic (Balbas et al. 2013).

Published by Bioscientifica Ltd.

Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access

A

B

R752

R752

Figure 6

Similar binding modes of bic and enz to the AR ligand-binding pocket.

In silicomodel of bic (A) and enz (B) binding as an antagonist in the ligand-

binding domain of the human AR according to Voet et al. (2013). Both

molecules show key conserved interactions in the deeper end of the pocket

where the common trifluoromethyl cyano benzyl group is accommodated

in a highly hydrophobic area with the exception of one hydrogen bridge

with arginine 752 (R752).

Endocrine-RelatedCancer

Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa

21 :4 T113

This was confirmed not only by transfection experiments

with AR F876L (where ARN-509 also performed as an

agonist), but also by the detection of the AR F876L

mutation in the plasma DNA of ARN-509-treated CRPC

patients (Balbas et al. 2013, Joseph et al. 2013).

Structural similarities for the current anti-

androgens Strikingly, the available first- and second-

generation antiandrogens share a common structural

element, an anilide core motif (Fig. 6). For some

compounds, the amide of the anilide can be a part of

(thio)hydantoin. The benzene ring of the anilide has a

trifluoromethyl group in meta-position and a nitro- or

cyano-group in para-position. The chemical scaffold of

Bic has been studied well by means of structure–activity

relationships (Kirkovsky et al. 2000, Bohl et al. 2005b) and

has also served as a template for the development of

several selective AR modulators (SARMs), such as Ostarine

and LGD-4033 (Dalton et al. 2013). The structures of

RD162, MDV3100 (enz), and ARN-509 are based on that

http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain

of RU59063, a non-steroidal arylthiohydantoin AR agonist

that binds AR with the highest known affinity (in the

nanomolar range) (Jung et al. 2010). Holding on to this

structural element, however, diminishes the structural

diversity of AR ligands and could therefore be the cause of

cross-resistance in case of sequential therapy. Molecular

modeling of bic and enz in the ligand-binding pocket

of AR shows a highly conserved interaction required for

binding to AR (Voet et al. 2013; Fig. 6). Structurally more

diverse AR LBD antagonists could thus provide an

innovative way of inhibiting AR, by introducing a

different conformational change in AR and hence also a

different helix 12 position.

From the latest studies on enz resistance and the much

earlier reports of bic and flut resistance, it is almost certain

that eventually every LBD inhibitor, which has been and

will be developed, will lead to the introduction of a

somatic mutation that causes a switch to agonist. There-

fore, it seems that the future of AR antagonists lies in the

development of compounds with different targets or

different strategies. For instance, compounds that do not

act via the ligand-binding pocket but via other sites on the

LBD, the NTD or compounds that could affect AR protein

levels will be of interest. Furthermore, the combination

of compounds with a complementary action mechanism

could lead to a more efficient inhibitory action of AR and

thus a better control of the disease.

Experimental AR-targeted therapiesInhibitors binding to the ligand-binding pocket We and others

have screened for novel AR antagonists belonging to

classes that are structurally different from those that are

currently used in the clinic (Helsen et al. 2012b, Voet et al.

2013). Although such molecules have the advantage that

they might still work in case of resistance to bic, flut, or

enz, they still need to be developed further before they

could be tested in a clinical trial setting.

ODM-201 is a novel AR antagonist that binds to AR

with a higher affinity than enz. Antiproliferative effects

of ODM-201 have been demonstrated in subcutaneous

VCaP xenografts and, due to its unique pharmacological

properties, it has also been shown to have superior

preclinical efficacy in phase 1 studies with no side effects

on the CNS. The most common adverse effects were

asthenia, diarrhea, and nausea (Fizazi et al. 2012).

Inhibitors of AR that do not bind to the ligand-binding pocketEPI-001 is

a bisphenol A diglycidyl ether-like compound that has

been reported to affect the transactivation mediated by the

AR NTD. It inhibits the AR regardless of ligand and inhibits

Published by Bioscientifica Ltd.

Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access

Endocrine-RelatedCancer

Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa

21 :4 T114

androgen-induced gene expression and proliferation both

in vitro and in LNCaP xenograft mice models (Andersen

et al. 2010, Myung et al. 2013). EPI-001 is an alternative

drug candidate for PCa as it does not act via the LBD.

EPI-001 might circumvent escape mechanisms such as

LBD mutation or truncation and should therefore still be

active in many forms of CRPC.

An alternative way of action compared with enz and bic

was discovered for ASC-J9, an AR-binding compound that

destabilizes full-length AR as well as the AR splice variants

involved in castration resistance of PCa (Yamashita et al.

2012). They all inhibit PCa proliferation and reduce PSA

levels, but only ASC-J9 was able to suppress cell invasion

and thus the formation of metastases in in vitro and in vivo

models (Lin et al. 2013a). A different modulation of the

STAT3–CCL2 signaling pathway was suggested to lie at the

base of this observed difference (Lin et al. 2013b).

Affecting AR localization SNARE-1 binds WT and mutant ARs

via the LBD. It not only inhibits nuclear translocation of

the AR, but also facilitates nuclear export leading to

reduced nuclear AR levels. Furthermore, it promotes

degradation of the AR via the ubiquitination pathway.

Its mechanism of action is completely different compared

with the clinically available antiandrogens and its activity

has been demonstrated on PCa xenografts in mice

(Narayanan et al. 2010).

Affecting AR mRNA half-life EZN-4176 is a 16-mer antisense

oligonucleotide that decreases full-length AR protein

expression by binding to exon 4 of AR mRNA (the

hinge). Both in vitro and in animal models, EZN-4176

can inhibit the proliferation of androgen-sensitive and

CRPC cells (Zhang et al. 2011). A small study with 22 CRPC

patients who were progressive (prior abiraterone or

enzalutamide treatment was allowed) demonstrated only

little biochemical and soft tissue response and only three

out of eight patients showed a reduction in circulating

tumor cells at the doses used (Bianchini et al. 2013b); side

effects such as fatigue and liver toxicity prevented further

dose escalation (Bianchini et al. 2013b).

Inhibitors binding to BF3 of AR Next to the ligand-binding

pocket, a newly discovered surface pocket of AR, called

binding function 3 (BF3), could be targeted to influence

coactivator binding (Estebanez-Perpina et al. 2007). Several

structural scaffolds have been identified through virtual

screening as binders to this BF3 region and were confirmed

to have antagonistic effects not only on AR transcriptional

activity (Lack et al. 2011), but also on proliferation of

LNCaP and enz-resistant cells (Munuganti et al. 2013).

http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain

Future perspectives

A new era has started in treating mCRPC patients thanks

to the development of multiple new potent AR-targeted

therapies. These agents first have to prove their efficacy in

the post-chemotherapeutic setting, as have abiraterone and

enzalutamide, leading to their FDA and EMA approval. For

ARN-509, a safety, pharmacokinetic, and proof-of-concept

study is currently ongoing (NCT01171898). The efficacy of

these AR-targeted compounds in these advanced stages has

confirmed that CRPC is not an AR-independent disease

and these novel treatments are even being considered to be

used at an earlier stage during the course of the disease.

When resistance to these novel agents will arise, the eluci-

dation of the underlying mechanisms will tell us what

the targets of the next generation of compounds should be.

The emergence of AR splice variants and the antagonist-

to-agonist switching mutation AR F876L indicate that the

AR can also circumvent the new LBD inhibitors, which

are being developed and might necessitate the develop-

ment of structurally or strategically different AR inhibitors.

Will the AR keep its critical role in PCa treatment or will

it be replaced by completely different targets?

Declaration of interest

The authors declare that there is no conflict of interest that could be

perceived as prejudicing the impartiality of the review.

Funding

This work was supported by the fund from the KU Leuven (OT08-11) and

the FWO (G.0684-12/N and G.0830-13N), and the authors gratefully

acknowledge the financial support from the company Ravago Distribution

Center NV (LUOR fonds).

Acknowledgements

The authors would like to acknowledge Servier for producing Figs 2 and 4

using Servier Medical Art (www.servier.com).

References

Andersen RJ, Mawji NR, Wang J, Wang G, Haile S, Myung JK, Watt K, Tam T,

Yang YC, Banuelos CA et al. 2010 Regression of castrate-recurrent

prostate cancer by a small-molecule inhibitor of the amino-terminus

domain of the androgen receptor. Cancer Cell 17 535–546. (doi:10.1016/

j.ccr.2010.04.027)

Armstrong AJ, Haggman M, Stadler WM, Gingrich JR, Assikis V, Polikoff J,

Damber JE, Belkoff L, Nordle O, Forsberg G et al. 2013 Long-term

survival and biomarker correlates of tasquinimod efficacy in a multi-

center randomized study of men with minimally symptomatic

metastatic castration-resistant prostate cancer. Clinical Cancer Research

19 6891–6901. (doi:10.1158/1078-0432.CCR-13-1581)

Published by Bioscientifica Ltd.

Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access

Endocrine-RelatedCancer

Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa

21 :4 T115

Attard G, Reid AH, A’Hern R, Parker C, Oommen NB, Folkerd E, Messiou C,

Molife LR, Maier G, Thompson E et al. 2009 Selective inhibition of

CYP17 with abiraterone acetate is highly active in the treatment of

castration-resistant prostate cancer. Journal of Clinical Oncology 27

3742–3748. (doi:10.1200/JCO.2008.20.0642)

Balbas MD, Evans MJ, Hosfield DJ, Wongvipat J, Arora VK, Watson PA,

Chen Y, Greene GL, Shen Y & Sawyers CL 2013 Overcoming mutation-

based resistance to antiandrogens with rational drug design. eLife 2

e00499. (doi:10.7554/eLife.00499)

Belikov S, Oberg C, Jaaskelainen T, Rahkama V, Palvimo JJ & Wrange O

2012 FoxA1 corrupts the antiandrogenic effect of bicalutamide but only

weakly attenuates the effect of MDV3100 (Enzalutamide). Molecular and

Cellular Endocrinology 365 95–107. (doi:10.1016/j.mce.2012.10.002)

Bianchini D, Lorente D, Rodriguez-Vida A, Omlin A, Pezaro C, Ferraldeschi R,

Zivi A, Attard G, Chowdhury S & de Bono JS 2013aAntitumour activity of

enzalutamide (MDV3100) in patients with metastatic castration-resistant

prostate cancer (CRPC) pre-treated with docetaxel and abiraterone.

European Journal of Cancer 50 78–84. (doi:10.1016/j.ejca.2013.08.020)

Bianchini D, Omlin A, Pezaro C, Lorente D, Ferraldeschi R, Mukherji D,

Crespo M, Figueiredo I, Miranda S, Riisnaes R et al. 2013b First-

in-human Phase I study of EZN-4176, a locked nucleic acid antisense

oligonucleotide to exon 4 of the androgen receptor mRNA in patients

with castration-resistant prostate cancer. British Journal of Cancer 109

2579–2586. (doi:10.1038/bjc.2013.619)

Bisson WH, Abagyan R & Cavasotto CN 2008 Molecular basis of agonicity

and antagonicity in the androgen receptor studied by molecular

dynamics simulations. Journal of Molecular Graphics & Modelling 27

452–458. (doi:10.1016/j.jmgm.2008.08.001)

Boccardo F, Barichello M, Battaglia M, Carmignani G, Comeri G, Ferraris V,

Lilliu S, Montefiore F, Portoghese F, Cortellini P et al. 2002 Bicalutamide

monotherapy versus flutamide plus goserelin in prostate cancer:

updated results of a multicentric trial. European Urology 42 481–490.

(doi:10.1016/S0302-2838(02)00435-9)

Boccon-Gibod L, Fournier G, Bottet P, Marechal JM, Guiter J, Rischman P,

Hubert J, Soret JY, Mangin P, Mallo C et al. 1997 Flutamide versus

orchidectomy in the treatment of metastatic prostate carcinoma.

European Urology 32 391–395 discussion 395–396.

Bohl CE, Gao W, Miller DD, Bell CE & Dalton JT 2005a Structural basis for

antagonism and resistance of bicalutamide in prostate cancer. PNAS

102 6201–6206. (doi:10.1073/pnas.0500381102)

Bohl CE, Miller DD, Chen J, Bell CE & Dalton JT 2005b Structural basis for

accommodation of nonsteroidal ligands in the androgen receptor.

Journal of Biological Chemistry 280 37747–37754. (doi:10.1074/jbc.

M507464200)

de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, Gravis G,

Bodrogi I, Mackenzie MJ, Shen L et al. 2010 Prednisone plus cabazitaxel

or mitoxantrone for metastatic castration-resistant prostate cancer

progressing after docetaxel treatment: a randomised open-label trial.

Lancet 376 1147–1154. (doi:10.1016/S0140-6736(10)61389-X)

de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN,

Jones RJ, Goodman OB Jr, Saad F et al. 2011 Abiraterone and increased

survival in metastatic prostate cancer. New England Journal of Medicine

364 1995–2005. (doi:10.1056/NEJMoa1014618)

Brawer MK 2001 The evolution of hormonal therapy for prostatic

carcinoma. Reviews in Urology 3 (Suppl 3) S1–S9.

Bruno RD, Vasaitis TS, Gediya LK, Purushottamachar P, Godbole AM,

Ates-Alagoz Z, Brodie AM & Njar VC 2011 Synthesis and biological

evaluations of putative metabolically stable analogs of VN/124-1

(TOK-001): head to head anti-tumor efficacy evaluation of VN/124-1

(TOK-001) and abiraterone in LAPC-4 human prostate cancer xenograft

model. Steroids 76 1268–1279. (doi:10.1016/j.steroids.2011.06.002)

Bubley GJ 2001 Is the flare phenomenon clinically significant? Urology 58

5–9. (doi:10.1016/S0090-4295(01)01235-3)

Clegg NJ, Wongvipat J, Tran C, Ouk S, Dilhas A, Joseph J, Chen Y, Grillot K,

Bischoff ED, Cai L et al. 2012 ARN-509: a novel anti-androgen for

http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain

prostate cancer treatment. Cancer Research 72 1494–1503. (doi:10.1158/

0008-5472.CAN-11-3948)

Crawford ED, Tombal B, Miller K, Boccon-Gibod L, Schroder F, Shore N,

Moul JW, Jensen JK, Olesen TK & Persson BE 2011 A phase III extension

trial with a 1-arm crossover from leuprolide to degarelix: comparison of

gonadotropin-releasing hormone agonist and antagonist effect on

prostate cancer. Journal of Urology 186 889–897. (doi:10.1016/j.juro.

2011.04.083)

Dalton JT, Taylor RP, Mohler ML & Steiner MS 2013 Selective androgen

receptor modulators for the prevention and treatment of muscle

wasting associated with cancer. Current Opinion in Supportive and

Palliative Care 7 345–351. (doi:10.1097/SPC.0000000000000015)

Danila DC, Morris MJ, de Bono JS, Ryan CJ, Denmeade SR, Smith MR,

Taplin ME, Bubley GJ, Kheoh T, Haqq C et al. 2010 Phase II multicenter

study of abiraterone acetate plus prednisone therapy in patients with

docetaxel-treated castration-resistant prostate cancer. Journal of Clinical

Oncology 28 1496–1501. (doi:10.1200/JCO.2009.25.9259)

Dawson NA,Conaway M, Halabi S,Winer EP, Small EJ, LakeD & VogelzangNJ

2000 A randomized study comparing standard versus moderately

high dose megestrol acetate for patients with advanced prostate

carcinoma: cancer and leukemia group B study 9181. Cancer 88 825–834.

(doi:10.1002/(SICI)1097-0142(20000215)88:4!825::AID-CNCR13O3.0.

CO;2-N)

Denayer S, Helsen C, Thorrez L, Haelens A & Claessens F 2010 The rules of

DNA recognition by the androgen receptor. Molecular Endocrinology 24

898–913. (doi:10.1210/me.2009-0310)

Dotzlaw H, Moehren U, Mink S, Cato AC, Iniguez Lluhi JA & Baniahmad A

2002 The amino terminus of the human AR is target for corepressor

action and antihormone agonism. Molecular Endocrinology 16 661–673.

(doi:10.1210/mend.16.4.0798)

Estebanez-Perpina E, Arnold LA, Nguyen P, Rodrigues ED, Mar E, Bateman R,

Pallai P, Shokat KM, Baxter JD, Guy RK et al. 2007 A surface on the

androgen receptor that allosterically regulates coactivator binding.

PNAS 104 16074–16079. (doi:10.1073/pnas.0708036104)

Farla P, Hersmus R, Trapman J & Houtsmuller AB 2005 Antiandrogens

prevent stable DNA-binding of the androgen receptor. Journal of Cell

Science 118 4187–4198. (doi:10.1242/jcs.02546)

Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW,

Comber H, Forman D & Bray F 2013 Cancer incidence and mortality

patterns in Europe: estimates for 40 countries in 2012. European

Journal of Cancer 49 1374–1403. (doi:10.1016/j.ejca.2012.12.027)

Fizazi K, Massard C, James N, Culine S, Jones R, Oksala R, Moilanen A,

Aho E, Ravanti L & Kallio P 2012 ARADES trial: a first-in-man,

open-label, phase I/II safety, pharmacokinetic, and proof-of-concept

study of ODM-201 in patients with progressive metastatic castration-

resistant prostate cancer. In 2013 Genitourinary Cancers Symposium.

Journal of Clinical Oncology 31 (February 20 Supplement) abstract 65.

Foster WR, Car BD, Shi H, Levesque PC, Obermeier MT, Gan J, Arezzo JC,

Powlin SS, Dinchuk JE, Balog A et al. 2011 Drug safety is a barrier to the

discovery and development of new androgen receptor antagonists.

Prostate 71 480–488. (doi:10.1002/pros.21263)

Fourcade RO, Chatelain C & Poterre M 1998 An open multicentre

randomised study to compare the effect and safety of ‘Casodex’

(bicalutamide) 150 mg monotherapy with castration plus nilutamide in

metastatic prostate cancer In 13th EAU Congress, p88 (abstract #349).

Barcelona, Spain: European Urology.

Furr BJ 1996 The development of Casodex (bicalutamide): preclinical

studies. European Urology 29 (Suppl 2) 83–95.

Furr BJ & Tucker H 1996 The preclinical development of bicalutamide:

pharmacodynamics and mechanism of action. Urology 47 13–25

discussion 29–32. (doi:10.1016/S0090-4295(96)80003-3)

Garnick MB & Mottet N 2012 New treatment paradigm for prostate

cancer: abarelix initiation therapy for immediate testosterone

suppression followed by a luteinizing hormone-releasing hormone

agonist. BJU International 110 499–504. (doi:10.1111/j.1464-410X.

2011.10708.x)

Published by Bioscientifica Ltd.

Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access

Endocrine-RelatedCancer

Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa

21 :4 T116

Georget V, Terouanne B, Nicolas JC & Sultan C 2002 Mechanism of

antiandrogen action: key role of hsp90 in conformational change and

transcriptional activity of the androgen receptor. Biochemistry 41

11824–11831. (doi:10.1021/bi0259150)

Guerrero J, Alfaro IE, Gomez F, Protter AA & Bernales S 2013 Enzalutamide,

an androgen receptor signaling inhibitor, induces tumor regression in a

mouse model of castration-resistant prostate cancer. Prostate 73

1291–1305. (doi:10.1002/pros.22674)

Harrison MR, Wong TZ, Armstrong AJ & George DJ 2013 Radium-223

chloride: a potential new treatment for castration-resistant prostate

cancer patients with metastatic bone disease. Cancer Management and

Research 5 1–14. (doi:10.2147/CMAR.S25537)

Heidenreich A, Bellmunt J, Bolla M, Joniau S, Mason M, Matveev V,

Mottet N, Schmid HP, van der Kwast T, Wiegel T et al. 2011 EAU

guidelines on prostate cancer. Part 1: screening, diagnosis, and

treatment of clinically localised disease. European Urology 59 61–71.

(doi:10.1016/j.eururo.2010.10.039)

Helsen C, Kerkhofs S, Clinckemalie L, Spans L, Laurent M, Boonen S,

Vanderschueren D & Claessens F 2012a Structural basis for nuclear

hormone receptor DNA binding. Molecular and Cellular Endocrinology

348 411–417. (doi:10.1016/j.mce.2011.07.025)

Helsen C, Marchand A, Chaltin P, Munck S, Voet A, Verstuyf A & Claessens F

2012b Identification and characterization of MEL-3, a novel AR

antagonist that suppresses prostate cancer cell growth. Molecular Cancer

Therapeutics 11 1257–1268. (doi:10.1158/1535-7163.MCT-11-0763)

Hendriksen PJ, Dits NF, Kokame K, Veldhoven A, van Weerden WM,

Bangma CH, Trapman J & Jenster G 2006 Evolution of the androgen

receptor pathway during progression of prostate cancer. Cancer Research

66 5012–5020. (doi:10.1158/0008-5472.CAN-05-3082)

Higano CS & Crawford ED 2011 New and emerging agents for the

treatment of castration-resistant prostate cancer. Urologic Oncology 29

S1–S8. (doi:10.1016/j.urolonc.2011.08.013)

Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L,

Provost N & Frohlich MW 2009 Integrated data from 2 randomized,

double-blind, placebo-controlled, phase 3 trials of active cellular

immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer

115 3670–3679. (doi:10.1002/cncr.24429)

Hodgson MC, Shen HC, Hollenberg AN & Balk SP 2008 Structural basis for

nuclear receptor corepressor recruitment by antagonist-liganded

androgen receptor. Molecular Cancer Therapeutics 7 3187–3194.

(doi:10.1158/1535-7163.MCT-08-0461)

Huggins C 1942 Effect of orchiectomy and irradiation on cancer of the

prostate. Annals of Surgery 115 1192–1200. (doi:10.1097/00000658-

194206000-00030)

Irani J, Salomon L, Oba R, Bouchard P & Mottet N 2010 Efficacy of

venlafaxine, medroxyprogesterone acetate, and cyproterone acetate for

the treatment of vasomotor hot flushes in men taking gonadotropin-

releasing hormone analogues for prostate cancer: a double-blind,

randomised trial. Lancet Oncology 11 147–154. (doi:10.1016/

S1470-2045(09)70338-9)

Jacobi GH, Altwein JE, Kurth KH, Basting R & Hohenfellner R 1980

Treatment of advanced prostatic cancer with parenteral cyproterone

acetate: a phase III randomised trial. British Journal of Urology 52

208–215. (doi:10.1111/j.1464-410X.1980.tb02961.x)

Joseph JD, Lu N, Qian J, Sensintaffar J, Shao G, Brigham D, Moon M,

Maneval EC, Chen I, Darimont B et al. 2013 A clinically relevant

androgen receptor mutation confers resistance to second-generation

antiandrogens enzalutamide and ARN-509. Cancer Discovery 3

1020–1029. (doi:10.1158/2159-8290.CD-13-0226)

Jung ME, Ouk S, Yoo D, Sawyers CL, Chen C, Tran C & Wongvipat J 2010

Structure–activity relationship for thiohydantoin androgen receptor

antagonists for castration-resistant prostate cancer (CRPC). Journal of

Medicinal Chemistry 53 2779–2796. (doi:10.1021/jm901488g)

Kauppi B, Jakob C, Farnegardh M, Yang J, Ahola H, Alarcon M, Calles K,

Engstrom O, Harlan J, Muchmore S et al. 2003 The three-dimensional

structures of antagonistic and agonistic forms of the glucocorticoid

http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain

receptor ligand-binding domain: RU-486 induces a transconformation

that leads to active antagonism. Journal of Biological Chemistry 278

22748–22754. (doi:10.1074/jbc.M212711200)

Kirkovsky L, Mukherjee A, Yin D, Dalton JT & Miller DD 2000 Chiral

nonsteroidal affinity ligands for the androgen receptor.1. Bicalutamide

analogues bearing electrophilic groups in the B aromatic ring. Journal of

Medicinal Chemistry 43 581–590. (doi:10.1021/jm990027x)

Knudsen KE & Kelly WK 2012 Outsmarting androgen receptor: creative

approaches for targeting aberrant androgen signaling in advanced

prostate cancer. Expert Review of Endocrinology & Metabolism 6 483–493.

(doi:10.1586/eem.11.33)

Korpal M, Korn JM, Gao X, Rakiec DP, Ruddy DA, Doshi S, Yuan J,

Kovats SG, Kim S, Cooke VG et al. 2013 An F876L mutation in

androgen receptor confers genetic and phenotypic resistance to

MDV3100 (enzalutamide). Cancer Discovery 3 1030–1043.

(doi:10.1158/2159-8290.CD-13-0142)

Lack NA, Axerio-Cilies P, Tavassoli P, Han FQ, Chan KH, Feau C, LeBlanc E,

Guns ET, Guy RK, Rennie PS et al. 2011 Targeting the binding function

3 (BF3) site of the human androgen receptor through virtual screening.

Journal of Medicinal Chemistry 54 8563–8573. (doi:10.1021/jm201098n)

Levine GN, D’Amico AV, Berger P, Clark PE, Eckel RH, Keating NL,

Milani RV, Sagalowsky AI, Smith MR & Zakai N 2010 Androgen-

deprivation therapy in prostate cancer and cardiovascular risk:

a science advisory from the American Heart Association, American

Cancer Society, and American Urological Association: endorsed by

the American Society for Radiation Oncology. Circulation 121

833–840. (doi:10.1161/CIRCULATIONAHA.109.192695)

Lin TH, Lee SO, Niu Y, Xu D, Liang L, Li L, Yeh SD, Fujimoto N, Yeh S &

Chang C 2013a Differential androgen deprivation therapies with anti-

androgens casodex/bicalutamide or MDV3100/Enzalutamide versus

anti-androgen receptor ASC-J9(R) Lead to promotion versus suppres-

sion of prostate cancer metastasis. Journal of Biological Chemistry 288

19359–19369. (doi:10.1074/jbc.M113.477216)

Lin TH, Izumi K, Lee SO, Lin WJ, Yeh S & Chang C 2013b Anti-androgen

receptor ASC-J9 versus anti-androgens MDV3100 (Enzalutamide) or

Casodex (Bicalutamide) leads to opposite effects on prostate cancer

metastasis via differential modulation of macrophage infiltration and

STAT3-CCL2 signaling. Cell Death & Disease 4 e764. (doi:10.1038/cddis.

2013.270)

Loblaw DA, Virgo KS, Nam R, Somerfield MR, Ben-Josef E, Mendelson DS,

Middleton R, Sharp SA, Smith TJ, Talcott J et al. 2007 Initial hormonal

management of androgen-sensitive metastatic, recurrent, or pro-

gressive prostate cancer: 2006 update of an American Society of Clinical

Oncology practice guideline. Journal of Clinical Oncology 25 1596–1605.

(doi:10.1200/JCO.2006.10.1949)

Lusher SJ, Raaijmakers HC, Vu-Pham D, Dechering K, Lam TW, Brown AR,

Hamilton NM, Nimz O, Bosch R, McGuire R et al. 2011 Structural basis

for agonism and antagonism for a set of chemically related

progesterone receptor modulators. Journal of Biological Chemistry 286

35079–35086. (doi:10.1074/jbc.M111.273029)

Mahler C & Denis L 1990 Clinical profile of a new non-steroidal

antiandrogen. Journal of Steroid Biochemistry and Molecular Biology 37

921–924. (doi:10.1016/0960-0760(90)90444-P)

Marques RB, Dits NF, Erkens-Schulze S, van Ijcken WF, van Weerden WM &

Jenster G 2011 Modulation of androgen receptor signaling in hormonal

therapy-resistant prostate cancer cell lines. PLoS ONE 6 e23144.

(doi:10.1371/journal.pone.0023144)

Masiello D, Cheng S, Bubley GJ, Lu ML & Balk SP 2002 Bicalutamide

functions as an androgen receptor antagonist by assembly of a

transcriptionally inactive receptor. Journal of Biological Chemistry 277

26321–26326. (doi:10.1074/jbc.M203310200)

Massard C & Fizazi K 2011 Targeting continued androgen receptor

signaling in prostate cancer. Clinical Cancer Research 17 3876–3883.

(doi:10.1158/1078-0432.CCR-10-2815)

McLeod DG 1997 Tolerability of nonsteroidal antiandrogens in the

treatment of advanced prostate cancer. Oncologist 2 18–27.

Published by Bioscientifica Ltd.

Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access

Endocrine-RelatedCancer

Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa

21 :4 T117

Moffat LE 1990 Comparison of Zoladex, diethylstilbestrol and cyproterone

acetate treatment in advanced prostate cancer. European Urology

18 (Suppl 3) 26–27.

Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS,

True LD & Nelson PS 2008 Maintenance of intratumoral androgens in

metastatic prostate cancer: a mechanism for castration-resistant

tumor growth. Cancer Research 68 4447–4454. (doi:10.1158/0008-5472.

CAN-08-0249)

Munuganti RS, Leblanc E, Axerio-Cilies P, Labriere C, Frewin K, Singh K,

Hassona MD, Lack NA, Li H, Ban F et al. 2013 Targeting the binding

function 3 (BF3) site of the androgen receptor through virtual

screening. 2. development of 2-((2-phenoxyethyl) thio)-1H-benzimi-

dazole derivatives. Journal of Medicinal Chemistry 56 1136–1148.

(doi:10.1021/jm3015712)

Myung JK, Banuelos CA, Fernandez JG, Mawji NR, Wang J, Tien AH, Yang YC,

Tavakoli I, Haile S, Watt K et al. 2013 An androgen receptor N-terminal

domain antagonist for treating prostate cancer. Journal of Clinical

Investigation 123 2948–2960. (doi:10.1172/JCI66398)

NarayananR,YepuruM,Szafran AT,SzwarcM,BohlCE,YoungNL,MillerDD,

Mancini MA & Dalton JT 2010 Discovery and mechanistic characteri-

zation of a novel selective nuclear androgen receptor exporter for the

treatment of prostate cancer. Cancer Research 70 842–851. (doi:10.1158/

0008-5472.CAN-09-3206)

Ning YM, Pierce W, Maher VE, Karuri S, Tang S, Chiu HJ, Palmby T,

Fourie Zirkelbach J, Marathe D, Mehrotra N et al. 2013 Enzalutamide

for treatment of patients with metastatic castration-resistant prostate

cancer who have previously received docetaxel: U.S. Food and Drug

Administration Drug Approval Summary. Clinical Cancer Research 19

6067–6073. (doi:10.1158/1078-0432.CCR-13-1763)

Osguthorpe DJ & Hagler AT 2011 Mechanism of androgen receptor

antagonism by bicalutamide in the treatment of prostate cancer.

Biochemistry 50 4105–4113. (doi:10.1021/bi102059z)

Ozono S, Ueda T, Hoshi S, Yamaguchi A, Maeda H, Fukuyama Y, Takeda K,

Ohashi Y, Tsukamoto T, Naito S et al. 2012 The efficacy and safety of

degarelix, a GnRH antagonist: a 12-month, multicentre, randomized,

maintenance dose-finding phase II study in Japanese patients with

prostate cancer. Japanese Journal of Clinical Oncology 42 477–484.

(doi:10.1093/jjco/hys035)

Patel SR, Kvols LK, Hahn RG, Windschitl H, Levitt R & Therneau T 1990

A phase II randomized trial of megestrol acetate or dexamethasone in

the treatment of hormonally refractory advanced carcinoma of the

prostate. Cancer 66 655–658. (doi:10.1002/1097-

0142(19900815)66:4!655::AID-CNCR2820660409O3.0.CO;2-P)

Pavone-Macaluso M, de Voogt HJ, Viggiano G, Barasolo E, Lardennois B,

de Pauw M & Sylvester R 1986 Comparison of diethylstilbestrol,

cyproterone acetate and medroxyprogesterone acetate in the treatment

of advanced prostatic cancer: final analysis of a randomized phase III

trial of the European Organization for Research on Treatment of Cancer

Urological Group. Journal of Urology 136 624–631.

Pavone-Macaluso M, Schroder FH, de Voogt HJ, Viggiano G, Barasolo E,

Lardennois B, de Pauw M, Sylvester R, Smith PH & Suciu S 1989 EORTC

protocol 30761: a randomized study of non-metastatic and metastatic

prostatic cancer treated by cyproterone acetate versus diethylstilbestrol

and medroxyprogesterone acetate, European Organization for Research

on Treatment of Cancer Urological Group. Progress in Clinical and

Biological Research 303 111–116.

Pereira de Jesus-Tran K, Cote PL, Cantin L, Blanchet J, Labrie F & Breton R

2006 Comparison of crystal structures of human androgen receptor

ligand-binding domain complexed with various agonists reveals

molecular determinants responsible for binding affinity. Protein Science

15 987–999. (doi:10.1110/ps.051905906)

Pridjian G, Schmit V & Schreiber J 1987 Medroxyprogesterone acetate:

receptor binding and correlated effects on steroidogenesis in rat

granulosa cells. Journal of Steroid Biochemistry 26 313–319. (doi:10.1016/

0022-4731(87)90095-1)

http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain

Rathkopf DE, Morris MJ, Fox JJ, Danila DC, Slovin SF, Hager JH, Rix PJ,

Chow Maneval E, Chen I, Gonen M et al. 2013 Phase I study of

ARN-509, a novel antiandrogen, in the treatment of castration-resistant

prostate cancer. Journal of Clinical Oncology 31 3525–3530.

(doi:10.1200/JCO.2013.50.1684)

Richards J, Lim AC, Hay CW, Taylor AE, Wingate A, Nowakowska K,

Pezaro C, Carreira S, Goodall J, Arlt W et al. 2012 Interactions of

abiraterone, eplerenone, and prednisolone with wild-type and mutant

androgen receptor: a rationale for increasing abiraterone exposure

or combining with MDV3100. Cancer Research 72 2176–2182.

(doi:10.1158/0008-5472.CAN-11-3980)

Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K,

Mainwaring P, Piulats JM, Ng S et al. 2013 Abiraterone in metastatic

prostate cancer without previous chemotherapy. New England

Journal of Medicine 368 138–148. (doi:10.1056/NEJMoa1209096)

Sarosdy MF 1999 Which is the optimal antiandrogen for use in combined

androgen blockade of advanced prostate cancer? The transition from a

first- to second-generation antiandrogen Anticancer Drugs 10 791–796.

(doi:10.1097/00001813-199910000-00001)

Sarosdy MF, Schellhammer PF, Soloway MS, Vogelzang NJ, Crawford ED,

Presti J, Chodak GW, Mitchell P & Porter L 1999 Endocrine effects, efficacy

and tolerability of a 10.8-mg depot formulation of goserelin acetate

administered every 13 weeks to patients with advanced prostate cancer.

BJU International 83 801–806. (doi:10.1046/j.1464-410x.1999.00028.x)

Schally AV, Comaru-Schally AM & Gonzalez-Barcena D 1992 Present status

of agonistic and antagonistic analogs of LH-RH in the treatment of

advanced prostate cancer. Biomedicine and Pharmacotherapy 46

465–471. (doi:10.1016/0753-3322(92)90004-Q)

Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL,

Sarosdy M, Vogelzang N, Jones J & Kolvenbag G 1996 Maximal

androgen blockade for patients with metastatic prostate cancer:

outcome of a controlled trial of bicalutamide versus flutamide, each in

combination with luteinizing hormone-releasing hormone analogue

therapy. Casodex Combination Study Group. Urology 47 54–60

discussion 80–84. (doi:10.1016/S0090-4295(96)80010-0)

Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R,

Mulders P, Chi KN, Shore ND et al. 2012 Increased survival with

enzalutamide in prostate cancer after chemotherapy. New England

Journal of Medicine 367 1187–1197. (doi:10.1056/NEJMoa1207506)

Schrader AJ, Boegemann M, Ohlmann CH, Schnoeller TJ, Krabbe LM, Hajili T,

Jentzmik F, Stoeckle M, Schrader M, Herrmann E et al. 2013 Enzalutamide

in castration-resistant prostate cancer patients progressing after docetaxel

and abiraterone. European Urology 65 30–36. (doi:10.1016/j.eururo.2013.

06.042)

Schroder FH 1993 Cyproterone acetate – mechanism of action and clinical

effectiveness in prostate cancer treatment. Cancer 72 3810–3815.

(doi:10.1002/1097-0142(19931215)72:12C!3810::AID-

CNCR2820721710O3.0.CO;2-O)

Schroder FH, Whelan P, de Reijke TM, Kurth KH, Pavone-Macaluso M,

Mattelaer J, van Velthoven RF, Debois M & Collette L 2004 Metastatic

prostate cancer treated by flutamide versus cyproterone acetate. Final

analysis of the "European Organization for Research and Treatment

of Cancer" (EORTC) Protocol 30892. European Urology 45 457–464.

(doi:10.1016/j.eururo.2003.11.016)

Seidenfeld J, Samson DJ, Hasselblad V, Aronson N, Albertsen PC,

Bennett CL & Wilt TJ 2000 Single-therapy androgen suppression

in men with advanced prostate cancer: a systematic review and

meta-analysis. Annals of Internal Medicine 132 566–577. (doi:10.7326/

0003-4819-132-7-200004040-00009)

Sharifi R & Browneller R 2002 Serum testosterone suppression and

potential for agonistic stimulation during chronic treatment with

monthly and 3-month depot formulations of leuprolide acetate

for advanced prostate cancer. Journal of Urology 168 1001–1004.

(doi:10.1016/S0022-5347(05)64560-0)

Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA & Greene GL

1998 The structural basis of estrogen receptor/coactivator recognition

Published by Bioscientifica Ltd.

Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access

Endocrine-RelatedCancer

Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa

21 :4 T118

and the antagonism of this interaction by tamoxifen. Cell 95 927–937.

(doi:10.1016/S0092-8674(00)81717-1)

Siegel R, Naishadham D & Jemal A 2013 Cancer statistics, 2013. CA: A

Cancer Journal for Clinicians 63 11–30. (doi:10.3322/caac.21166)

Soloway MS, Chodak G, Vogelzang NJ, Block NL, Schellhammer PF,

Smith JA Jr, Scott M, Kennealey G & Gau TC 1991 Zoladex versus

orchiectomy in treatment of advanced prostate cancer: a randomized

trial. Zoladex Prostate Study Group. Urology 37 46–51. (doi:10.1016/

0090-4295(91)80077-K)

Sternberg CN, de Bono JS, Chi KN, Fizazi K, Mulders P, Cerbone L, Hirmand M,

Forer D & Scher HI 2014 Improved outcomes in elderly patients with

metastatic castration-resistant prostate cancer treated with the androgen

receptor inhibitor enzalutamide: results from the phase III AFFIRM trial.

Annals of Oncology 25 429–434. (doi:10.1093/annonc/mdt571)

Taplin ME & Balk SP 2004 Androgen receptor: a key molecule in the

progression of prostate cancer to hormone independence. Journal of

Cellular Biochemistry 91 483–490. (doi:10.1002/jcb.10653)

Thompson IM 2001 Flare associated with LHRH-agonist therapy. Reviews

in Urology 3 (Suppl 3) S10–S14.

Thorpe SC, Azmatullah S, Fellows GJ, Gingell JC & O’Boyle PJ 1996 A

prospective, randomised study to compare goserelin acetate (Zoladex)

versus cyproterone acetate (Cyprostat) versus a combination of the

two in the treatment of metastatic prostatic carcinoma. European

Urology 29 47–54.

Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J,

Smith-Jones PM, Yoo D, Kwon A et al. 2009 Development of a

second-generation antiandrogen for treatment of advanced prostate

cancer. Science 324 787–790. (doi:10.1126/science.1168175)

Tyrrell CJ, Kaisary AV, Iversen P, Anderson JB, Baert L, Tammela T,

Chamberlain M, Webster A & Blackledge G 1998 A randomised

comparison of ’Casodex’ (bicalutamide) 150 mg monotherapy versus

castration in the treatment of metastatic and locally advanced prostate

cancer. European Urology 33 447–456. (doi:10.1159/000019634)

Van PoppelH,TombalB,de laRosette JJ, PerssonBE, JensenJK & Kold Olesen T

2008 Degarelix: a novel gonadotropin-releasing hormone (GnRH)

receptor blocker – results from a 1-yr, multicentre, randomised, phase 2

dosage-finding study in the treatment of prostate cancer. European Urology

54 805–813. (doi:10.1016/j.eururo.2008.04.065)

Vasaitis T, Belosay A, Schayowitz A, Khandelwal A, Chopra P, Gediya LK,

Guo Z, Fang HB, Njar VC & Brodie AM 2008 Androgen receptor

inactivation contributes to antitumor efficacy of 17a-hydroxyl-

ase/17,20-lyase inhibitor 3b-hydroxy-17-(1H-benzimidazole-1-yl)

http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain

androsta-5,16-diene in prostate cancer. Molecular Cancer Therapeutics 7

2348–2357. (doi:10.1158/1535-7163.MCT-08-0230)

Voet A, Helsen C, Zhang KY & Claessens F 2013 The discovery of novel

human androgen receptor antagonist chemotypes using a combined

pharmacophore screening procedure. ChemMedChem 8 644–651.

(doi:10.1002/cmdc.201200549)

Vogelzang NJ, Chodak GW, Soloway MS, Block NL, Schellhammer PF,

Smith JA Jr, Caplan RJ & Kennealey GT 1995 Goserelin versus

orchiectomy in the treatment of advanced prostate cancer: final results

of a randomized trial. Zoladex Prostate Study Group. Urology 46

220–226. (doi:10.1016/S0090-4295(99)80197-6)

Waller AS, Sharrard RM, Berthon P & Maitland NJ 2000 Androgen receptor

localisation and turnover in human prostate epithelium treated with

the antiandrogen, casodex. Journal of Molecular Endocrinology 24

339–351. (doi:10.1677/jme.0.0240339)

Wang Q, Li W, Zhang Y, Yuan X, Xu K, Yu J, Chen Z, Beroukhim R, Wang H,

Lupien M et al. 2009 Androgen receptor regulates a distinct

transcription program in androgen-independent prostate cancer. Cell

138 245–256. (doi:10.1016/j.cell.2009.04.056)

Wex J, Sidhu M, Odeyemi I, Abou-Setta AM, Retsa P & Tombal B 2013

Leuprolide acetate 1-, 3- and 6-monthly depot formulations in

androgen deprivation therapy for prostate cancer in nine European

countries: evidence review and economic evaluation. ClinicoEconomics

and Outcomes Research 5 257–269. (doi:10.2147/CEOR.S44855)

Williams SP & Sigler PB 1998 Atomic structure of progesterone complexed

with its receptor. Nature 393 392–396. (doi:10.1038/30775)

Yamaoka M, Hara T, Hitaka T, Kaku T, Takeuchi T, Takahashi J, Asahi S,

Miki H, Tasaka A & Kusaka M 2012 Orteronel (TAK-700), a novel

non-steroidal 17,20-lyase inhibitor: effects on steroid synthesis in

human and monkey adrenal cells and serum steroid levels in

cynomolgus monkeys. Journal of Steroid Biochemistry and Molecular

Biology 129 115–128. (doi:10.1016/j.jsbmb.2012.01.001)

Yamashita S, Lai KP, Chuang KL, Xu D, Miyamoto H, Tochigi T, Pang ST,

Li L, Arai Y, Kung HJ et al. 2012 ASC-J9 suppresses castration-resistant

prostate cancer growth through degradation of full-length and splice

variant androgen receptors. Neoplasia 14 74–83.

Zhang Y, Castaneda S, Dumble M, Wang M, Mileski M, Qu Z, Kim S, Shi V,

Kraft P, Gao Y et al. 2011 Reduced expression of the androgen receptor

by third generation of antisense shows antitumor activity in models of

prostate cancer. Molecular Cancer Therapeutics 10 2309–2319.

(doi:10.1158/1535-7163.MCT-11-0329)

Received in final form 21 February 2014Accepted 13 March 2014Made available online as an Accepted Preprint17 March 2014

Published by Bioscientifica Ltd.

Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access