Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC)

Abstract

Recently, the standard of care for metastatic Castration Resistant Prostate Cancer (mCRPC) has changed considerably. Persistent androgen receptor (AR) signaling has been identified as a target for novel therapies and reengages the fact that AR continues to be the primary target responsible for metastatic prostate cancer. Androgen receptor gene amplification and over expression have been found to result in a higher concentration of androgen receptors on tumor cells, making them extremely sensitive to low levels of circulating androgens. Additionally, prostate cancer cells are able to maintain dihydrotestosterone (DHT) concentration in excess of serum concentrations to support tumor growth. For many years ketoconazole was the only CYP17 inhibitor that was used to treat mCRPC. However, significant toxicities limit its use. Newly approved chemotherapeutic agents such as Abiraterone (an oral selective inhibitor of CYP17A), which blocks androgen biosynthesis both within and outside the prostate cancer cells), and enzalutamide (blocks AR signaling) have improved overall survival. There are also ongoing phase III trials for Orteronel (TAK- 700), ARN- 509 and Galeterone (TOK-001), which targets androgen signaling. In this review, we will present the rationale for the newly approved hormonal treatments, their indications and complications, and we will discuss ongoing trials that are being done to improve the efficacy of the approved agents. Finally, we will talk about the potential upcoming hormonal treatments for mCRPC.

Full text

R E V I E W Open Access
Changing paradigms in management of metastatic
Castration Resistant Prostate Cancer (mCRPC)
Eva Gupta
1*
, Troy Guthrie
2
and Winston Tan
1
Abstract
Recently, the standard of care for metastatic Castration Resistant Prostate Cancer (mCRPC) has changed
considerably. Persistent androgen receptor (AR) signaling has been identified as a target for novel therapies and
reengages the fact that AR continues to be the primary target responsible for metastatic prostate cancer. Androgen
receptor gene amplification and over expression have been found to result in a higher concentration of androgen
receptors on tumor cells, making them extremely sensitive to low levels of circulating androgens. Additionally,
prostate cancer cells are able to maintain dihydrotestosterone (DHT) concentration in excess of serum concentrations
to support tumor growth. For many years ketoconazole was the only CYP17 inhibitor that was used to treat mCRPC.
However, significant toxicities limit its use. Newly approved chemotherapeutic agents such as Abiraterone (an oral
selective inhibitor of CYP17A), which blocks androgen biosynthesis both within and outside the prostate cancer cells),
and enzalutamide (blocks AR signaling) have improved overall survival. There are also ongoing phase III trials for
Orteronel (TAK- 700), ARN- 509 and Galeterone (TOK-001), which targets androgen signaling. In this review, we will
present the rationale for the newly approved hormonal treatments, their indications and complications, and we will
discuss ongoing trials that are being done to improve the efficacy of the approved agents. Finally, we will talk about
the potential upcoming hormonal treatments for mCRPC.
Keywords: Castration resistant prostate cancer, CYP17 inhibition, Androgen deprivation therapy, Abiraterone,
Enzalutamide, Ketoconazole, Orteronel, ARN-509, Galeterone (TOK-001)
Introduction
Prostate cancer is the most common cancer affecting men
and represents the second leading cause of cancer related
mortality in the western world [1]. In 1941, Huggins and
Hodges et al. [2], demonstrated that androgen withdrawal
led to regression of prostate cancer and alleviation of pain
in these patients. This demonstrated the androgen de-
pendence of normal prostate and prostate cancer cells for
growth and survival.
The initial standard of care in many high-risk patients
includes androgen deprivation therapy (ADT) [3,4] and
radiation therapy. ADT can be achieved by either medical
or surgical castration (bilateral orchidectomy) [5]. Castra-
tion reduces the serum testosterone to very low levels,
which is known as the castration level. Until recently, me-
dical castration was achieved by Gonadotropin-releasing
hormone (GnRH) agonists. GnRH agonists inhibit the
pituitary release of luteinizing hormone, which is ne-
cessary for testicular androgen production. Degarelix is a
GnRH antagonist, which lowers androgen levels but cau-
ses an unacceptably high rate (40%) of local injection site
reactions and has not found much favor in clinical prac-
tice. Anti-androgens, such as flutamide and bicalutamide,
can block the interaction of testosterone and DHT with
its receptor. Combination GnRH agonists and androgen
blockers has been called total androgen blockade (TAB)
and was popular in the 1990’s to treat metastatic prostate
cancer. Despite total androgen blockade, prostate cancer
is known to progress in 18 to 48 months and is referred to
as castration resistant prostate cancer (CRPC). CRPC is
characterized by elevated levels of prostate specific antigen
PSA despite low levels of testosterone. Prostate cancer
deaths are typically the result of metastatic castrate resist-
ant prostate cancer (mCRPC), and historically, the median
survival for men with mCRPC has been less than 2 years
[6]. Randomized studies with TAB have failed to demon-
strate improvement in overall survival (OS) [7]. This is
* Correspondence: gupta.eva@mayo.edu
1
Mayo Clinic, 4500 San Pablo Rd S, Jacksonville 32224, FL, USA
Full list of author information is available at the end of the article
© 2014 Gupta et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.
Gupta et al. BMC Urology 2014, 14:55
http://www.biomedcentral.com/1471-2490/14/55

thought to occur due to multiple escape mechanisms that
fuel tumor growth [8]. Previously this was thought to be a
hormone refractory state, but recently it has been recog-
nized that androgen receptor expression is never lost. In
the castration resistant state, androgen receptor gene am-
plification [9,10], alterations in expression of coactivators,
and androgen receptor gene over expression have been
found to result in higher concentrations of androgen re-
ceptors on tumor cells, making them extremely sensitive
to low levels of circulating androgens. Prostate cancer cells
have also been found to be able to maintain dihydrotestos-
terone (DHT) concentrations in excess of serum concen-
trations to support growth and proliferation [11]. They
may also synthesize DHT de-novo [12] or convert adrenal
steroids to DHT, which has five fold greater affinity than
testosterone for the androgen receptor. In addition, select-
ive mutations in the androgen receptor when exposed to
anti-androgens may be responsible for resistance. Meta-
static CRPC is an invariably fatal disease. Chemother-
apy including docetaxel [13] as first-line, cabazitaxel
as second-line, and active cellular immunotherapy with
sipuleucel-T [14] has also not been found to produce a
major survival improvement in mCRPC.
Focus has now shifted to the inhibitors of steroid bio-
synthesis [15]. CYP17 is a cytochrome P450 enzyme [16]
that catalyzes two key reactions involved in the production
of sex steroids (Figure 1). The 17α-hydroxylase activity
converts pregnenolone to 17α-hydroxypregnenolone,
which is a major precursor of metabolism into miner-
alocorticoids, glucocorticoids and androgens Treatment
with ketoconazole, which inhibits 17α-hydroxylase, leads
to suppression of glucocorticoid and mineralocorticoid
production and causes a secondary increase in pituitary
ACTH. In addition to suppression of androgens, it has
been shown to slow tumor activity. Ketoconazole is a
non-steroidal imidazole anti-fungal agent with CYP17 in-
hibition that has been used off-label as second-line hor-
monal therapy for prostate cancer since the 1980s [17-20].
It is an inhibitor of testicular and adrenal androgen syn-
thesis, and high doses have typically been used to suppress
tumor activity. High dose ketoconazole (HDK) has been
has shown to have PSA response, but no survival benefit
has been shown [21]. It is also associated with potential
and significant adverse events, including fatal hepatic dys-
function, adrenal insufficiency (bone fragility, hypotension,
and hyperkalemia), nausea and vomiting, gynecomastia,
QT prolongation, and potentially fatal drug interactions.
In a trial to evaluate the efficacy of ketoconazole along
with simultaneous anti-androgen withdrawal (AAWD) in
20 patients with CRPC, Small et al. found 55% had a grea-
ter than 50% fall in prostatic specific antigen (PSA) [22].
In another study of 50 patient [23], Small et al. demon-
strated that patients who have progressive disease despite
anti-androgen withdrawal also benefit from subsequent
Figure 1 Pathways of steroid synthesis. A. Pathways of steroid synthesis in the adrenal gland. B. Pathways of steroid synthesis in leydig cells
of testis.
Gupta et al. BMC Urology 2014, 14:55 Page 2 of 8
http://www.biomedcentral.com/1471-2490/14/55

ketoconazole therapy. In a larger phase III study of HDK
therapy [24] the authors randomized 260 patients to
AAWD alone (n = 132), or together with oral Ketocona-
zole (400 mg tid) and hydrocortisone (30 mg by mouth
each morning, 10 mg by mouth. each evening; n = 128).
PSA response (27% vs. 11%) and objective response (20%
vs. 2%) were significantly more in the ketoconazole group
compared to AAWD alone, although there was no differ-
ence in survival. Androgen levels have been shown to de-
cline with Ketoconazole therapy, but the levels then climb
at the time of progression. Progressive disease while on
Ketoconazole has been postulated due to an escape from
HDK induced androgen suppression, and it highlights the
need for more effective agents.
In addition to blocking CYP17 activity, ketoconazole
also inhibits other important metabolizing enzymes, such
as CYP3A and CYP24A1, suggesting that concomitant ke-
toconazole administration may alter drug exposure or
pharmacokinetic variability. This necessitates careful mo-
nitoring of adverse events and drug interactions. The re-
sponses observed after treatment with ketoconazole lead
to the investigation of stronger and more selective CYP 17
inhibitors with a more favorable toxicity profile than keto-
conazole [25].
The last several years, has seen new drug development
on the rational of targeted approaches based on a better
understanding of the disease process. These have created
a changing paradigm in the hormonal treatment of ad-
vanced prostate cancer.
Review
New approved hormonal treatments
Recently two new hormonal therapy agents have been ap-
proved by the US Food and Drug Administration (FDA)
for the treatment of patients with mCRPC: Abiraterone
acetate (Zytiga) [26] and enzalutamide previously known
as MDV3100 (now called Xtandi) [27].
Abiraterone (Zytiga) is an oral, selective and potent
irreversible inhibitor of CYP17A, which is an enzyme
that catalyzes both 17 alpha-hydroxylase and 17, 20-
lyase reactions. It blocks androgen biosynthesis both
within and outside of the prostate gland. It was first
found to be efficacious in Phase I-II studies [28] of
castrate-resistant prostate cancer. It was also tested in
the treatment of patients with CRPC, who are either
chemotherapy naive or have received prior therapy with
docetaxel [29,30]. Abiraterone decreases the production
of androgens by the adrenals, prostate, and also within
the tumor cells. Evidence from phase I and phase II stu-
dies [31,32] demonstrated that Abiraterone suppresses
the serum androgen levels and achieves PSA and clinical
responses in chemotherapy naïve and docetaxel pre-
treated patients with mCRPC. Phase II and III studies
have used a 1000 mg/day dose, although the maximum
tolerated dose was 2000mg/day. Abiraterone was gener-
ally well tolerated. Hypokalemia (88%), hypertension
(40%) and fluid overload (13%) were the most common
adverse events noted.
A large randomized controlled phase III trial of 1195
patients (COU-AA-301) [33] comparing Abiraterone-
prednisone vs. placebo-prednisone had to be terminated
early (median survival 12.8 months) when the study met
planned primary outcomes at the time of interim ana-
lysis. Patients with prior ketoconazole treatment for
prostate cancer and a history of adrenal gland or pituitary
disorders were excluded in this trial. The OS rate favored
abiraterone (14.8 months vs. 10.9 months). Secondary end
points, including time to PSA progression (10.2 vs. 6.6
months; P < 0.001), progression-free survival (5.6 months
vs. 3.6 months; P < 0.001), pain palliation (44% vs. 2%),
and PSA response rate (29% vs. 6%, P < 0.001) favored
the treatment group. Mineralocorticoid-related adverse
events, including fluid retention (31% vs. 22% placebo;
P < 0.001) and hypokalemia (17% vs. 8% placebo), were
more frequently reported in the Abiraterone acetate–
prednisone group than in the placebo–prednisone group.
There was a non-significant increase in grade 1–2cardiac
events in the treatment group (13% vs. 11% placebo).
Seventy percent of patients in this trial had received
one prior chemotherapy regimen, and 30% had been
treated with two prior chemotherapeutic regimens. Ab-
iraterone acetate is now considered standard of care for
patients following chemotherapy. This study led to the
approval of Abiraterone acetate for docetaxel pretreated
CRPC in April 2011.
In December 2012, Abiraterone in combination with
prednisone received FDA approval for treatment of
mCRPC in chemotherapy naïve patients as well. In a
phase III randomized controlled trial (COU-AA-302)
[34], 1088 patients with mCRPC who had not received
chemotherapy were assigned either to abiraterone and
prednisone (N = 546) or placebo plus prednisone (N =
542). The primary endpoints were radiographic progres-
sion free survival (rPFS) and overall survival (OS). The
study was unblinded after a planned interim analysis,
which was performed after 43% of the expected deaths
had occurred. Abiraterone improved rPFS (16.5 months
vs. 8.3 months, HR 0.53; 95% CI 0.45-0.62; P < 0.001). It
also showed a trend towards improved OS (median not
reached, vs. 27.2 months for prednisone alone; HR 0.75;
95% CI, 0.61 to 0.93; P = 0.01). Abiraterone–prednisone
showed superiority over prednisone alone with respect
to time to initiation of cytotoxic chemotherapy (25.2
vs. 16.8 months, p-value <0.001) opiate use for cancer-
related pain (not reached vs. 23.7 months, p-value <0.001),
prostate-specific antigen progression (11.1 vs. 5.6 months,
p-value <0.001), and decline in performance status (12.3
vs. 10.9 months, p-value 0.005).
Gupta et al. BMC Urology 2014, 14:55 Page 3 of 8
http://www.biomedcentral.com/1471-2490/14/55

Toxicity profile- the main adverse events of Abiraterone
are related to excess mineralocorticoid, which includes
fluid retention (33%) and hypokalemia (18%). This is due
to the inhibition of 17 alpha hydroxylase, which causes a
compensatory rise in ACTH. Abiraterone should be
administered with prednisone daily and monthly po-
tassium and blood pressure monitoring is essential
during treatment. While co-administration of prednis-
one is manageable, long term use in earlier disease
phases could be problematic due to the potential adverse
events. These include diabetes, weight gain, Cushing
syndrome and osteoporosis. Fatigue, joint swelling, edema,
cough, vomiting, elevated liver enzymes, hyperglycemia
and hypercholesterolemia have also been reported.
In a recent retrospective study, Peer et al. [35] found
abiraterone to be superior to ketoconazole in the treat-
ment of docetaxel refractory mCRPC. PSA response was
46% in the abiraterone group vs. 19% in the ketocona-
zole group (OR 4.3, P = 0.04), median biochemical pro-
gression free survival (PFS) 7 vs. 2 months (HR 1.54,
P = 0.02), median radiological PFS 8 vs. 2.5 months (HR
1.8, P = 0.043), median OS 19 vs. 11 months (HR 0.53,
P = 0.79) and treatment interruption due to severe adverse
events 8% (n = 2) versus 31% (n = 8) (0R 0.6, P = 0.023).
Enzalutamide (Xtandi)
Enzalutamide (formerly MDV300) is an oral, second-
generation androgen receptor antagonist that competi-
tively inhibits androgen binding to the AR. In contrast
to the first generation anti-androgens such as flutamide
and bicalutamide, enzalutamide binds to the receptor
with greater affinity [36]. In the setting of increased AR
expression, bicalutamide is associated with AR recruit-
ment to enhancer regions and aberrant recruitment of
coactivators to these transcription complexes, leading to
target gene activation rather than repression [37]. Enza-
lutamide does not display agonism in AR-overexpressing
cells and this may explain its increased molecular effi-
cacy. Enzalutamide may induce a conformational change
in AR distinct from that induced by bicalutamide mak-
ing it more efficacious in inhibiting the translocation of
AR to the nucleus and its DNA interaction. In a phase
I-II study [36], 140 men including 78% with mCRPC
received doses ranging from 30-600mg daily. Half of
the patients had previously received chemotherapy and
three-fourths had received at least two lines of hormonal
therapy. PSA responses were observed in 62% of the
chemotherapy naïve patients and 51% in docetaxel trea-
ted patients [36]. 22% of the patients had a soft tissue re-
sponse and 56% of the patients with bone disease had
stabilized bone disease. The maximum tolerated dose
was determined to be 240 mg daily. The median rPFS
was 56 weeks and 24 weeks in the chemotherapy naïve
and the chemotherapy pretreated group, respectively.
Enzalutamide was approved after the publication of a
phase III [37], double-blind placebo-controlled random-
ized trial by Scher et el (AFFIRM TRIAL) in which 1199
men with mCRPC were randomized after chemotherapy
to placebo vs. oral enzalutamide at a dose of 160 mg per
day. The median OS was 18.4 months in the enzalu-
tamide group versus 13.6 months in the placebo group
(P < 0.001). The secondary endpoints including the PSA-
level response rate (54% in the enzalutamide group vs.
2% in the placebo group), soft tissue response rate (29%
vs. 4%), the time to PSA progression (8.3 months in the
enzalutamide group vs. 3 months in the placebo group),
rPFS (8.3 months in the enzalutamide group vs. 2.9
months in the placebo group), time to the first skeletal
event (16.7 months in the enzalutamide group vs. 13.3
months in the placebo group) quality of life response
rate (43% in the enzalutamide group vs. 18% in the pla-
cebo group) pain palliation achieved in (45% in the en-
zalutamide group vs. 7% in the placebo group) showed
significant improvement in the enzalutamide group. The
enzalutamide group had higher incidence of fatigue, hot
flashes, musculoskeletal pain and headaches. Rates of
hyperglycemia, weight gain and glucose intolerance were
not different between the two groups. Cardiac disorders
were seen in 6% of the patients receiving enzalutamide
and 8% in the placebo group. Hypertension was seen in
6.6% in the enzalutamide group vs. 3.3% in the placebo
group. Seizures were reported in 0.6% in the enzaluta-
mide group vs. placebo.
The results of the large phase III randomized trial
(PREVAIL trial) [38] were recently presented at the 2014
Genitourinary Cancer Symposium. This trial evaluated
enzalutamide against placebo in chemotherapy naïve men
with mCRPC. In the study, 1,717 chemotherapy naïve pa-
tients with mCRPC were assigned to receive 160 mg/day
of enzalutamide vs. placebo in a double blind fashion.
After a median follow-up of 20 months, interim analysis
showed that enzalutamide significantly reduced the risk of
death by 29% (HR 0.706, 95% CI 0.60-0.84, p <0.0001) and
decreased the risk of radiographic progression by 81% (HR
0.186,95% CI 0.15-0.23, P < 0.0001). 59% of the patients in
the enzalutamide group had a soft tissue response com-
pared with 5% in the placebo arm. Enzalutamide also de-
layed the median time to chemotherapy initiation by 17
months as compared to placebo. The patients on the pla-
cebo arm needed to start cytotoxic chemotherapy after a
median of 10.8 months due to disease progression. Median
time to PSA progression was 2.8 months in the placebo
group vs. 11.2 months in the enzalutamide group. The ad-
verse effects included grade 1–2 fatigue (36% vs. 26%), back
pain (27% vs. 22%) constipation (22% vs. 17%) and arthral-
gia (20% vs. 16%) in the enzalutamide vs. placebo group.
The patients with a history of seizure disorders were ex-
cluded from the trial.
Gupta et al. BMC Urology 2014, 14:55 Page 4 of 8
http://www.biomedcentral.com/1471-2490/14/55

The results of the PREVAIL data will be submitted to
the FDA for approval. If enzalutamide gets approval,
there will be more choices available to treat chemothe-
rapy naïve patients with mCRPC.
Toxicity profile- enzalutamide is reported to cause fa-
tigue (11%), hot flashes (20%), headache (12%), nausea,
diarrhea, constipation and musculoskeletal pain. Other
reported adverse events include hyperglycemia, weight
gain and glucose intolerance. Seizure was reported in
0.6% of the enzalutamide group at 360 to 600 mg doses.
Thus the maximum tolerated dose (MTD) is 240 mg/day
(Table 1).
New drugs under development
Orteronel (TAK 700) - is a non-steroidal, selective in-
hibitor of 17, 20 lyase, which is involved in androgenic
steroid production. Selective inhibition improves its tox-
icity profile as compared to CYP17 inhibition. Orteronel
causes less treatment related adverse events. In phase I
and II studies [39], Orteronel given in twice daily doses
of 100, 200,300,400 and 600 mg was well tolerated. The
most common adverse events were gastrointestinal tox-
icity and grade 3 fatigue. At 12 weeks, the median
DHEA-S and testosterone levels decreased from baseline
in all the groups [39]. The mean number of circulating
tumor cells decreased from 16.6 (per 7.5 ml blood) at
baseline to 3.9 at 12 weeks.
The results of a large randomized, double blind, multi-
center phase III study (ELM-PC4) was presented at the
ASCO symposium in January 2014. The results showed
that there was no improvement in OS with orteronel +
prednisone vs. placebo in patients with mCRPC that
progressed during or following chemotherapy. However
there was improvement in rPFS over the control arm.
Currently the Radiation Therapy Oncology Group
(RTOG) has a trial using TAK/orteronel in addition to
conventional LHRH agonist to test if it will improve
overall survival. The southwest oncology group (SWOG)
is conducting a trial to compare overall survival in newly
diagnosed metastatic prostate cancer patients who were
randomly assigned to androgen deprivation therapy
(ADT) + TAK-700 vs. ADT + bicalutamide.
ARN509- is a small molecule that is structurally simi-
lar to enzalutamide. It inhibits both AR nuclear trans-
location and AR binding to DNA [40]. In contrast to
bicalutamide, it exhibits no agonist activity in prostate
cancer cells that over express AR. In a phase I study [41]
of men with mCRPC, it was shown to have an excellent
safety profile at 240 mg/day. Preliminary results were re-
ported by the Prostate Cancer Working Group in 2013
at the GU cancer symposium [42]. Among 46 men with
mCRPC, 26 were treatment naïve and 21 had prior treat-
ment with abiraterone. At 12 weeks, the PSA response
was 88% in the treatment naïve and 29% in the prior-
treatment group. The toxicity profile included fatigue
(38%), nausea (29%) and pain (24%). Currently, a phase
II multicenter study (NCT01171898) is evaluating the
activity of ARN-509 in three different populations of
men with mCRPC (high risk non-metastatic CRPC, me-
tastatic treatment naïve CRPC and progressive disease
after abiraterone acetate) and further phase III trials are
planned.
Galeterone (TOK-001) - is another addition to the next
generation androgen receptor antagonists and CYP17A1
inhibitors. It works by disrupting multiple androgen signal-
ing pathways simultaneously and by down regulating the
androgen receptor [43,44]. ARMOR 1 [45] was a multicen-
ter dose escalation study of Galeterone for the treatment of
chemotherapy naïve non-metastatic prostate cancer and
mCRPC. The data from ARMOR 1 were presented at the
2012 AACR and 2012 ASCO meetings, showed that the
drug is well tolerated. ARMOR2 is an ongoing phase II
Table 1 Newly approved hormonal agents for the treatment of mCRPC
Drug Date of FDA approval and indication Mechanism of action Side effects
Abiraterone acetate
(Zytiga)
December2012- (COU-AA-301) An androgen biosynthesis inhibitor
of 17 alpha hydroxylase/C-17,20-lyase
within prostate cancer cells and
outside
Fatigue, joint swelling, edema, hot flashes,
diarrhea, cough.
In combination with prednisone for
treatment of patients in mCRPC [29] Administration of prednisone is necessary
to overcome hypertension, hypokalemia,
fluid overload from mineralocorticoid
excess induced by CYP17-inhibition
April 2012- (COU-AA-302) [30]
Treatment of mCRPC in patients with
have received prior chemotherapy
containing Docetaxel
Enzalutamide (Xtandi)
Previously known as
MDV3100
August 2012- AFFIRM trial [34] Androgen receptor inhibitor- inhibits
multiple steps in AR signaling
Fatigue, hot flashes, musculoskeletal pain,
hyperglycemia, weight gain, Seizures in 0.6%
of the patients.
Monotherapy for mCRPC who have
previously received Docetaxel
January 2014- PREVAIL trial [35]
Survival benefit in chemotherapy naïve
patients. Awaiting FDA approval.
Gupta et al. BMC Urology 2014, 14:55 Page 5 of 8
http://www.biomedcentral.com/1471-2490/14/55

multicenter trial to evaluate the efficacy and safety of
Galeterone in the following populations - metastatic
treatment naïve patients, non-metastatic treatment naïve
patients, patients who have progressed on Abiraterone
and patients who have progressed on Enzalutamide. The
primary endpoints of the study are reduction in PSA levels
and safety. The secondary endpoints include tumor
response by the Response Evaluation Criteria in Solid
Tumors (RECIST), AR modulation and levels of circulat-
ing tumor cells and markers of CYP17lyase inhibition
(Table 2).
Treatment sequencing and combination therapy
The last decade has seen tremendous progress in pros-
tate cancer research and has led to a better understan-
ding of prostate cancer biology. This understanding
has led to multiple new drugs that have been ap-
proved and have shown a survival benefit in patients
with metastatic disease. With the approval of abira-
terone and enzalutamide for castrate resistant pros-
tate cancer in the post chemotherapy setting and
abiraterone in the chemotherapy naïve state, there is
an emerging theme of questions on how we use the
new drugs sequentially. We would like to propose a
schema that might help the clinician, but the ultimate
answerwouldonlybeprovidedbyrandomizedclin-
ical trials. What we know based on the trials include
the following:
Chemotherapy naïve
Sipuleucel-T- (Provenge) - immunotherapy
Abiraterone
Docetaxel
Post chemotherapy- docetaxel
Cabazitaxel- chemotherapy
Abiraterone
Enzalutamide
Symptomatic bone metastasis
Radium 223 (Xofigo)
What we do not know is to whom we should give che-
motherapy first or if we should give chemotherapy after
initial therapies have failed. Clinically, physicians are giv-
ing sipuleucel-T or abiraterone first followed by chemo-
therapy. For those with significant visceral disease and
aggressive presentation most would start with docetaxel.
If enzalutamide is approved in the chemotherapy naïve
patients, which drug would become the first line of
treatment, enzalutamide or abiraterone? We would need
to do randomized trials of sequential treatments to an-
swer these questions.
When the data of ECOG 3809 (randomized trial of
chemotherapy- docetaxel for 6 cycles plus leuprolide
and bicalutamide or hormone therapy alone) is pub-
lished, should we start patients with metastatic disease
with hormone therapy plus chemotherapy upfront? Al-
though, it is good to have a plethora of treatment op-
tions today, there appears to be more questions than
answers.
Conclusion
It is amazing that we have turned around in the past few
years from calling progressive metastatic prostate cancer-
hormone refractory to castrate resistant disease. We now
realize that the optimal hormone suppression in the past
was not adequate. With a variety of better androgen
receptor blockers and targets, we are now at a point
Table 2 Newer agents under development for the treatment of mCRPC
Agent Mechanism of action Phase of development Side effects Ongoing trials
Orteronel
(TAK-700)
Non-steroidal, selective inhibitor
of 17, 20lyase, an enzyme required
for androgen biosynthesis.
The results of Phase III trial (ELM-PC 4)
did not show any survival benefit in
chemotherapy naïve patients. An
improvement in rPFS was seen.
Fatigue, GI
toxicity
RTOG and SWOG- TAK + LHRH
agonist to test whether
improvement in OS or not
Galeterone
(TOK-001)
Next generation AR antagonist and
CYP17A1 inhibitor
ARMOR 1- phase I study showed the
drug is well tolerated [42]
Fatigue, Nausea,
Diarrhea
ARMOR 2 is underway in 4
distinct populations
1. Metastatic and treatment naïve
2. Non metastatic and treatment naïve
3. Patients who have progressed on
abiraterone
4. Patients who have progressed on
enzalutamide
ARN-509 Inhibits AR translocation and AR
binding to DNA, does not exhibit
agonist properties in the context of
AR over-expression
Results from phase I studies showed
that the drug is well tolerated and
PSA decline at 12 weeks (>50% from
the baseline) were observed in 46.7%
of the patients. [38]
Fatigue, nausea,
pain
Phase II study is underway in patients
with mCRPC (NCT01171898)
Gupta et al. BMC Urology 2014, 14:55 Page 6 of 8
http://www.biomedcentral.com/1471-2490/14/55

where we can continue to improve the efficacy of these
agents. Should we stop LHRH agents once we use these
agents, what is the ideal testosterone level that we need to
achieve, what level would correlate with response, are
there markers that are better than testosterone and many
more? Future research should be directed towards op-
timizing efficacy through less toxic combinations and
should ultimately make a difference in improving the
survival and quality of life of our patients.
Competing interests
The authors declare that they have no competing interests.
Authors’contributions
EG, TG and WT contributed equally to this article. All authors read and
approved the final manuscript.
Author details
1
Mayo Clinic, 4500 San Pablo Rd S, Jacksonville 32224, FL, USA.
2
Baptist
Cancer Institute, Jacksonville, FL, USA.
Received: 20 March 2014 Accepted: 17 July 2014
Published: 25 July 2014
References
1. Siegel R, Naishadham D, Jemal A: Cancer statistics, 2013. CA Cancer J Clin
2013, 63(1):11–30.
2. Huggins C, Hodges CV: Studies on prostatic cancer. I. The effect of
castration, of estrogen and androgen injection on serum phosphatases
in metastatic carcinoma of the prostate. CA Cancer J Clin 1972,
22(4):232–240.
3. Borgmann V, Hardt W, Schmidt-Gollwitzer M, Adenauer H, Nagel R:
Sustained suppression of testosterone production by the luteinising-
hormone releasing-hormone agonist buserelin in patients with
advanced prostate carcinoma. A new therapeutic approach? Lancet 1982,
1(8281):1097–1099.
4. Sharifi N, Gulley JL, Dahut WL: Androgen deprivation therapy for prostate
cancer. J Am Med Assoc 2005, 294(2):238–244.
5. Becker LE, Birzgalis EP: Orchiectomy in the management of adenocarcinoma
of the prostate. Surg Gynecol Obstet 1966, 122(4):840–843.
6. Cookson MS, Roth BJ, Dahm P, Engstrom C, Freedland SJ, Hussain M, Lin
DW, Lowrance WT, Murad MH, Oh WK, Penson DF, Kibel AS, Cookson MS,
Roth BJ, Dahm P, Engstrom C, Freedland SJ, Hussain M, Lin DW, Lowrance
WT, Murad MH, Oh WK, Penson DF, Kibel AS: Castration-resistant prostate
cancer: AUA Guideline. J Urol 2013, 190(2):429–438.
7. Laufer M, Denmeade SR, Sinibaldi VJ, Carducci MA, Eisenberger MA:
Complete androgen blockade for prostate cancer: what went wrong?
J Urol 2000, 164(1):3–9.
8. Taplin ME, Bubley GJ, Shuster TD, Frantz ME, Spooner AE, Ogata GK, Keer HN,
Balk SP: Mutation of the androgen-receptor gene in metastatic androgen-
independent prostate cancer. N Engl J Med 1995, 332(21):1393–1398.
9. Cai C, He HH, Chen S, Coleman I, Wang H, Fang Z, Nelson PS, Liu XS, Brown
M, Balk SP: Androgen receptor gene expression in prostate cancer is
directly suppressed by the androgen receptor through recruitment of
lysine-specific demethylase 1. Cancer Cell 2011, 20(4):457–471.
10. Watson PA, Chen YF, Balbas MD, Wongvipat J, Socci ND, Viale A, Kim K,
Sawyers CL: Constitutively active androgen receptor splice variants
expressed in castration-resistant prostate cancer require full-length
androgen receptor. Proc Natl Acad Sci U S A 2010, 107(39):16759–16765.
11. Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS,
True LD, Nelson PS: Maintenance of intratumoral androgens in metastatic
prostate cancer: a mechanism for castration-resistant tumor growth.
Cancer Res 2008, 68(11):4447–4454.
12. Locke JA, Guns ES, Lubik AA, Adomat HH, Hendy SC, Wood CA, Ettinger SL,
Gleave ME, Nelson CC: Androgen levels increase by intratumoral de novo
steroidogenesis during progression of castration-resistant prostate
cancer. Cancer Res 2008, 68(15):6407–6415.
13. Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME,
Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D,
Crawford ED: Docetaxel and estramustine compared with mitoxantrone
and prednisone for advanced refractory prostate cancer. N Engl J Med
2004, 351(15):1513–1520.
14. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern
CH, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF,
IMPACT Study Investigators: Sipuleucel-T immunotherapy for castration-
resistant prostate cancer. N Engl J Med 2010, 363(5):411–422.
15. Reid AH, Attard G, Barrie E, de Bono JS: CYP17 inhibition as a hormonal
strategy for prostate cancer. Nat Clin Pract Urol 2008, 5(11):610–620.
16. De Coster R, Wouters W, Bruynseels J: P450-dependent enzymes as
targets for prostate cancer therapy. J Steroid Biochem Mol Biol 1996,
56(1–6SpecNo):133–143.
17. De Coster R, Mahler C, Denis L, Coene MC, Caers I, Amery W, Haelterman C,
Beerens D: Effects of high-dose ketoconazole and dexamethasone on
ACTH-stimulated adrenal steroidogenesis in orchiectomized prostatic
cancer patients. Acta Endocrinol 1987, 115(2):265–271.
18. Eichenberger T, Trachtenberg J: Effects of high-dose ketoconazole on
patients who have androgen-independent prostatic cancer. Can J Surg
1989, 32(5):349–352.
19. Pont A: Long-term experience with high dose ketoconazole therapy in
patients with stage D2 prostatic carcinoma. J Urol 1987, 137(5):902–904.
20. Witjes FJ, Debruyne FM, Fernandez del Moral P, Geboers AD: Ketoconazole
high dose in management of hormonally pretreated patients with
progressive metastatic prostate cancer. Dutch South-Eastern Urological
Cooperative Group. Urology 1989, 33(5):411–415.
21. Keizman D, Huang P, Carducci MA, Eisenberger MA: Contemporary
experience with ketoconazole in patients with metastatic castration-
resistant prostate cancer: clinical factors associated with PSA response
and disease progression. Prostate 2012, 72(4):461–467.
22. Small EJ, Baron A, Bok R: Simultaneous antiandrogen withdrawal and
treatment with ketoconazole and hydrocortisone in patients with
advanced prostate carcinoma. Cancer 1997, 80(9):1755–1759.
23. Small EJ, Baron AD, Fippin L, Apodaca D: Ketoconazole retains activity in
advanced prostate cancer patients with progression despite flutamide
withdrawal. J Urol 1997, 157(4):1204–1207.
24. Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, Gable P,
Torti FM, Kaplan E, Vogelzang NJ: Antiandrogen withdrawal alone or
in combination with ketoconazole in androgen-independent prostate
cancer patients: a phase III trial (CALGB 9583). JClinOncol2004,
22(6):1025–1033.
25. Chen Y, Clegg NJ, Scher HI: Anti-androgens and androgen-depleting
therapies in prostate cancer: new agents for an established target.
Lancet Oncol 2009, 10(10):981–991.
26. Abiraterone Acetate. http://www.fda.gov/drugs/informationondrugs/
approveddrugs/ucm331628.htm.
27. Enzalutamide (XTANDI Capsules). 2012. http://www.fda.gov/drugs/
informationondrugs/approveddrugs/ucm317997.htm.
28. Attard G, Reid AH, A’Hern R, Parker C, Oommen NB, Folkerd E, Messiou C,
Molife LR, Maier G, Thompson E, Olmos D, Sinha R, Lee G, Dowsett M,
Kaye SB, Dearnaley D, Kheo h T, Molina A, de Bono JS: Selective
inhibition of CYP17 with abiraterone acetate is highly active in the
treatment of castration-resistant prostate cancer. JClinOncol2009,
27(23):3742–3748.
29. Danila DC, Morris MJ, de Bono JS, Ryan CJ, Denmeade SR, Smith MR,
TaplinME,BubleyGJ,KheohT,HaqqC,MolinaA,AnandA,Koscuiszka
M, Larson SM, Schwartz LH, Fleisher M, Scher HI: Phase II multicenter
study of abiraterone acetate plus prednisone therapy in patients
with docetaxel-treated castration-resistant prostate cancer. JClin
Oncol 2010, 28(9):1496–1501.
30. Reid AH, Attard G, Danila DC, Oommen NB, Olmos D, Fong PC, Molife LR,
Hunt J, Messiou C, Parker C, Dearnaley D, Swennenhuis JF, Terstappen LW,
Lee G, Kheoh T, Molina A, Ryan CJ, Small E, Scher HI, de Bono JS:
Significant and sustained antitumor activity in post-docetaxel, castration-
resistant prostate cancer with the CYP17 inhibitor abiraterone acetate.
J Clin Oncol 2010, 28(9):1489–1495.
31. Attard G, Reid AH, Yap TA, Raynaud F, Dowsett M, Settatree S, Barrett M,
Parker C, Martins V, Folkerd E, Clark J, Cooper CS, Kaye SB, Dearnaley D,
LeeG,deBonoJS:Phase I clinical trial of a selective inhibitor of
CYP17, abiraterone acetate, confirms that castration-resistant
prostate cancer commonly remains hormone driven. JClinOncol
2008, 26(28):4563–4571.
Gupta et al. BMC Urology 2014, 14:55 Page 7 of 8
http://www.biomedcentral.com/1471-2490/14/55

32. Ryan CJ, Shah S, Efstathiou E, Smith MR, Taplin ME, Bubley GJ, Logothetis CJ,
Kheoh T, Kilian C, Haqq CM, Molina A, Small EJ: Phase II study of
abiraterone acetate in chemotherapy-naive metastatic castration-
resistant prostate cancer displaying bone flare discordant with serologic
response. Clin Cancer Res 2011, 17(14):4854–4861.
33. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones
RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW,
Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN,
Ellard SL, Fléchon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D,
Loriot Y, Chieffo N, Kheoh T, et al:Abiraterone and increased survival in
metastatic prostate cancer. N Engl J Med 2011, 364(21):1995–2005.
34. Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P,
Fizazi K, Mainwaring P, Piulats JM, Ng S, Carles J, Mulders PF, Basch E,
Small EJ, Saad F, Schrijvers D, Van Poppel H, Mukherjee SD, Suttmann
H, Gerritsen WR, Flaig TW, George DJ, Yu EY, Efstathiou E, Pantuck A,
Winquist E, Higano CS, Taplin ME, Park Y, Kheoh T, et al:Abiraterone in
metastatic prostate cancer without previous chemotherapy. NEnglJ
Med 2013, 368(2):138–148.
35. Peer A, Gottfried M, Sinibaldi V, Carducci MA, Eisenberger MA, Sella A,
Leibowitz-Amit R, Berger R, Keizman D: Comparison of abiraterone
acetate versus ketoconazole in patients with metastatic castration
resistant prostate ca ncer refractory to docetaxel. Prostate 2014,
74(4):433–440.
36. Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, Rathkopf D,
Shelkey J, Yu EY, Alumkal J, Hung D, Hirmand M, Seely L, Morris MJ, Danila
DC, Humm J, Larson S, Fleisher M, Sawyers CL, Prostate Cancer Foundation/
Department of Defense Prostate Cancer Clinical Trials Consortium:
Antitumour activity of MDV3100 in castration-resistant prostate cancer: a
phase 1–2 study. Lancet 2010, 375(9724):1437–1446.
37. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R,
Mulders P, Chi KN, Shore ND, Armstrong AJ, Flaig TW, Fléchon A,
Mainwaring P, Fleming M, Hainsworth JD, Hirmand M, Selby B,
Seely L, de Bono JS, AFFIRM Investigators: Increased survival with
enzalutamide in prostate cancer after chemotherapy. NEnglJMed
2012, 367(13):1187–1197.
38. Beer TM, Armstrong AJ, Sternberg CN, Higano CS, Iversen P, Loriot Y,
Rathkopf DE, Bhattacharya S, Carles J, De Bono JS, Evans CP, Joshua AM,
Kim C-S, Kimura G, Mainwaring PN, Mansbach HH, Miller K, Noonberg SB,
Venner PM, Tombal B: Enzalutamide in men with chemotherapy-naive
metastatic prostate cancer (mCRPC): Results of phase III PREVAIL study.
J Clin Oncol 2014, 32(4 Suppl):LBA1.
39. Agus WMS DB, Shevrin DH, Hart L, MacVicar GR, Hamid O, Hainsworth JD,
Gross ME, Wang J, de Leon L, MacLean D, Dreicer R: Safety, efficacy, and
pharmacodynamics of the investigational agent TAK-700 in metastatic
castration-resistant prostate cancer (mCRPC): Updated data from a phase
I/II study. J Clin Oncol 2011, 29(15_suppl):4531.
40. Clegg NJ, Wongvipat J, Joseph JD, Tran C, Ouk S, Dilhas A, Chen Y, Grillot K,
Bischoff ED, Cai L, Aparicio A, Dorow S, Arora V, Shao G, Qian J, Zhao H,
Yang G, Cao C, Sensintaffar J, Wasielewska T, Herbert MR, Bonnefous C,
Darimont B, Scher HI, Smith-Jones P, Klang M, Smith ND, De Stanchina E,
Wu N, Ouerfelli O, et al:ARN-509: a novel antiandrogen for prostate
cancer treatment. Cancer Res 2012, 72(6):1494–1503.
41. Rathkopf DE, Morris MJ, Fox JJ, Danila DC, Slovin SF, Hager JH, Rix PJ,
Chow Maneval E, Chen I, Gonen M, Fleisher M, Larson SM, Sawyers CL,
Scher HI: Phase I Study of ARN-509, a Novel Antiandrogen, in the
Treatment of Castration-Resistant Prostate Cancer. J Clin Oncol 2013,
31(28):3525–3530.
42. Smith MR: ARN-509 in men with high-risk nonmetastatic castration-
resistant prostate cancer (CRPC). J Clin Oncol 2013, 31(6 Suppl):7.
43. Vasaitis T, Belosay A, Schayowitz A, Khandelwal A, Chopra P, Gediya LK,
Guo Z, Fang HB, Njar VC, Brodie AM: Androgen receptor inactivation
contributes to antitumor efficacy of 17{alpha}-hydroxylase/17,20-lyase
inhibitor 3beta-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene
in prostate cancer. Mol Cancer Ther 2008, 7(8):2348–2357.
44. Purushottamachar P, Godbole AM, Gediya LK, Martin MS, Vasaitis TS,
Kwegyir-Afful AK, Ramalingam S, Ates-Alagoz Z, Njar VC: Systematic
structure modifications of multitarget prostate cancer drug candidate
galeterone to produce novel androgen receptor down-regulating
agents as an approach to treatment of advanced prostate cancer.
J Med Chem 2013, 56(12):4880–4898.
45. Taplin M, Chu F, Morrison J, Pili R, Rettig M, Stephenson J, Vogelzang N,
Montgomery R: ARMOR1: safety of galeterone (TOK-001) in a phase 1
clinical trial in chemotherapy naïve patients with castration resistant
prostate cancer (CRPC). Cancer Res 2012, 72(8 Supplement):CT-07.
doi:10.1186/1471-2490-14-55
Cite this article as: Gupta et al.:Changing paradigms in management of
metastatic Castration Resistant Prostate Cancer (mCRPC). BMC Urology
2014 14:55.
Submit your next manuscript to BioMed Central
and take full advantage of:
• Convenient online submission
• Thorough peer review
• No space constraints or color figure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution
Submit your manuscript at
www.biomedcentral.com/submit
Gupta et al. BMC Urology 2014, 14:55 Page 8 of 8
http://www.biomedcentral.com/1471-2490/14/55