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Androgen Receptor Targeted Treatments of Prostate Cancer:
35 Years of Progress with Antiandrogens
E. David Crawford,*,† Paul F. Schellhammer, David G. McLeod, Judd W. Moul,‡
Celestia S. Higano, Neal Shore, Louis Denis, Peter Iversen, Mario A. Eisenberger
and Fernand Labrie
From the University of Colorado-Denver (EDC), Aurora, Colorado, Eastern Virginia Medical School (PFC), Norfolk, Virginia, Center
for Prostate Disease Research, Uniformed Services University of the Health Sciences (DGM), Bethesda and Sidney Kimmel
Comprehensive Cancer Center at Johns Hopkins (MAE), Baltimore, Maryland, Duke Cancer Institute, Duke University (JWM),
Durham, North Carolina, Fred Hutchinson Cancer Research Center, University of Washington (CSH), Seattle, Washington,
Carolina Urologic Research Center (NS), Myrtle Beach, South Carolina, Europa Uomo, Oncology Centre Antwerp (LD), Antwerp,
Belgium, Copenhagen Prostate Cancer Center, University of Copenhagen (PI), Copenhagen, Denmark, and Endoceutics (FL),
Quebec City, Quebec, Canada
Purpose: Antiandrogens inhibit the androgen receptor and have an important
role in the treatment of prostate cancer. This review provides a historical
perspective on the development and clinical benefit of antiandrogens in the
treatment of prostate cancer.
Materials and Methods: We searched PubMedÒ for clinical trials with the
search terms antiandrogens and prostate cancer combined with drug names for
antiandrogens. This article represents a collaboration of clinical investigators
who have made critical scientific contributions leading to the approval of antiandrogens for treating patients with prostate cancer.
Results: Antiandrogens differ in chemical structure and exert varying efficacy
and safety profiles. The unfavorable therapeutic index of steroidal antiandrogens
led to replacement by safer nonsteroidal agents. Flutamide, nilutamide and
bicalutamide, which were designed to target the androgen receptor, were
developed primarily for use in combination with castration to provide combined
androgen blockade. Modest clinical benefits were observed with the combination
of first generation antiandrogens and castration vs castration alone. With
increased knowledge of androgen receptor structure and its biological functions a
new generation of antiandrogens without agonist activity was designed to provide more potent inhibition of the androgen receptor. Randomized clinical trials
in patients with metastatic, castration resistant prostate cancer showed significant survival benefits, which led to the approval of enzalutamide in August
2012. Apalutamide was recently approved while darolutamide is not yet
approved in the United States. These next generation antiandrogens are being
actively tested in earlier disease states such as nonmetastatic prostate cancer.
Abbreviations
and Acronyms
ADT ¼ androgen deprivation
therapy
AE ¼ adverse event
AR ¼ androgen receptor
CPA ¼ cyproterone acetate
CRPC ¼ castration resistant
prostate cancer
DHT ¼ dihydrotestosterone
FDA ¼ Food and Drug
Administration
PC ¼ prostate cancer
PSA ¼ prostate specific androgen
No direct or indirect commercial incentive associated with publishing this article.
The corresponding author certifies that, when applicable, a statement(s) has been included in the manuscript documenting institutional
review board, ethics committee or ethical review board study approval; principles of Helsinki Declaration were followed in lieu of formal ethics
committee approval; institutional animal care and use committee approval; all human subjects provided written informed consent with guarantees of confidentiality; IRB approved protocol number; animal approved project number.
Supported by Janssen Scientific Affairs (IM).
* Correspondence: Urologic Oncology, University of Colorado, Denver, Mail Stop F 710, P. O. Box 6510, Aurora, Colorado 80045 (telephone:
720-848-0195; e-mail: edc@edavidcrawford.com).
† Financial interest and/or other relationship with Tolmar, Bayer, MDx, Genomic Health, Janssen, Dendreon and Ferring.
‡ Financial interest and/or other relationship with Janssen and Pfizer.
Supplementary references 51-73 for this article can be obtained at http://jurology.com/.
0022-5347/18/2005-0001/0
THE JOURNAL OF UROLOGY®
Ó 2018 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
Dochead: Review Article
https://doi.org/10.1016/j.juro.2018.04.083
Vol. 200, 1-12, November 2018
Printed in U.S.A.
www.jurology.com
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j
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ANDROGEN RECEPTOR TARGETED TREATMENTS OF PROSTATE CANCER
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Key Words: prostatic neoplasms; androgen antagonists; neoplasm metastasis; receptors, androgen;
184
castration
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experience with the newer generation of compounds
CHANGING ANTIANDROGEN THERAPY
188
studied in various clinical disease states
STRATEGIES IN PROSTATE CANCER
189
½F1 190
(fig. 1).1,3,4,10e17
TREATMENT
191
HUGGINS and Hodges found that lowering circulating
192
androgen levels by surgical castration or estrogen
MATERIALS AND METHODS
193
therapy could palliate symptoms of advanced PC.
Ò
We searched PubMed for clinical trials of antiandrogens
194
This finding established the seminal concept that
in the treatment of PC. Search terms included prostate
195
PC is androgen sensitive.1 Especially in its early
cancer and antiandrogen combined with the drug name
196
stages PC relies on androgens for proliferation2 and
(diethylstilbestrol, cyproterone, megestrol, medrox197
partial ADT by medical or surgical castration alone
yprogesterone, flutamide, nilutamide, bicalutamide,
198
initially controls the disease, sometimes for many
enzalutamide, apalutamide [ARN-509] and darolutamide
199
years. However, eventually most PC becomes
[ODM-201]). The CYP17 inhibitors abiraterone acetate
and
ketoconazole
were
not
considered
as
the
focus
of
the
200
resistant to ADT and this PC is called CRPC. In the
current
review
was
antiandrogens.
No
time
restriction
201
early 1980s after castration significant levels of
was placed on the searches since the aim was to identify
202
androgens were shown to exist in PC cells despite a
pivotal clinical trials offering a historical perspective on
203
95% or greater decrease in serum testosterone.3,4
the development of antiandrogen therapy. Randomized
204
CRPC,5 formerly referred to as hormone recontrolled trials, observational trials and retrospective
205
fractory or androgen independent disease, is defined
analyses were considered for study inclusion if in the
206
as 2 to 3 rising serum PSA concentrations from
opinion of the authors they represented a seminal
207
nadir and/or evidence of radiographic disease procontribution to understanding the role of antiandrogen
208
gression despite castrate levels of serum testostherapy in the treatment of patients with PC or they
209
terone.
Responses
to secondary
hormonal
indicated a new avenue of research.
210
manipulation with agents such as ketoconazole or
Understanding Current Androgen Receptor
211
diethylstilbestrol suggested that the disease was
Targeted Therapy
212
still sensitive to endocrine manipulations. AccordAndrogens are critical for the development and regulation
213
ingly the term hormone refractory was replaced by
of normal prostatic morphology and functions. Androgen
214
the more biologically accurate term castration
signaling is initiated when circulating or locally made
215
resistant. Better understanding of the biology of the
androgens bind to ARs in normal or cancerous prostatic
3,18,19
216
AR and resistance mechanisms led to the recognicells.
AR is a steroid hormone receptor with ligand
217
tion that androgen signaling remains a significant
binding and DNA binding domains as well as multiple
phosphorylation sites.20 Upon ligand binding the receptor
218
driver of progression even in the presence of casdimerizes, becomes phosphorylated and is translocated
219
trate levels of testosterone in the blood.
from the cytoplasm to the nucleus. There it mediates
220
The AR was first discovered and characterized at
transcription and activation of various pathways,
221
3 laboratories in the late 1960s.6e9 In response to
including those responsible for cellular proliferation and
222
increasing understanding of the importance of the
differentiation, and the prevention of cell death (anti223
AR in driving PC antiandrogens were developed
apoptotic pathways).20
224
which would compete with endogenous androgens for
The balance between the rate of cell proliferation and
225
the ligand-binding domain of the AR. In this review
the programmed cell death of prostatic epithelial cells is
226
we describe the clinical development path of the
lost as abnormal AR signaling drives neoplastic cell pro20
227
antiandrogens from the beginning phases of the first
liferation and cell survival promotion. Mutations can
228
United States FDA drug approvals to current
generate gene fusions to bring together the promoter
Evolving knowledge of resistance mechanisms to androgen receptor targeted treatments will stimulate
research and drug discovery for additional compounds. Further testing in nonmetastatic castration resistant
prostate cancer as well as castration sensitive disease states will hopefully augment our ability to treat a
broader spectrum of patients with prostate cancer.
Conclusions: Antiandrogens have already provided important benefits for prostate cancer treatment. Greater
knowledge about the structural and functional biology of the androgen receptor in prostate cancer will
facilitate further discovery and development of further improved antiandrogens with enhanced clinical activity in patients with advanced metastatic disease. Testing these new agents earlier in the course of prostate
cancer may further improve the survival and quality of life of patients with current local and/or systemic
treatment modalities.
Dochead: Review Article
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ANDROGEN RECEPTOR TARGETED TREATMENTS OF PROSTATE CANCER
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Huggins and colleagues
demonstrate the efficacy
of androgen ablation in
patients with mPC
(Huggins and Hodges, 1941)
1940
1950
1960
Nilutamide
available
(1996)
1970
1980
1990
Flutamide shown
to compete with
testosterone for
the AR binding site
(1970s)
Discovery and
characterization
of androgen
receptor
Steroidal
antiandrogens shown
to slow neoplastic
growth
Androgen receptor
mutations recognized
as a mechanism of
antiandrogen resistance
(2013)
Bicalutamide
available
(1995)
Medical castration
first achieved with
GnRH agonist
(Labrie et al, 1980)
Huggins awarded
the Nobel Prize in
Physiology and
Medicine
(Nobel Prize, 1966)
Second-generation
antiandrogen
enzalutamide
synthesized
(2008)
Flutamide plus
GnRH agonist
superior to GnRH
alone
(Crawford et al, 1989)
First-generation
antiandrogen
flutamide
synthesized
(Neri et al, 1967)
3
2000
Apalutamide
in nmCRPC
(Smith et al, 2018)
2010
Combined androgen
blockade in
localized PC
(Labrie et al, 2002)
Combined androgen
blockade
first and second lines
(Labrie et al, 1982)
(Labrie et al, 1985)
2020
Darolutamide in
phase 1-2 mCRPC
TRIAL
(Fizazi et al, 2014)
Enzalutamide in mPC
(Tran et al, 2009)
(Scher et al, 2010)
Figure 1. Timeline of the development of antiandrogen therapy for prostate cancer shows significant events and key studies associated
with clinical development path of antiandrogens, including work by Huggins and Hodges,1 Neri et al,10 Labrie et al 1980,11 1982,4 19853
and 2002,13 and Crawford,12 Smith,16 Tran,14 Scher15 and Fizazi17 et al.
½F2
½F3
sequence of AR responsive genes and the activity of
various transcription factors which activate proliferative
and cell survival pathways. Withdrawal of androgens or
blockade of the AR results in the abrogation of AR mediated signaling and such mechanisms are thought to
explain the antineoplastic effect.
The term antiandrogen is used to describe a class of
agents which compete with the binding of circulating or
locally derived androgens to the AR (fig. 2).21e23 Antiandrogens are globally classified as steroidal or nonsteroidal (Appendix 1 and fig. 3).24 They differ in chemical
structure, pharmacological effects and safety profiles
(supplementary Appendix 1, http://jurology.com/).12,16,25e41
Steroidal antiandrogens can lower testosterone levels and
also bind to other hormone receptors. Nonsteroidal antiandrogens used as monotherapy tend to raise testosterone
levels in intact individuals and are more specific for
the AR.42,43
or diethylstilbestrol for treating advanced PC.44 Other
steroidal antiandrogens are megestrol acetate and
medroxyprogesterone acetate. Steroidal antiandrogens
have many off target effects, including loss of libido and
impotence due to lowering testosterone levels and they
have some androgenic activity.43 These undesirable side
effects led to a search for antiandrogens with more
selective activity for the AR.
Nonsteroidal. Nonsteroidal antiandrogens were developed in the late 1960s and early 1970s, and targeted only
the AR without the progestational effects of CPA.42,43 As
single agents in noncastrated men nonsteroidal
antiandrogens increase testosterone levels with the
possibility of increased libido and potency. Nonsteroidal
antiandrogens eventually proved to be safer than their
steroidal counterparts, which are seldom used now to
treat PC in the Western world (supplementary Appendix 2,
http://jurology.com/).
Antiandrogens
First Generation Nonsteroidal Antiandrogens
Steroidal. Steroidal antiandrogens preceded the development of nonsteroidal compounds to treat patients with
advanced disease (Appendix 1). CPA, the first steroidal
antiandrogen,
competitively
blocked
DHT
and
testosterone from binding to the AR. When used as
single agent, CPA was as effective as medical castration
The first generation nonsteroidal antiandrogens flutamide and nilutamide, and the second generation nonsteroidal antiandrogen bicalutamide as discussed are derived
from anilide. These compounds have similar potency and
can eventually develop agonist rather than antagonist
activity due to stimulation of the AR, causing PSA to rise.
Dochead: Review Article
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ANDROGEN RECEPTOR TARGETED TREATMENTS OF PROSTATE CANCER
Figure 2. Antiandrogen mechanism of action with focus on newer generation antiandrogens, including blockade of androgen induced
AR activation, prevention of AR nuclear translocation and inhibition of DNA binding and impeded AR mediated transcription as well as
potential resistance pathways, including AR point mutations, variants and amplification. Adapted from Nelson,21 and Siberstein22 and
Tan23 et al.
Clinically the development of agonist activity is demonstrated when PSA decreases after the antiandrogen is
discontinued, which is called the antiandrogen withdrawal phenomenon. Occasionally there is also disease
regression on imaging and yet the average duration of the
response is in the range of 3 months.45
Flutamide
Flutamide was first described in 1967 by Neri et al as a
bacteriostatic agent.42 However, subsequent animal
studies demonstrated its antiandrogenic activity.46 Flutamide has a short half-life of 6 to 8 hours, which necessitates thrice daily administration. Originally tested in
the prePSA era, flutamide was shown to be safe and was
mostly administered with medical or surgical castration.3,4,18,19,47 In fact, since medical or surgical castration
can easily eliminate testicular androgens, antiandrogens
are essentially indicated to neutralize androgens made
Dochead: Review Article
locally in the prostate, mostly from DHEA (dehydroepiandrosterone) of adrenal origin (fig. 4).48e50 This was the
first combination of drugs3,4,12,18,19 approved by health
authorities in Canada in 1984 and in 1989 in the United
States. The concept of combined androgen blockade was
based on the observation that after castration androgens
of adrenal origin could continue to stimulate PC growth
based on the mechanism of intracrinology (supplementary
Appendix 3, http://jurology.com/).
The pivotal trial of flutamide in the United States
compared daily subcutaneous administration of leuprolide
acetate with flutamide or an identical placebo (double
blinded) in men with newly diagnosed metastatic PC. The
combination of flutamide and leuprolide resulted in
improved median overall survival of 36 vs 28 months with
leuprolide alone and in 1989 led to FDA approval.12 Toxicities seen in this pivotal trial included diarrhea and
anemia25,26 but hepatotoxicity was also noted in the
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½F4
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ANDROGEN RECEPTOR TARGETED TREATMENTS OF PROSTATE CANCER
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5
Steroidal antiandrogens
Cyproterone acetate
Medroxyprogesterone acetate
Megestrol acetate
Nonsteroidal antiandrogens
First generation
Flutamide
Second generation
Nilutamide
Bicalutamide
Third generation
Enzalutamide
Apalutamide
O
F3C
NC
N
O
O
N
H
S
N
F
Darolutamide
NC
F3C
N
S
N
N
H
N
F
O
Figure 3. Molecular structures of antiandrogens, including steroidal antiandrogens cyproterone acetate, medroxyprogesterone acetate
and megestrol acetate, and nonsteroidal antiandrogens. Nomenclature of nonsteroidal antiandrogens is differentiated as first
generationdflutamide and nilutamide, second generationdbicalutamide and third generationdenzalutamide, apalutamide and
darolutamide.
½F5
post-marketing setting, necessitating the FDA mandate
that liver enzymes should be monitored.51
Analysis of all studies performed with flutamide and
nilutamide associated with castration compared with
castration plus placebo showed that overall survival was
increased by an average of 3 to 6 months (fig. 5). It should
be noted that in all clinical trials comparing combined
androgen blockade with placebo (castration only) the
antiandrogen was added at the time of progression in
the placebo group while the antiandrogen was stopped in
the antiandrogen treated group. Thus, all these studies
were of early vs late combination therapy.
intolerance in 6% to 19%.28,29 Interstitial pneumonitis
was experienced by 1% of patients53 and elevated liver
enzymes were noted in 8%.52 Other toxicities associated
with nilutamide include hot flashes, breast pain and
gynecomastia, which are also associated with low serum
androgen levels.28,52,54,55 Nilutamide, the first nonsteroidal antiandrogen used in combination with castration,
showed encouraging results, which led to the demonstration of the importance of androgens made locally in
the prostate independently of the testes.3,4
Nilutamide. Nilutamide has a half-life of approximately
2 days, which allows for once daily dosing after 2 weeks
of twice daily dosing. In human trials nilutamide
monotherapy demonstrated activity in patients with
hormone sensitive metastatic PC.28,29 The pivotal trial
comparing orchiectomy vs orchiectomy plus nilutamide
showed improved median time to death and progression,
providing the basis for the 1996 FDA approval in
combination with orchiectomy or GnRHa (gonadotropinreleasing hormone agonist).52
The most common AEs seen with nilutamide were
gastrointestinal toxicity in 65% of cases, nausea in 27%,
delayed adaptation to darkness in 27% to 33% and alcohol
Bicalutamide was synthesized in the 1980s and approved
to treat PC in the United States in 1995. Like flutamide
and nilutamide, bicalutamide selectively inhibits the AR.
The efficacy of bicalutamide is in the same range as that of
flutamide and nilutamide. Bicalutamide has a longer halflife of 7 days compared with first generation antiandrogens, which enables once daily dosing. Due to
increased testosterone and, therefore, increased estrogen
levels when used as monotherapy, bicalutamide 50 mg per
day as a single agent is associated with breast pain in 76%
of patients, gynecomastia in 60%, hot flashes in 25%,
decreased libido and impotence in 25% to 28% and suboptimal PSA responses.56
Dochead: Review Article
Second Generation Nonsteroidal Antiandrogen
Bicalutamide
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ANDROGEN RECEPTOR TARGETED TREATMENTS OF PROSTATE CANCER
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CHOLESTEROL
CYP17A1
CYP11A1
CYP17A1
17β-HSD 1
CYP17A1
17-OH-PREG
PREDNENOLONE
HYDROXYLASE
(PREG)
DHEA
5-DIOL
LYASE
17β-HSD 2, 4
3β-HSD 2
3β-HSD 2
CYP17A1
17-OH-PROG
PROGESTERONE
HYDROXYLASE
(PROG)
17β-HSD 5
CYP17A1
4-DIONE
TESTOSTERONE
(TESTO)
17β-HSD 2, 10
LYASE
aromatase
aromatase
17β-HSD 1, 7, 12
5αreductases
ALDOSTERONE
ESTRONE
(E1)
17β-HSD 2, 4, 8, 14
ESTRADIOL
(E2)
5αreductases
CORTISOL
17β-HSD 5, 15
ANDROSTANEDIONE
(5α-DIONE)
17β-HSD 2, 9, 10
DIHYDROTESTOSTERONE
(DHT)
Peripheral Tissues
Intracrinology
Adrenals
Figure 4. Human steroid biosynthesis pathways in adrenal glands and peripheral intracrine tissues. Adrenals produce DHEA, which is
converted into active androgens, including most potent natural androgen dihydrotestosterone, by prostate and peripheral tissues via
illustrated biosynthetic pathways.48e50 CYP11A1, cholesterol side-chain cleavage enzyme. CYP17A1, steroid 17a-dydroxylase/17/20
desmolase. HSD, hydroxysteroid dehydrogenase. 4-dione, androstenedione. 5-diol, androst-5-ene-3b,17b-diol. Source: Labrie.73
Due to the latter finding subsequent trials of high dose
(150 mg) single agent bicalutamide were performed and
compared with the standard of care alone (medical or
surgical castration) in men with locally advanced or
metastatic PC.30,31,57 No significant difference in survival
Favors combined
androgen blockade
Favors castration
PCTCG: nilutamide (n=1751)
*
PCTCG: flutamide (N=4803)
†
PCTCG: nilutamide + flutamide (n=6554)
*
Caubet: NSAA (n=3732)
†
Caubet: NSAA (n=1978)
†
Caubet: NSAA (n=2357)
Klotz: NSAA (n=5015)
*
Debruyne: niludamide (n=1191)
*
Bennett: flutamide (n=4128)
*
0.5
1.0
HR and 95% confidence limits
2.0
Figure 5. Meta-analysis comparing combined androgen
blockade with medical or surgical castration. Combined
androgen blockade consisted of medical (GnRH agonist) or
surgical castration vs castration alone as first treatment.
Antiandrogen was usually added to castration at time of
progression. PCTCG, Prostate Cancer Trialists Collaborative
Group. NSAA, nonsteroidal antiandrogen. Caubet: NSAA
(3732), Caubet: NSAA (1978) and Caubet: NSAA (2357), Caubet
JF: Urology 1997; 49: 71. Debruyne: nilutamide, Debruyne FM:
Eur Urol, suppl, 1996; 30: 264. Bennett: flutamide, Bennett CL:
Prostate Cancer Prostatic Dis 1999; 2: 4. Asterisk indicates
2p <0.05. Dagger indicates 2p <0.01. Source: Labrie,73 adapted
from Klotz.72
Dochead: Review Article
could be found in men with locally advanced PC, although
the criteria for equivalence were not met.30 In addition,
the higher dose of single agent bicalutamide resulted in
significant gynecomastia and breast pain. Like the first
generation antiandrogens, bicalutamide was associated
with liver and gastrointestinal toxicity.
Bicalutamide 150 mg was also studied as an adjuvant
to standard therapy (watchful waiting, radiotherapy and
radical prostatectomy) in 3 large, industry sponsored
global trials called the EPC (Early Prostate Cancer) trial
program.32,58 Combined analysis of these trials revealed
that bicalutamide was associated with improved survival
in men with early nonmetastatic PC who were receiving
primary radiation.58 In men with localized PC (T1-2, M0)
assigned to watchful waiting the addition of bicalutamide
resulted in poorer survival,58 which may have been
attributable to cardiovascular events.59 Based on the EPC
trials the indication for bicalutamide 150 mg monotherapy as a treatment option for localized PC was withdrawn in a number of countries. In a large trial of
adjuvant bicalutamide with salvage postoperative radiation therapy higher rates of long-term overall survival
were observed compared with those of radiation therapy
alone.60
The classically available antiandrogens flutamide,
bicalutamide and nilutamide exert pure AR antagonistic
activity and have shown major benefits in PC therapy.3,12,52,61 However, the affinity of these compounds for
the AR is relatively low,62e64 leaving an estimated 5% to
10% of DHT free to continue to stimulate the AR and
prostate cancer growth.65 Thus, there is a need to
discover and develop novel antiandrogens with higher
affinity for the AR to take optimal advantage of the well
demonstrated high responsiveness of PC to androgen
blockade.
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Third Generation Antiandrogens
Enzalutamide. Enzalutamide is a selective antagonist of
the AR which inhibits AR translocation to the cell nucleus, recruitment of AR cofactors and AR binding to
DNA. As previously reported enzalutamide was developed
using the nonsteroidal agonist RU59063 as a starting
chemical scaffold based on its high affinity and selectivity
for the AR as opposed to other nuclear hormone receptors.14,66 Enzalutamide has fivefold to eightfold higher
binding affinity for the AR compared with bicalutamide.
The half-life of enzalutamide is 6 days and like the first
and second generation antiandrogens enzalutamide
crosses the blood-brain barrier.67
Clinical trials of enzalutamide confirmed its efficacy in
the treatment of patients with metastatic CRPC. Pivotal
phase 3 trials, including the PREVAIL Study (ClinicalTrials.gov NCT03260517) in the metastatic CRPC predocetaxel setting and the AFFIRM (Safety and Efficacy
Study of MDV3100 in Patients With Castration-Resistant
Prostate Cancer Who Have Been Previously Treated With
Docetaxel-based
Chemotherapy,
ClinicalTrials.gov
NCT00974311) trial in the post-docetaxel setting of metastatic CRPC demonstrated that adding enzalutamide to
castration was superior to adding placebo to castration in
terms of overall survival.36,37 The AFFIRM study included
1,199 men with CRPC who had previously received
chemotherapy and were randomized to enzalutamide 160
mg daily or placebo. Median overall survival was 18.4
months in those treated with enzalutamide vs 13.6
months in the placebo group (HR 0.63, 95% CI 0.53e0.75,
p <0.001).37 The study was stopped at the time of the
planned interim analysis after 520 deaths had occurred.
The prechemotherapy PREVAIL Study was also terminated early when a planned interim analysis was done
after 540 deaths were reported.36 Significant survival and
progression-free survival benefits were observed in patients treated with enzalutamide 160 mg daily vs placebo.
The risk of disease progression was reduced by 81% (HR
0.19, 95% CI 0.15e0.23) and the risk of death was reduced
by 29% (HR 0.71, 95% CI 0.60e0.80, each p <0.001).
In the randomized phase 2 TERRAIN (A Study of
Enzalutamide Versus Bicalutamide in Castrate Men with
Metastatic
Prostate
Cancer,
ClinicalTrials.gov
NCT01288911) study enzalutamide demonstrated greater
activity than bicalutamide 50 mg daily in patients with
asymptomatic or mildly symptomatic metastatic CRPC.33
The primary end point of radiographic progression-free
survival was 15.7 months for enzalutamide compared
with 5.8 months for bicalutamide (HR 0.44, 95% CI
11.5e19.4, p <0.0001). Other end points showed
improvement, including PSA progression, the PSA
response, the objective tumor response and quality of life.
The AEs more frequently reported with enzalutamide
included fatigue, back pain, hot flush and hypertension
whereas nausea, constipation and arthralgia were more
common with bicalutamide.
STRIVE (Safety and Efficacy Study of Enzalutamide
versus Bicalutamide in Men with Prostate Cancer, ClinicalTrials.gov NCT01664923) is another randomized,
phase 2 study of patients with asymptomatic or mildly
symptomatic metastatic CRPC and nonmetastatic
CRPC.34 In that study progression-free survival was also
Dochead: Review Article
7
improved by enzalutamide compared with bicalutamide
(19.4 vs 5.7 months, HR 0.24, 95% CI 0.18e0.32,
p <0.001).34 The more frequently reported AEs of enzalutamide similarly included fatigue, back pain and hot
flushes. Constipation, diarrhea, anemia and urinary tract
infection were more frequent with bicalutamide.
Most recently promising enzalutamide monotherapy
activity has been reported in patients with hormone na€ıve
PC in a phase 2 trial.68 The global, phase 3 EMBARK
(Safety and Efficacy Study of Enzalutamide Plus Leuprolide in Patients with Nonmetastatic Prostate Cancer,
ClinicalTrials.gov NCT02319837) trial comparing leuprolide plus enzalutamide, leuprolide plus placebo and
enzalutamide monotherapy in men with biochemical
relapse who are at high risk for metastatic disease is
currently recruiting. In the PROSPER (Safety and Efficacy Study of Enzalutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer) study of
patients with nonmetastatic CRPC metastasis-free survival was significantly prolonged with enzalutamide vs
placebo (36.6 vs 14.7 months, HR 0.29, 95% CI 0.24e0.35,
p <0.0001).35
The most common AE associated with enzalutamide is
fatigue. Other AEs include hypertension, falls and seizures. In the recently published UPWARD (A Study to
Evaluate the Potential Increased Risk of Seizures among
Metastatic Castration-Resistant Prostate Cancer Patients
Treated
with
Enzalutamide,
ClinicalTrials.gov
NCT01977651) trial of men with at least 1 risk factor for
seizure the seizure rate was 1.1% during the first 4
months of therapy, indicating that enzalutamide could be
safely administered in that population.69 A rare but
related toxicity is posterior reversible encephalopathy
syndrome, which manifests clinically as headache, altered
mental status, seizures and loss of vision, and is diagnosed by magnetic resonance imaging. In such cases
enzalutamide should be permanently discontinued.
Apalutamide. Apalutamide (ARN-509) emerged from the
same medicinal chemistry laboratory as enzalutamide,
where more potent antiandrogens with no significant
agonistic activity were sought.66 Apalutamide had similar
in vitro activity but greater in vivo activity in xenograft
models compared with enzalutamide.14
In a first in human, phase 1 study of 30 patients with
progressing CRPC treated with apalutamide 46.7%
experienced a 50% or greater decline from baseline in
PSA.39 Fatigue was the most frequently reported AE,
noted by 47% of patients. The dose limiting toxicity was a
single case of grade 3 abdominal pain.39 The results of a
subsequent phase 2 study of apalutamide in patients with
CRPC showed that 89% with nonmetastatic disease had a
50% or greater decrease from baseline in PSA with a
median time to PSA progression of 24 months.40 In 46
patients with metastatic CRPC the 12-week PSA response
rate was 88% in those na€ıve to abiraterone acetate plus
prednisone and 22% in previously treated patients while
median time to PSA progression was 18.2 and 3.7 months,
respectively.38 The most common AE was fatigue (mainly
grade 1 or 2) and the only grade 3 AEs reported in more
than 1 patient receiving apalutamide were anemia and
back pain in 2 patients each.
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ACIS (NCT02257736) – Apalutamide
ARASENS (NCT02799602) – Darolutamide
PEACE III (NCT02194842) – Enzalutamide
m1CSPC
Localized
disease
BCR
mCRPC
nmCRPC
ATLAS (NCT02531516) –
Apalutamide
EMBARK
(NCT02319837) –
Enzalutamide
TITAN (NCT02489318) – Apalutamide
ARASENS (NCT02799602) – Darolutamide
ARCHES (NCT02677896) – Enzalutamide
ARAMIS (NCT02200614) – Darolutamide
Figure 6. Ongoing phase 3 trials with third generation antiandrogens according to disease state. Study of third generation
antiandrogens is now moving in direction of hormone na€ıve patients at earlier disease stages. BCR, biochemical recurrence.
nmCRPC, nonmetastatic CRPC.
Based on the activity and favorable toxicity profile of
apalutamide in these studies38e40 the pivotal phase 3
SPARTAN (Study of Apalutamide [ARN-509] in Men With
Non-Metastatic Castration-Resistant Prostate Cancer,
ClinicalTrials.gov NCT01946204) trial of nonmetastatic
CRPC was performed.16 Those data showed significantly
longer metastasis-free survival for apalutamide than for
placebo (40.5 vs 16.2 months, HR 0.28, 95% CI 0.23e0.35,
p <0.0001).
ARAMIS (Efficacy and Safety Study of Darolutamide
[ODM-201] in Men With High-risk Nonmetastatic
Castration-resistant Prostate Cancer, ClinicalTrials.gov
NCT02200614) trial in nonmetastatic CRPC cases.
There are numerous ongoing trials of the third generation antiandrogens in early stages of PC (supplementary
Appendix 1, http://jurology.com/).12,16,25e41
Darolutamide. Another third generation antiandrogen,
ODM-201 or darolutamide, is structurally distinct from
enzalutamide and apalutamide. Unlike enzalutamide,
darolutamide has low penetration of the blood-brain
barrier and it is undetectable in the brain 8 hours after
a dose.70 This difference may translate into a lower risk
of the central nervous system related events seen with
enzalutamide. Other significant differences are that
as a single agent darolutamide does not increase
testosterone levels in mice and it binds to mutated AR,
including the F876L mutation which confers resistance
to enzalutamide and apalutamide.71
In an open label, phase 1 study of chemotherapy na€ıve
patients with metastatic CRPC darolutamide 600 mg
twice daily demonstrated tumor responses with no central
nervous system side effects.41 Of 30 patients 25 (83%) had
a 50% or greater reduction in PSA from baseline at week
12 and 9 of 30 (30%) had a 90% or greater decline in PSA
from baseline. Median time to PSA progression was 54
weeks (95% CI 23-not reached). Darolutamide was well
tolerated and most AEs were grade 1 or 2. The most
common AEs were fatigue, which was grade 1 in all 4
cases (13%), and nausea, which was grades 1 to 3 in 4
(13%). Importantly no seizures have been reported to
date. Darolutamide is being studied in the phase 3
FUTURE THERAPEUTIC OPTIONS
Dochead: Review Article
Despite the progress to date in the discovery of
newer and more effective antiandrogens to treat PC
eventually clinical evidence of resistance to this
treatment develops in virtually all patients with
advanced disease. This observation possibly results
from starting treatment at too advanced a stage of
disease. In the last decade we have gained better
understanding of the mechanisms involved in
intracrine and paracrine androgen production, and
in the appreciation that AR signaling remains
active and continues to drive the growth of PC
following the androgen depletion used to date for
advanced disease.
Further demonstrations of the mechanisms of AR
resistance have led to new approaches to drug
development. For example, AR over expression was
established as a principal driver of CRPC and a
drug screen of antiandrogens that could retain activity even when AR was over expressed led to the
discovery of enzalutamide. Several AR dependent
mechanisms are recognized as drivers of CRPC,
including AR over expression with or without
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However, the evolving, previously summarized in971
formation illustrates that the development of these
972
compounds is now moving in the direction of hor973
mone na€ıve patients at earlier stages of disease
(Appendix 2 and fig. 6). Currently use of the newer, ½F6974
975
third generation antiandrogen darolutamide re976
mains investigational and efforts should be made to
977
enroll patients in clinical trials.
978
979
980
CONCLUSIONS
981
The evolution of antiandrogens from agents with
982
minimal or no clinical benefit to those that result in
983
significantly prolonged survival demonstrates the
984
power of rational drug development based on
985
improved understanding of the underlying biology
986
of androgen regulated growth and the mechanisms
987
of resistance to AR inhibition. It remains to be
988
determined whether using more potent inhibition of
989
the AR axis alone or combined with other drugs can
990
cure prostate cancer when applied earlier in the
991
course of disease.
992
993
ONGOING ANTIANDROGEN PHASE 3 TRIALS
ACKNOWLEDGMENTS
994
Most antiandrogen data are on patients with metDr. Ira Mills, PAREXELÒ, Waltham, Massachu995
astatic and primarily castration resistant disease.
setts, assisted with writing.
996
997
998
APPENDIX 1
999
Generations of antiandrogen treatments
1000
1001
FDA Approval
First Synthesized/
for Use in
1002
Agent
Discovered
Prostate Cancer
Mechanism of Action
1003
1004
Steroidal antiandrogens
1005
Cyproterone acetate
First patent filing in 1962
No
Full antagonist of androgen receptor, also has progesterone-like effects and is able to
activate progesterone receptor
1006
Medroxyprogesterone
1958
No
Agonist of androgen receptor
1007
acetate
1008
Megestrol acetate
1959 (synthesized from
No
High affinity antagonist/weak partial agonist of androgen receptor, binds with similar
medroxyprogesterone
affinity to progesterone receptor
1009
acetate)
1010
Nonsteroidal antiandrogens
1011
1012
First generation:
1013
Flutamide
1967
1989
Selective, competitive antagonist of androgen receptor, binds to androgen receptor
1014
and inhibits nuclear translocation
1015
Nilutamide
1980s
1996
Selective competitive antagonist of androgen receptor, affinity for androgen receptor
similar to that of flutamide
1016
Second generation
1980s
1995
Selective competitive antagonist of androgen receptor, fourfold greater affinity for
1017
(bicalutamide)
androgen receptor vs flutamide and fivefold higher affinity vs nilutamide
1018
Third generation:
1019
1020
Enzalutamide
2008
2012
Inhibitor of androgen receptor translocation to cell nucleus, recruitment of androgen
receptor cofactors and androgen receptor binding to DNA, selective antagonist of
1021
androgen receptor, fivefold to eightfold higher binding affinity for androgen
1022
receptor vs bicalutamide
1023
Apalutamide
2007
2018
Selective competitive androgen receptor inhibitor; fivefold to tenfold greater binding
affinity for androgen receptor vs bicalutamide
1024
Darolutamide
2009
Not yet submitted
Selective antagonist of androgen receptor, higher affinity for androgen receptor vs
1025
enzalutamide and apalutamide
1026
amplification, AR mutations, AR variants, intratumor production of testosterone and DHT, over
expression of the glucocorticoid receptor and AR
loss. Drugs that target these resistance mechanisms
are in development. However, administering these
agents earlier in the disease process seems likely to
yield improved results.
Drug resistance through AR independent pathways in response to enzalutamide has included the
acquisition of neuroendocrine characteristics which
may lead to highly aggressive and lethal tumors.72
Therapeutic modalities with novel combinatorial
agents along with antiandrogens could lead to
improved outcomes in the treatment of patients
with distinct resistance pathways. Additionally,
specific approaches to target biological pathway
might offer advantages. One such potential
pathway is noncanonical activation of the Hedgehog
oncogenic signaling pathway by the interaction of
transcriptionally active AR proteins with Gli3,
leading to prostate cancer cell growth and
progression.72
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1076
1077
1078
1079
1080
1081
1082
1083
APPENDIX 2
Clinical profile of nonsteroidal antiandrogens studied to date for prostate cancer treatment
Agent
Patient Population
Efficacy Profile
Key Toxicities
1st Generation
Flutamide
Nilutamide
Newly diagnosed, previously
untreated metastatic hormone
sensitive prostate cancer
Advanced metastatic, hormone
sensitive prostate cancer
Stage D, previously untreated
prostate cancer
Improved median overall survival when added to leuprolide vs leuprolide alone12
Diarrhea, hepatotoxicity,
including fatal12,25,26
Improved survival when combined with surgical castration27
Nausea, dark light
accommodation,
alcohol intolerance,
hepatotoxicity28,29
Moderate activity as monotherapy:
Partial response rate 41.6%28
Median progression-free survival 9 months and overall survival 23 months29
2nd Generation
Bicalutamide
Locally advanced and metastatic
prostate cancer
Nonmetastatic prostate cancer
No survival benefit compared with castration, statistically significant benefit for
bicalutamide for quality of life measures including sexual interest30
Less effective than castration in patients with metastatic disease, statistically
significant improvement in subjective response rate (70%) vs castration (58%)31
EPC (Early Prostate Cancer) trial overall no survival benefit of bicalutamide compared
with placebo. However, bicalutamide improved overall survival significantly in
patients with locally advanced disease undergoing radiotherapy. In watchful waiting
patients with localized disease there was survival trend in favor of placebo (p ¼
0.054)32
Gastrointestinal and
hepatoxicity30,31
Third generation
Enzalutamide
Metastatic prostate cancer
Nonmetastatic castration resistant
prostate cancer
Apalutamide
Metastatic castration resistant
prostate cancer
Nonmetastatic castration resistant
prostate cancer
Darolutamide
Chemotherapy na€ıve metastatic
castration resistant prostate
cancer
37% Reduction in risk of death (p <0.001)37 (post-chemotherapy)
81% Reduction in risk of radiographic progression and 29% reduction in risk of death vs
placebo (each outcome p <0.001)36 (prechemotherapy)
Significantly improved progression-free survival vs bicalutamide (15.7 vs 5.8 months,
p <0.0001)33
76% Reduction in risk of progression or death vs bicalutamide (p <0.001)34
Phase 3 study showing significantly prolonged median metastasis-free survival vs
placebo (36.6 vs 14.7 months, HR 0.29, 95% CI 0.24e0.35,
p <0.0001)35
Phase 1 study in 30 patients, 46.7% of patients with 50% or greater reduction from
baseline in prostate specific antigen at 12 weeks39
Phase 2 study 12-week prostate specific antigen response rate 88% in patients
previously treated with abiraterone acetate and 22% in those previously untreated38
Phase 2 study in 51 patients with 89% prostate specific antigen response rate at 12
weeks40
Phase 3 study showing significantly longer metastasis-free survival (40.5 vs 16.2
months, HR 0.28, 95% CI 0.23e0.35, p <0.0001)16
Prostate specific antigen and tumor responses 83% prostate specific antigen response
rate at 12 weeks and median 66 weeks to radiographic tumor progression41
Fatigue, hypertension
and anemia36,37
Seizures36,37
Fatigue, anemia and
gastrointestinal
disturbance38e40
Fatigue and nausea41
APPENDIX 3
Ongoing phase 3 clinical trials of antiandrogen therapy
Study (ClinicalTrials.gov
identifier)
Apalutamide:
ATLAS (NCT02531516)
ACIS (NCT02257736)
TITAN (NCT02489318)
Darolutamide:
ARAMIS (NCT02200614)
Target Population
Primary Efficacy
Survival Outcome
High risk prostate cancer
receiving primary
radiation therapy
Chemotherapy na€ıve
metastatic castration
resistant prostate cancer
Metastatic hormone
sensitive prostate cancer
Metastasis-free
High risk nonmetastatic
castration resistant
prostate cancer
Primary
Completion
Date
Comparator Arms
Apalutamide plus luteinizing hormone-releasing hormone analog
vs luteinizing hormone-releasing hormone analog plus
bicalutamide (cycles 1-4)
Apalutamide and abiraterone acetate plus prednisone vs
abiraterone acetate plus prednisone
12/2022
Radiographic
progression-free and
overall
Apalutamide plus luteinizing hormone-releasing hormone analog
vs luteinizing hormone-releasing hormone analog
11/2020
Metastasis-free
Darolutamide vs placebo
Radiographic
progression-free
12/2018
4/2018
(Continued on next page)
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11
Continued
Study (ClinicalTrials.gov
identifier)
ARASENS
(NCT02799602)
Enzalutamide:
EMBARK (NCT02319837)
ARCHES (NCT02677896)
PEACE III (NCT02194842)
Target Population
Primary Efficacy
Survival Outcome
Comparator Arms
Primary
Completion
Date
Metastatic hormone
sensitive cancer
Overall
Darolutamide and androgen deprivation therapy and docetaxel vs
androgen deprivation therapy and docetaxel
8/2022
Nonmetastatic cancer with
biochemical recurrence
Metastasis-free
3/2021
Metastatic hormone
sensitive cancer
Asymptomatic or mildly
symptomatic metastatic
castration resistant
prostate cancer (bone)
Radiographic
progression-free
Radiographic
progression-free
Enzalutamide plus luteinizing hormone-releasing hormone analog
vs enzalutamide vs luteinizing hormone-releasing hormone
analog
Enzalutamide and androgen deprivation therapy vs androgen
deprivation therapy
Enzalutamide and 223Ra vs enzalutamide
4/2020
11/2019
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