Download The changing therapeutic landscape of castration

REVIEWS
The changing therapeutic landscape
of castration-resistant prostate cancer
Timothy A. Yap, Andrea Zivi, Aurelius Omlin and Johann S. de Bono
Abstract | Castration-resistant prostate cancer (CRPC) has a poor prognosis and remains a significant
therapeutic challenge. Before 2010, only docetaxel-based chemotherapy improved survival in patients with
CRPC compared with mitoxantrone. Our improved understanding of the underlying biology of CRPC has
heralded a new era in molecular anticancer drug development, with a myriad of novel anticancer drugs for
CRPC entering the clinic. These include the novel taxane cabazitaxel, the vaccine sipuleucel‑T, the CYP17
inhibitor abiraterone, the novel androgen-receptor antagonist MDV‑3100 and the radioisotope alpharadin.
With these developments, the management of patients with CRPC is changing. In this Review, we discuss
these promising therapies along with other novel agents that are demonstrating early signs of activity in
CRPC. We propose a treatment pathway for patients with CRPC and consider strategies to optimize the use
of these agents, including the incorporation of predictive and intermediate end point biomarkers, such as
circulating tumor cells.
Yap, T. A. et al. Nat. Rev. Clin. Oncol. 8, 597–610 (2011); published online 9 August 2011; doi:10.1038/nrclinonc.2011.117
Introduction
Prostate cancer is the most common malignancy, and the
second leading cause of cancer mortality among men.1,2
Approximately 10–20% of patients with prostate cancer
present with advanced-stage disease, while others develop
disease progression to castration-resistant prostate cancer
(CRPC), which has a poor prog­nosis and is a therapeutic
challenge.3,4 Strategies developed to counter­act androgendeprivation therapy (ADT) resistance have had only modest
clinical benefit.5–8 Indeed, before 2010, only docetaxelbased chemo­t herapy improved overall survival in
patients with CRPC compared with mitoxantrone.9,10
Improved understanding of the biology underlying
CRPC has heralded a new era in molecular-targeted anticancer drug development.11 Many novel anticancer drugs
are currently in clinical studies, and several promis­ing
agents are nearing completion or have recently completed
late-phase clinical trials. It is likely that the treatment
landscape for patients with CRPC will change inextri­
cably in the near future. In this Review, we focus on these
promising therapies, propose a treatment pathway for
patients with CRPC and suggest strategies to optimize
the application of these agents. Finally, we detail promising novel targets, against which future agents in CRPC
Competing interests
T. A. Yap, A. Zivi, A. Omlin and J. S. de Bono declare an
association with the following organization: The Institute of
Cancer Research. J. S. de Bono also declares associations with
the following companies: Amgen, Astellas, AstraZeneca,
Boehringer Ingelheim, Bristol-Myers Squibb, Cougar
Biotechnology, Dendreon, Enzon, Exelixis, Genentech,
GlaxoSmithKline, Medivation, Merck, Novartis, Pfizer, Roche,
Sanofi-Aventis, Supergen, Takeda. See the article online for full
details of the relationships.
may potentially be developed, and consider paradigms
for modern clinical therapy for CRPC.
Targeting the AR
The development of CRPC is characterized by a rise in
prostate-specific antigen (PSA) and subsequent prog­
ression of disease despite castrate blood levels of testo­
sterone (<50 ng/dl or 1.7 nmol/l).12 There is a growing
body of evidence of the continued dependence of
CRPC on androgen-receptor (AR) signaling and related
under­lying mechanisms.13 Androgens from the adrenal
glands account for 10–30% of serum androgens and
are an important source of continued AR activation.14
Importantly, dehydroepiandrosterone (DHEA) and
other precursor steroids secreted by the adrenal glands
can be converted into potent androgens.15 Recurrent
prostate cancer might be able to synthesize testicular
androgens through intracrine production from adrenal
androgens and chol­esterol.16 Maintained AR signaling
that leads to CRPC can be explained by a number of
mechanisms (Box 1).
Current AR antagonists in CRPC
Translocation of the AR into the nucleus and subsequent
receptor activation is mediated by androgen binding.17
Available AR antagonists have agonistic properties
in advanced-stage CRPC, either by increased sensiti­
vity and activity caused by AR mutation, or through
AR overexpression.18,19
Antiandrogens can be divided into steroidal and nonsteroidal agents and compete with endogenous androgens for the AR binding site.12 The steroidal compounds
(mifepristone, spironolactone and cyproterone acetate)
NATURE REVIEWS | CLINICAL ONCOLOGY Drug Development Unit,
The Royal Marsden
NHS Foundation Trust
and The Institute of
Cancer Research,
Downs Road, Sutton,
Surrey SM2 5PT, UK
(T. A. Yap, A. Zivi,
A. Omlin, J. S. de Bono).
Correspondence to:
J. S. de Bono
johann.de-bono@
icr.ac.uk
VOLUME 8 | OCTOBER 2011 | 597
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REVIEWS
Key points
■■ Castration-resistant prostate cancer (CRPC) is associated with a poor prognosis
and remains a significant therapeutic challenge
■■ Before 2010, there was an urgent unmet clinical need for more-effective and
well-tolerated therapies for CRPC
■■ Improved understanding of the underlying biology of CRPC heralded a new era
in molecular anticancer drug development
■■ New treatments for CRPC imparting an overall survival benefit include
cabazitaxel, sipuleucel‑T, abiraterone and alpharadin
■■ The management of patients with CRPC is changing; therefore, we propose
a novel treatment pathway including the incorporation of predictive and
intermediate end point biomarkers
Box 1 | Mechanisms of maintained androgen-receptor signaling leading to CRPC
■■ Increased androgen-receptor (AR) copy number is found in 25–30% of patients
with CRPC.19,164,165 AR amplification is significantly higher in CRPC tumors
compared with androgen-dependent disease (20% versus 2%; P = 0.0085).166
■■ AR point mutations decrease the binding specificity of AR, allowing activation
through related molecules, such as endogenous steroids and antiandrogens,
in up to 20% of locally advanced tumors and 50% of patients with distant
metastasis.167–174 AR mutations are the most likely explanation for the
antiandrogen withdrawal syndrome observed in patients with CRPC on
maximum androgen blockade (gonadotropin-releasing hormone agonist and AR
antagonist), where prostate-specific antigen declines following discontinuation
of the AR antagonist.8,175,176
■■ Activation of the AR can occurr through alternative signaling pathways such as
the Ras/Raf/MEK/ERK pathway, or tyrosine kinases Src and Ack1.177–182
■■ HER2 activates AR through the PI3K/AKT pathway; inhibition of the PI3K
pathway in PTEN-negative prostate cancer results in feedback signaling to
HER2/HER3, resulting in AR activation. Conversely, AR blockade leads to
activation of AKT through decreased levels of FKBP5 impairing the stability
of the phosphatase PHLPP.183–185 Insulin-like growth factor‑1 is associated
with androgen-independent AR activation;182,186,187 and the AR represses the
expression of c‑Met in a ligand-dependent manner.188
■■ Altered levels of co-factors, especially proteins that co-activate AR, include
nuclear receptor co-activator 1, 2 and 4, steroid receptor co-activator 3,
melanoma-associated antigen 11 and nuclear factor κB p100 subunit.177,189–192
■■ Intratumoral enzymes involved in androgen biosynthesis, such as cytochrome
P450 (CYP)17 (steroid 17α-hydroxylase/C17,20 lyase) and CYP19A1, are
frequently unregulated in CRPC.165
■■ Constitutively active AR splice variants, which lack the ligand-binding domain,
can be expressed alone or as a heterodimer with full-length AR.193
have variable levels of androgenic activity; therefore,
they are not frequently used for CRPC treatment.15,18
The nonsteroidal antiandrogens flutamide, nilutamide
and bicalutamide are used either alone or in combination
with gonadotropin-releasing hormone (GnRH) agonists
as neoadjuvant therapy, with radiation therapy, and in
intermittent androgen suppression; the clinical benefits
of these agents are modest at best.20
Corticosteroids including prednisone, hydro­cortisone
and dexamethasone suppress adrenal androgens and have
PSA response rates of 20–25%.21 However, in most cases,
these therapies are associated with a short median timeto-disease progression (<5 months with prednisone and
5–7 months with dexamethasone).7,22–28 In vitro studies
have shown agonistic effects of endogenous steroi­ds and
dexamethasone on the Thr877Ala-mutant AR; the clinical
significance of this finding has not been demonstrated.29
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Synthesized 20-aminosteroids inhibited both wild-type
and Thr877Ala-mutant AR‑mediated transactivation,
indicating AR antagonistic function; these agents are the
first steroids that are complete AR antagonists and may
represent promising novel anti­tumor compounds.30
AR antagonists in development
In preclinical studies, the second generation AR antagonist MDV3100 (Medivation, CA, USA) had fivefold to
eightfold increased affinity for the AR compared with
bicalutamide, reduced the efficiency of AR nuclear translocation and prevented co-activator recruitment of the
ligand–receptor complex.31 In a multicenter phase I–II
trial, 140 patients with metastatic CRPC received daily
oral MDV3100 (30–600 mg).32 This trial established a
maximum-tolerated dose of 240 mg daily after seizures
were observed in patients receiving higher doses. The
most common grade 3 or 4 toxic effect was dose-dependent fatigue. Antitumor activity was observed at all doses,
and included PSA responses of ≥50% in 56% of patients.32
MDV3100 is being assessed in multinational phase III,
randomized double-blind placebo-controlled studies in
chemotherapy-naive patients with CRPC (PREVAIL)
and patients with CRPC who have been previously
treated with docetaxel-based chemotherapy (AFFIRM).
A concern for all the ongoing clinical trials in this disease
setting is that there is likely to be crossover of patients to
other—potentially highly efficacious—experi­mental or
novel therapies after disease progression on the original
trial. This could confound the results for the efficacy of the
trial drug. Other novel AR inhibitors currently in earlyphase clinical trials include the small molecules ARN‑509
(Aragon Pharmaceuticals, CA, USA) and BMS‑641988
(Bristol-Myers Squibb, NY, USA).33
CYP17 inhibitors
Abiraterone
Abiraterone acetate is a small-molecule inhibitor of cytochrome P450 (CYP)17.34–37 CYP17 is a key enzyme with
dual functions of 17α-hydroxylase and C17,20-lyase acti­
vity, which are necessary for both adrenal and intratumoral
de novo biosynthesis of androgen hormones.38 Abiraterone
is highly potent and selective and is 10–30 fold more potent
against CYP17 than ketoconazole.4 Ketoconazole—a
weak, reversible and nonspecific inhibitor of CYP17—is
associated with toxicities that result in early treatment
discontinuation in up to 20% of patients.4 Despite this,
ketoconazole has antitumor activity in prostate cancer,
with PSA response rates of 20–62% and a median duration of response of 3–7 months; however, it has never been
demonstrated to improve overall survival.38
Although initial clinical studies of abiraterone in
patients with non-castrate prostate cancer showed
suppres­sion of testosterone to castrate levels, this was
followed by a gonadotropin surge, which restored
serum testosterone levels.39 Therefore, a phase I study
was conducted to assess a continuous dosing schedule of abiraterone in patients with CRPC, administered with a GnRH analog to overcome the feedback
gonado­tropin surge; abiraterone was well tolerated with
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promis­ing antitumor activity.40 Phase II clinical trials
in patients with CRPC in both chemotherapy-naive
and post‑docetaxel settings reported a PSA response of
≥50% in 67% and 51% of patients and a median timeto-PSA progression of 225 days and 169 days, respectively.41,42 A separate trial of abiraterone in patients with
docetaxel-naive CRPC showed PSA responses of ≥50%
in nine of 19 ketoconazole‑pretreated and nine of 14
ketoconazole-naive patients.43 A further phase II trial of abiraterone in combination with prednisone in patients with
docetaxel-treated CRPC demon­strated PSA responses of
≥50% in both ketoconazole-pretreated (seven of 27) and
ketoconazole-naive (14 of 31) patients.44
The early-phase studies confirmed the safety and tolerability of abiraterone, with the main (expected) toxic
effects of mild-to-moderate hypertension, hypokalemia
and fluid retention, which are class effects and effectively
managed with treatment with the mineralo­corticoid
antagonist eplerenone and/or a low dose of steroids
to blunt the secon­dary adrenocorticotropic hormone
feedback loop.41,42
A phase III multinational, multicenter, randomized,
double-blind, placebo-controlled study of 1,000 mg of
abiraterone plus 5 mg twice daily of prednisone versus
placebo plus prednisone was conducted in 1,195 patients
with docetaxel-treated CRPC.45 Abiraterone improved
median overall survival compared with the placebo arm
(14.8 months versus 10.9 months; P <0.001). Importantly,
the survival benefit was similar between patients who
had received one or two previous lines of chemo­therapy
and across all patient subgroups studied, including
age, performance status and the presence of visceral
disease. All secondary end points achieved signifi­cance
in favor of abiraterone, including time-to-PSA progression (P <0.001), radiological-progression-free survival
(P <0.001) and confirmed PSA response rate (P <0.001).
Adverse events were similar in both arms of treatment.
Of note, grade 3 or 4 mineralocorticoid toxic effects were
only seen in less than 4% of patients. Based on this trial,
abiraterone was approved by the FDA for the treatment
of CRPC in the post-docetaxel setting.46
A separate phase III trial of abiraterone plus prednisone in patients with chemotherapy-naive and ketoconazole-naive CRPC has completed patient accrual
(NCT00887198);33 this trial will address the efficacy in
treatment-naive patients. Future trials will be required
to determine the optimum use of steroids in combination with abiraterone and the efficacy of abiraterone in
the first-line treatment of patients with prostate cancer.
Abiraterone has the highest chance of having an impact
by increasing cure rates in high-risk disease. However,
the potential adverse effects associated with long-term
administration of prednisone and the castrating effects of
abiraterone, especially with regards to potential increased
cardio­vascular effects and bone health effects of protracted
ADT, will need to be considered.
Orteronel
In a phase I–II trial, 26 patients with CRPC received the
selective 17,20-lyase inhibitor orteronel (100–600 mg
twice daily) as monotherapy and six patients received
orteronel (400 mg twice daily) in combination with prednisone (5 mg twice daily).47 Drug-related toxic effects
included fatigue (including three patients with grade
≥3 fatigue at 600 mg) and gastrointestinal symptoms.
Pharmacokinetics were dose proportional. Following
4 weeks of orteronel treatment, median testosterone and
DHEA levels decreased from 5.5 ng/dl to 0.6 ng/dl
and 50.0 μg/dl to below quantifiable levels, respectively.
All patients treated at doses ≥300 mg had a reduction in
PSA levels; in 12 patients the reduction was ≥50% and in
four it was ≥90%. The phase II expansion of the study and
a randomized, double-blind, phase III study evaluating
orteronel plus prednisone versus placebo plus prednisone
in both chemotherapy-naive patients and post-docetaxel
patients with CRPC are ongoing.33
TOK‑001
TOK‑001 (Tokai Pharmaceuticals, MA, USA) is an oral
small-molecule inhibitor of AR and CYP17.48,49 It is being
assessed in a phase I–II study (ARMOR) and results
are expected soon. Although inhibition of the AR by
TOK‑001 may enhance its CYP17-mediated anti­tumor
activity, the binding of the inhibitor to the AR might
result in an agonistic effect on AR signaling if genetic
aberrations of the AR result in ligand promiscuity.4
Chemotherapy in prostate cancer
Mitoxantrone
In a phase III study, the combination of type II topoiso­
merase inhibitor mitoxantrone with predisone was
signifi­cantly more efficacious than prednisone alone for
palliative symptom management.22 When these palliative benefits were confirmed in the CALGB 9182 study,23
regu­latory approval for mitoxantrone was obtained from
the FDA. No significant differences in median overall
survival were found between the treatment arms, probably because of small patient numbers (242 patients).
Prostate cancer was considered to be predominately
insensitive to chemotherapy until results from two
key phase III clinical trials assessing docetaxel chemo­
therapy (TAX327 and SWOG9916) were published in
2004 (Table 1).9,10
Docetaxel and docetaxel combinations
The TAX327 phase III clinical trial enrolled 1,006 men
with chemotherapy-naive metastatic CRPC to receive
prednisone (5 mg twice daily) and were randomly
assigned to weekly docetaxel for 5 out of 6 weeks or
mitoxantrone or docetaxel every 3 weeks (Table 1).9
Compared with the men in the mitoxantrone group
(overall survival 16.5 months), patients in the 3‑weekly
docetaxel group had an increased overall survival of
18.9 months with a hazard ratio (HR) for death of 0.76
(95% CI 0.62–0.94; P = 0.009). A total of 45% of patients
had a ≥50% decline in their serum PSA levels (P <0.001);
35% had predefined reductions in pain (P = 0.01),
and 22% had improvements in their quality of life
(P = 0.009).9 The updated extended follow-up survival
data from this study showed an absolute median overall
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Table 1 | Completed clinical trials in patients with CRPC*
Agent
Phase
n (setting)
PSA RR >50%
Median OS
(months)
Median PFS
(months)
Conclusions
Prednisone + 3-weekly docetaxel
vs prednisone + 1-weekly docetaxel
vs prednisone + mitoxantrone9
III
1,006 (CT-naive)
45% vs 48%
vs 32%
18.9 vs 17.4
vs 16.5
NA
Docetaxel approved as first-line
therapy for CRPC
Docetaxel + estramustine
vs mitoxantrone + prednisone10
III
770 (CT-naive)
50% vs 27%
17.5 vs 15.6
6.3 vs 3.2
Estramustine increased side
effects without enhancing efficacy
Prednisone + satraplatin
vs prednisone + placebo106
III
950 (post-CT)
25.4% vs 12.2%
(overall PSA RR)
15.3 vs 15.4
2.8 vs 2.4
No statistical improvement of OS
(P = 0.8)
Sipuleucel‑T vs placebo78
III
512 (CT-naive)
2.6% vs 1.3%
25.8 vs 21.7
3.7 vs 3.6
(TTrP)
Sipuleucel‑T approved for CT‑naive
patients with asymptomatic or
mildly symptomatic CRPC
Prednisone + abiraterone
vs prednisone + placebo45
III
1,195 (post-CT)
29.1% vs 5.5%
14.8 vs 10.9
5.6 vs 3.6
Abiraterone approved for
post-docetaxel setting
Docetaxel + prednisone vs docetaxel + prednisone + bevacizumab53
III
1,050 (CT-naive)
69.5% vs 57.9%
22.6 vs 21.5
9.9 vs 7.5
No significant improvement of OS
(P = 0.181)
Prednisone + cabazitaxel vs prednisone + mitoxantrone61
III
755 (post-CT)
39.2% vs 17.8%
(overall PSA RR)
15.1 vs 12.7
2.8 vs 1.4
Cabazitaxel new standard
second-line chemotherapy
MDV310032
I–II
140 (CT-naive [46%]
and post-CT [54%])
56%
NA
10.8 (TTrP)
Phase III trials ongoing
Docetaxel + prednisone vs docetaxel + prednisone + oblimersen107
II
115 (CT-naive)
37% vs 46%
NA
4.4 vs 6.2
(TTP)
Primary end point of PSA
response not met
Sunitinib108
II
36 (post-CT)
12.1%
NA
4.9
Phase III trial halted for lack
of efficacy
Cetuximab + docetaxel109
II
38 (post-docetaxel)
17%
NA
NA
Combination was well tolerated
Atrasentan vs placebo84
III
809 (CT-naive)
NA
20.5 vs 20.3
NA
Primary end point (TTP, radiological
and biochemical) not met
*The alpharadin phase III trial data were not fully available at the time of publication; however, in June 2011 a press release reported that this trial had met its primary end point of improved
OS, improving OS by 2.7 months. Abbreviations: CRPC, castration-resistant prostate cancer; CT, chemotherapy, NA, not available; OS, overall survival; PFS, progression-free survival;
PSA, prostate-specific antigen; RR, response rate; TTP, time to progression; TTrP, time to radiological progression.
survival of 19.2 months (95% CI 17.5–21.3 months) in
the 3‑weekly docetaxel arm versus 16.3 months (95% CI
14.3–17.9 months) in the mitoxantrone arm.50
Since the absolute advantage in overall survival in
patients receiving docetaxel was only approximately
3 months, several docetaxel-based trials were designed
with the goal of improving these results (Table 1).
Particularly interesting are studies evaluating the combination of novel molecular therapies with the docetaxel
and prednisone regimen in the first-line chemo­
therapy setting. These include two large randomized
phase II trials of high-dose calcitriol (ASCENT‑1 and
ASCENT‑2).51 Docetaxel and prednisone were also combined with a vaccine (GVAX) and a monoclonal antibody
against VEGF (bevacizumab).52,53 Unfortunately, all of
these trials failed to meet their respective primary end
points. Other trials are currently ongoing (Supplementary
Table 1 online) and we are cautiously optimistic that with
the large range of agents undergoing trials, we will ultimately be able to improve the survival benefit for patients
using docetaxel-based treatments.
A recent small study suggested that docetaxel clearance is raised approximately twofold in patients with
CRPC when compared with patients with non-CRPC,
due to increased hepatic drug uptake and thus decreased
systemic exposure. Therefore, patients with CRPC might
have altered docetaxel dose requirements. 54 These
600 | OCTOBER 2011 | VOLUME 8
findings might explain the low incidence of neutropenia
in patients with CRPC following docetaxel treatment.
A key challenge in CRPC is the management of
patients with disease progression during or following
docetaxel-based chemotherapy. Since docetaxel is the
gold-standard treatment for CRPC, mitoxantrone is
often used as a second-line treatment. However, there
have been no data that show an improvement in overall
survival with this treatment. A number of new treatments
are in late-phase trials, with the intent of improving the
outcomes of patients with CRPC who have developed
disease progression on docetaxel-based chemotherapy
(Table 1 and Supplementary Table 2 online).
Several small retrospective studies have shown that
patients with advanced-stage CRPC who responded
to first-line docetaxel-based chemotherapy continue to
be sensitive to retreatment, with favorable toxicity profiles.55,56 It should, however, be noted that the extent
and duration of response to docetaxel decreases with
each consecutive line of retreatment, and docetaxel
retreatment has not been demonstrated to result in any
survival benefits.57
Satraplatin
The SPARC phase III trial was conducted in patients with
metastatic CRPC who had received at least one line of
chemotherapy,58 to evaluate satraplatin, the first orally
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available platinum compound.59 A total of 950 patients
with CRPC were randomly assigned to receive prednisone
(5 mg twice daily) with or without satraplatin (80 mg/m2)
for 5 days every 4 weeks.58 Despite significantly higher
PSA declines (P <0.001), pain responses (P <0.005),
time-to-pain progression (P <0.001) and median
progression-free survival (PFS; P <0.001) in the satra­platin
arm, the primary end point of significantly improved
overall survival was not achieved (HR = 0.98) and the
drug was not approved. Despite this result, satraplatin
might have a role in patients with BRCA1 and/or BRCA2
mutated CRPC—or in those who display a ‘BRCAness’
phenotype—since BRCA-mutated tumors are exquisitely
sensi­tive to platinum-based chemotherapies.60
Cabazitaxel
Cabazitaxel has also been investigated in the postdocetaxel setting in patients with CRPC.61 Cabazitaxel is
a taxane that is as potent as docetaxel in tumor cell lines,62
and exhibits antitumor activity in preclinical models
resistant to paclitaxel and docetaxel.63,64 A phase I clinical study established neutropenia as the dose-limiting
toxi­city and 20 mg/m2 as the recommended dose.65 A
higher dose (25 mg/m2) was examined in the phase II
trial of cabazitaxel in patients with taxane-resistant metastatic breast cancer in patients who did not experience
significant toxicity during the first cycle.66
Cabazitaxel was progressed from phase I directly
to a randomized open-label phase III trial (EFC6193;
TROPIC); 755 patients with docetaxel-treated metastatic
CRPC were treated with prednisone (5 mg twice daily)
and either mitoxantrone (12 mg/m2; n = 377) or cabazitaxel (25 mg/m2; n = 378).61 The median overall survival
was 15.1 months (95% CI 14.1–16.3) in the cabazitaxel
group and 12.7 months (95% CI 11.6–13.7) in the mito­
xantrone group. The HR for death of men treated with
cabazitaxel compared with those taking mitoxantrone
was 0.70 (95% CI 0.59–0.83; P <0.0001).
The most common grade 3 or worse toxic effects
included neutropenia and diarrhea.61 In addition, 8% of
patients in the cabazitaxel group and 1% in the mito­
xantrone group had febrile neutropenia, suggesting
that cabazitaxel treatment will require close surveillance; prophylactic granulocyte-colony-stimulating
factors (G-CSF) and a low threshold for dose modifi­
cations should be considered in high-risk patients.
These high-risk patients might be identified based
on pharmaco­g enomic factors such as mutations in
CYP3A4 and CYP3A5, which are associated with slow
cabazitaxel clearance.62
Cabazitaxel is the first drug to improve overall survival
in patients with metastatic CRPC who had developed
disease progression during and after docetaxel-based
therapy. 61 As a result of these data, cabazitaxel was
recently approved by the FDA as the new standard of
care for the second-line treatment of CRPC following
failure of docetaxel chemotherapy.67
Although the cabazitaxel phase III trial was a ‘success’,
several criticisms have been made against this study.
For example, one has to question if it is reasonable to
bypass conducting a phase II trial with a potentially
toxic agent. In addition, despite exclusion of patients
who had extensive prior radiotherapy or concurrent
serious illness, the treatment-related death rate was 5%,
with no data demonstrating improved quality of life.
Further studies evaluating drug safety in this patient
population and assessing the quality-of-life benefits
imparted by cabazi­taxel are warranted. Finally, would
the results of this phase III trial have been significant
if the comparator arm was docetaxel retreatment,
especially given the lack of a standardized definition
of docetaxel progression or resistance? The superiority of
cabazitaxel versus docetaxel is being addressed by a randomized, open-label, multicenter phase III study comparing cabazitaxel (25 mg/m2 and 20 mg/m² 3‑weekly)
with docetaxel, both in combination with prednisone;
however, this study is being conducted in patients with
chemotherapy-naive CRPC.33
Other novel chemotherapies
Apart from cabazitaxel, other microtubule stabilizers,
including third-generation taxanes (TPI‑287 [Tapestry
Pharmaceuticals, CO, USA]) and the epothilones
(ixabepilone and patupilone) are currently in phase II
clinical trials in patients with CRPC and are showing
promising antitumor activity.33,68,69 It is likely that they
will need to be compared head-to-head with cabazitaxel
in a phase III post-docetaxel trial setting.
Immunotherapy
The concept of immune modulation—aimed at generating a clinically meaningful antitumor immune response
—has been extensively evaluated in melanoma and renal
cancers.70 This principle has since been extended to prostate cancer because it can be a slow-growing, indolent
disease, allowing sufficient time for the generation of
an effective antitumor immune response. 71 Moreover,
recent data have demonstrated that prostate cancer is
more immunogenic than previously appreciated, with
evidence of prostate cancer-specific auto­antibodies in
blood samples of patients.72
The challenges in the successful development of
immunotherapy for prostate cancer are multifold. First,
prostate cancer is not a homogenous disease, implying
that there are several antigenic targets that could have a
role in the development of an immune response. Second,
defining clinical responses and demonstrating a clear
relationship between the induction of antigen-specific
immune responses and clinical outcomes is challenging.
Third, there is a mismatch between the need to have a
rapid and realistic drug development timeline and the
selection of patients with a low likelihood of immunosuppressive mechanisms—that is, enrolling patients with
minimal disease burden, but in whom time to clinically
meaningful events such as disease progression or death
can be prohibitively long. The most promising immuno­
therapies are sipuleucel‑T and ipilimumab (Table 2) and
antibodies to the immune checkpoint programmed
death‑1 (PD‑1) protein, of which only sipuleucel‑T has
received FDA approval for CRPC.73–75
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Table 2 | Immunotherapy clinical trials in patients with CRPC
Agent
Immuno­therapy
mechanism of action
Phase
n (setting)
Conclusions
Docetaxel (q3w) + GVAX
or prednisone33
2 prostate cancer cell lines
(engineered to secrete
G‑CSF) to increase DC
antigen presentation
III
1,006 (CT-naive)
Trial halted early because of negative futility analysis
(NCT00133224)
Docetaxel + prednisone
vs GVAX33
2 prostate cancer cell lines
(engineered to secrete
G‑CSF) to increase DC
antigen presentation
III
770 (CT-naive)
Trial halted early because of increased rate of death in the
experimental arm (NCT00089856)
Ipilimumab (3 mg/kg
q4w × 4) ± docetaxel
(75 mg/m2 × 1)110
Anti-CTLA‑4 monoclonal
antibody
II
43 (CT-naive)
3 patients in each arm had PSA decrease >50%; most
frequent adverse events were fatigue (44%), pruritus (26%),
nausea (19%), rash (12%), constipation (12%) and weight
loss (12%); 6% experienced an immune breakthrough
event—phenomenon correlated in other studies with efficacy;
no enhancement of activity by co-administration of docetaxel
Ipilimumab vs placebo111
Anti-CTLA‑4 monoclonal
antibody
III
Estimated 600 (CT-naive,
asymptomatic/minimally
symptomatic
Primary end point overall survival (NCT01057810)
Ipilimumab vs placebo112
Anti-CTLA‑4 monoclonal
antibody
III
Estimated 800 (post-CT)
Primary end point overall survival (NCT00861614)
Leuprolide + bicalutamide
± ipilimumab113
Anti-CTLA‑4 monoclonal
antibody
II
Estimated 108
(advanced-stage or
post-surgery for
recurrent cancer)
Primary end point PFS; patients treated with
ipilimumab + hormonotherapy were more likely to have an
undetectable PSA by 3 months (55% vs 38%); some
patients treated with ipilimumab experienced a significant
clinical response and disease downstaging; the most
common severe (grade 3 or 4) immune-related (ipilimumab
arm) adverse events were colitis (4.5%) and diarrhea
(4.5%); 15 patients (27.7%) treated with ipilimumab
experienced cutaneous changes (NCT00170157)
Ipilimumab + leuprolide114
Anti-CTLA‑4 monoclonal
antibody
II
Estimated 20
(neoadjuvant)
In 12 patients treated, the combination seems to facilitate
a profound local tumor response; trial ongoing and
recruiting (NCT01194271)
Ipilimumab + sargramostim
+ PROSTVAC115,116
Anti-CTLA‑4 monoclonal
antibody + pox-virus based
vaccine expressing PSA and
3 co-stimulatory molecules
I
30 (CT-naive, metastatic
CRPC)
No dose-limiting toxicity found; 20 grade ≥2 immune-related
adverse events and no grade >2 adverse events attributed
to PROSTVAC; this combination has clinical activity in this
patient population
Ipilimumab + sargramostim117
Anti-CTLA‑4 monoclonal
antibody
I
Estimated 36 (CT-naive)
3 of 24 patients experienced a >50% decline in PSA; 1
patient had PR by RECIST criteria on liver metastasis at
week 12 confirmed by a follow-up scan 12 weeks later, 1
patient had grade 3 pan-hypopituitarism, 1 patient had
grade 3 temporal arteritis, 1 patient had grade 3 stroke
(unlikely related), 1 patient had grade 3 diarrhea and 1
patient had grade 3 rash; trial ongoing (NCT00064129)
PROSTVAC + G-CSF
vs placebo118
Pox-virus based vaccine
expressing PSA and 3
co-stimulatory molecules
II
125 (post-docetaxel)
Overall survival: 25.1 vs 16.6 months (HR = 0.56 [95% CI,
0.37–0.85]); PFS: 3.8 vs 3.7 months (HR = 0.88 [95% CI,
0.57–1.38]); primary end point PFS
ONY‑P1 vs placebo33
3 irradiated cancer cell
lines
II
Estimated 54 (CT-naive,
M0)
Trial ongoing (NCT00514072); primary end point
time-to-progression
Abbreviations: CRPC, castration-resistant prostate cancer; CT, chemotherapy; DC, dendritic cell; G‑CSF, granulocyte-colony-stimulating factor; HR, hazard ratio; PFS, progression-free survival;
PR, partial response; PSA, prostate-specific antigen; q3w, every 3 weeks; q4w, every 4 weeks.
Sipuleucel‑T is an immunotherapeutic comprising the
reinfusion of autologous peripheral blood mononuclear
cells, including antigen-presenting cells (APCs) activated
ex vivo with the recombinant fusion protein PA2024.74
PA2024 is formed by prostatic acid phosphatase fused
to granulocyte macrophage colony-stimulating factor
(GM-CSF). The vaccine is created by harvesting white
blood cells from patients, then dendritic cell precursors
are enriched and incubated with PA2024 before being
infused back into the patient.
Following two randomized, placebo-controlled
phase III clinical trials involving sipuleucel‑T in patients
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with CRPC that did not show significant effects on the
time-to-disease progression,76,77 a double-blind, placebocontrolled, multicenter trial (IMPACT) involving
patients with metastatic CRPC was conducted (Table 1).
A total of 512 asympto­m atic or minimally sympto­
matic men were randomized to receive sipuleucel‑T or
placebo. There was a relative reduction of 22% in the risk
of death in the sipuleucel‑T group (HR = 0.78; 95% CI
0.61–0.98; P = 0.03) representing an absolute 4.1 month
improvement in median overall survival (25.8 months
versus 21.7 months). Toxic effects observed more frequently in the sipuleucel‑T arm included chills, fever,
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and headaches.78 Based on these results, sipuleucel‑T was
approved by the FDA for the treatment of asymptomatic
or minimally symptomatic metastatic CRPC, representing the first therapeutic cancer vaccine in prostate cancer
to receive FDA approval.79
Alpharadin
Alpharadin (Bayer Schering Pharma, Berlin, Germany) is
a radioisotope containing an α‑particle emitting nuclide,
which was recently assessed in a randomized, placebocontrolled phase III trial (ALSYMPCA) in 922 patients
with symptomatic CRPC with bone metastases. 33,80
Alpharadin targets bone metastases with high-energy
α radiation of extremely short range that spares bone
marrow and, therefore, limits toxic effects. Based on a
recommendation from an Independent Data Monitoring
Committee following a pre-planned interim analysis,
the phase III study was stopped and patients on the
placebo arm were offered treatment with alpharadin.81
The primary end point of the study, overall survival, was
signifi­cantly increased in the alpharadin arm (two-sided
P value = 0.0022, HR = 0.699); the median overall survival
was 14.0 months for patients in the alpharadin arm and
11.2 months for those receiving placebo.80
Key issues for drug development
There is now an impressive range of targeted therapies being assessed at different phases of clinical trial
develop­ment (Tables 1–3 and Supplementary Tables 1
and 2 online). These include novel agents against a
wide array of rational targets involving multiple key
biological mechanistic drivers of CRPC, ranging from
anti­angiogenic agents to MET inhibitors (Figure 1 and
Table 3).
Multiple compounds have proceeded to phase I–II
trials following promising preclinical data, although
not all have been assessed in CRPC-specific studies. It
is important to note, however, that despite this myriad
of agents making the transition to phase II trials, many of
these studies are failing to correctly predict phase III
trial outcomes.38 Examples of these include zibotentan
and atrasentan.82–84 These expensive and late-stage failures cause a major impact and strain on patient care, the
pharmaceutical and health-care industry and academic
institutions. Therefore, to optimize the development of
molecular therapies for CRPC, several key issues need
to be considered, such as combinatorial studies and
biomarkers, including predictive and intermediate end
point assays.
Combination studies
Given the selective nature of targeted molecular therapeutics, it is likely that combinatorial regimens will be
key to the future of drug development in CRPC. The
increased number of novel compounds being tested and
new high-throughput technologies available for the generation of molecular data have facilitated the study of
the most promising combinations.85 In theory, ‘vertical
combinations’—drugs that act along the same pathway
—or ‘horizontal combinations’—drugs that target
parallel pathways—seem rational approaches (Figure 1).
However, the likely reality is one that involves complex
interplay and crosstalk between signaling networks,
and feedback loops within individual pathways, rather
than simple linear pathways. Nonetheless, a combinatorial strategy will be key to the future development of
effective regimens in CRPC management.
Patient stratification
A cancer biomarker is a molecule that can be objectively measured and evaluated as an indicator of normal
bio­l ogical, pathogenic, or pharmacologic responses
to a therapeutic intervention. 86 Predictive and intermediate end point biomarkers should be scientifically
sound and analytically validated to ensure robust and
reproducible results.
Predictive biomarkers
Predictive biomarkers to define the appropriate patient
population for molecular therapies are likely to be essential for the development of novel agents for CRPC. Such
an approach will not be applicable to all therapeutics (for
example, chemotherapies such as docetaxel and cabazitaxel); however, in a heterogeneous disease such as CRPC,
a strategy using predictive biomarkers will help define
antitumor responses to selective targeted agents.87
A recent example is that of the TMPRSS2–ETS gene
fusion, which can be detected by fluorescence in situ
hybridization in tumor cells and circulating tumor
cells (CTCs) of patients with CRPC and might predict
antitumor responses to abiraterone.88 The ERG gene (a
member of the ETS family of oncogenes) was identified
as the most commonly overexpressed proto-oncogene in
prostate cancer—present in about 72% of cases89—and
TMPRSS2 (which codes for a serine protease secreted
in response to androgen exposure) was observed to be
fused to ERG.90 This TMPRSS2–ETS fusion leads to overexpression of ERG, initially under the control of androgen and the AR but androgen dependence may be lost
in advanced-stage disease; activation of this pathway
might be central to prostate oncogenesis.91,92 Clinical
trials assessing abiraterone have indicated that the presence of an ERG rearrangement was associated with the
magnitude of PSA decline following abiraterone treatment (P = 0.007).88 This association is being prospectively evaluated in the phase III trial of abiraterone and
prednisone versus placebo and prednisone and results
are expected soon.
Intermediate end point biomarkers
One of the main hurdles for studies assessing the efficacy
of agents in the post-docetaxel setting remains the lack of
a standardized definition for docetaxel progression or
resistance. This issue does not just belie docetaxel treatment, but is a wider challenge in patients with metastatic
CRPC. Current strategies to evaluate disease response
and progression employ a combination of parameters,
including rising serum PSA levels using the prostate
working group criteria, 93 RECIST radiological cri­
teria94 and worsening clinical symptoms. 95 However,
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Table 3 | Novel targets in prostate cancer
Target
Clinical data
HSP90
Phase II trial of 17-AAG in CRPC: closed prematurely owing to lack of response119,120
Clusterin
Phase II with OGX‑011 trial in chemotherapy-naive PC: improved PFS and OS121
BCL2
Phase I of oblimersen and mitoxantrone: good tolerance122
Phase I of oblimersen plus docetaxel in CRPC: PSA response in 7 of 12 taxane-naive patients, no
response in taxane-treated patients123
Randomized phase II trial of oblimersen and docetaxel vs docetaxel in CRPC: similar response
rates but increased toxicity in the combination arm107
Phase I–II trial of AT‑101 in CRPC: PSA declines124
Survivin
Phase I and II trials of YM155 in CRPC: PSA responses125
Combination of YM155, docetaxel and predisone: well tolerated with antitumor activity observed126
PARP‑1
Phase I trial of olaparib in BRCA1 or BRCA2 mutated CRPC: activity reported127
DNA methyltransferase
Phase II trial with azacitidine in CRPC: promising results128,129
HDACs
Phase II trial of vorinostat in CRPC: limited activity and considerable toxicity130
Phase I trial of vorinostat and docetaxel in solid tumors: poorly tolerated, no objective responses131
Phase II trial of romidepsin in CRPC: minimal activity and high toxicity132
VEGF or VEGFR
Phase II trial of docetaxel, estramustine and bevacizumab in CRPC: ≥50% PSA response in 75%
of patients with median OS of 24 months133
Phase III trial of docetaxel and prednisolone with or without bevacizumab: no improvement in OS53
Phase II trial of bevacizumab, thalidomide, docetaxel and prednisolone: PSA decline of ≥50%
in 90% of patients and a median OS of 28.2 months134
Phase II trial of sorafenib in CRPC: no objective responses and no PSA responses, regression
of bone disease was seen135
Two phase II trials of sorafenib in chemotherapy-naive CRPC: limited activity136,137
Sunitinib in CRPC after docetaxel failure: 12% of patients had >50% PSA decline, 11% of patients
with measurable disease had a partial response and, median PFS of 19.4 weeks138
Phase I–II trial of aflibercept in solid tumors: well tolerated with early signals of activity139
Phase II trials of cediranib in post-docetaxel CRPC: promising activity140
Vandetanib in CRPC: no activity compared with placebo141
PDGFR
Trial of imatinib and zoledronic acid: no response and the trial was closed prematurely142
Trial of imatinib plus docetaxel vs docetaxel: closed prematurely owing to gastrointestinal toxicity
in the combination arm143
Src
Phase I trial of saracatinib in solid tumors: well tolerated144
Phase II trial of dasatinib in chemotherapy-naive patients with CRPC: lack of disease progression
achieved in 21 (44%) patients at week 12 and in 8 (17%) patients at week 24145
Endothelin
Two placebo-controlled phase III trials of atrasentan in CRPC: no reduction in risk of disease
progression83,84
Phase III trial of atrasentan plus docetaxel: ongoing following results of phase I–II trial146
Randomized phase II trial of zibotentan vs placebo in CRPC: promising survival results82,147
EGFR
Phase Ib–IIa trial of doxorubicin and cetuximab in CRPC: minimal activity148
Several trials of gefitinib in CRPC: minimal activity as single agent,149–151 and no added efficacy
in combination with docetaxel152
HER2
Trastuzumab in CRPC: very limited activity153
Small study of docetaxel, estramustine and trastuzumab: 9 of 13 patients had a ≥50% PSA
decline154
Single-agent lapatinib in advanced-stage hormone-naive PC: no antitumor activity155
PI3K/Akt/‌mTOR
Everolimus, temsirolimus and OSI‑027: undergoing clinical trials in CRPC33
PKC-β
Phase II trial of enzastaurin: very limited activity, will be tested with docetaxel156
IGF pathway
Phase II trials of cixutumumab: ongoing157
Phase II trial of preoperative figitumumab in localized prostate cancer: 31% of patients had >50%
PSA decline158
Phase II trials of figitumumab and docetaxel in solid tumors: 3 of 18 patients with CRPC showed
PR, 41% (9/22) patients had ≥50% PSA response159
Phase II trial with figitumumab and docetaxel in CRPC ongoing33
IL-6R/JAK/‌STAT3
Phase II trial of siltuximab in post-chemotherapy CRPC: PSA response rate of 3.8% and stable
disease in 23%160
MET/VEGFR2/‌RET
Phase II trial of cabozantinib in CRPC with measurable soft-tissue disease: 56 of 65 patients with
bone metastasis from CRPC achieved either complete or partial resolution of lesions on bone
scan; evidence of tumor shrinkage in 84% of patients with measurable soft-tissue disease161
Phase I trials of specific MET inhibitor ARQ 197: CTC declines and RECIST PR in CRPC162,163
Abbreviations: CRPC, castration-resistant prostate cancer; CTC, circulating tumor cell; HDAC, histone deacetylase; IGF, insulin-like growth factor; OS, overall
survival; PARP, poly(ADP) ribose polymerase; PC, prostate cancer; PDGFR, platelet-derived growth factor receptor; PFS, progression-free survival; PR, partial
response; PSA, prostate-specific antigen.
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Extracellular
space
VEGFR
P
P
P
P
P
P
EGFR
P
P
P
HER2
P
P
P
P
P
P
P
P
P
MET
IGF-1R
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
ETA
IL-6
PDGFR
P
P
P
P
P
P
Cytoplasm
P
P
P
P
P
P
JAK/STAT3
Ras
P
P
P
Angiogenesis
Survival
PI3K
AR
Raf
Clusterin
MEK
Treatment
resistance
ERK
Src
AR
Akt
p53
BIM
BCL2
Survival
mTOR
NF-κB
Angiogenesis
Proliferation
Differentiation
Therapy resistance
Ribosomal protein synthesis
Apoptosis
Hsp90
AR
PKC
DNA repair
Methylation
PARP
DNMTs
Deacetylation
Survivin
Cell-cycle progression
Proliferation
Differentiation
AR
ER
ARE
Nucleus
ERE
AR
TMPRSS2
ER ligand
HDACs
ER
ERG
AR ligand
P
Phosphorylation
Figure 1 | Key signaling cascades involved in prostate cancer. A wide range of agents, both approved and under
development, target pathways that are involved in prostate cancer (Table 3). Abbreviations: AR, androgen receptor; BIM,
BLC2-interacting mediator of cell death; DNMT, DNA methyl transferase; ER, estrogen receptor; ET A, endothelin receptor
type A; HDAC, histone deacetylase; HSP, heat-shock protein; IGF-1R, insulin-like growth factor receptor 1; IL, interleukin;
mTOR, mammalian target of rapamycin; NF‑κB, nuclear factor κB; PARP, poly(ADP) ribose polymerase; PDGFR,
platelet derived growth factor receptor; STAT, signal transducers and activators of transcription.
with improved technologies and reduced costs, it is
likely that the use of novel analytically validated and
clinically qualified intermediate end point biomarkers
will become more commonplace. These are likely to
include the use of CTCs and functional imaging, such as
diffusion‑weighted MRI techniques.87,96
With multiple novel agents for CRPC, new approaches
for clinical trials are also essential. Overall survival is the
only robust end point, but this means greater chances
of treatment crossover as multiple new drugs are being
evalu­ated, which can jeopardize successful trial outcomes.
PFS is a poor surrogate for overall survival in prostate
cancer, with overall associations between PFS and overall
survival at best moderate (0.4 for radiographic PFS and
0.33 for PSA PFS).95 Therefore, it is essential that inter­
mediate end point biomarkers that are robust surrogates
of overall survival are developed to accurately reflect
treatment benefit at earlier time points.98
Historically, the biomarker associated with prostate
cancer for screening, and patient stratification at diagnosis and following primary local therapy is PSA. 99 To
improve the specificity and sensitivity of this biomarker,
several PSA algorithms have been described (such as
PSA doubling time);100 however, PSA level is not always
representative of the disease, especially in the advancedstage phases when CRPC may modify its phenotype.101
In addition, PSA fluctuations during the first 12 weeks
of treatment for CRPC are not indicative of early therapy
failure.95 Several studies have been conducted or are
ongoing to evaluate potential new markers that are able
to better represent the complexity of CRPC, including intact CTCs, CTC fragments or exosomes, circu­
lating plasma DNA, protein multiplex plasma assays
and metabolomics.102,103
The FDA has approved the CellSearch® CTC System
as a prognostic indicator for patients with metastatic
breast, colorectal and prostate cancers.104 The molecular
characterization of CTCs may potentially offer a ‘liquid
biopsy’ for patient selection, monitoring of treatment
efficacy and the identification of drug-resistant mechanisms. Recently, the relationship between post-therapy
CTC counts and overall survival was demonstrated
in patients with CRPC.98 A total of 231 patients were
stratified into predetermined ‘favorable’ or ‘unfavorable’ groups, based on the number of CTCs (<5 and
≥5 CTCs/7.5ml of blood). Patients with unfavorable
pre-treatment CTC levels had a shorter overall survival
than those in the favorable group (11.5 months versus
21.7 months; HR = 3.3; P <0.0001). CTC counts were
better at predicting overall survival than PSA algorithms
at all time points assessed (P = 0.0218). The prognosis for
patients with unfavorable baseline CTC counts who converted to favorable CTC counts improved (6.8 months to
21.3 months), while patients with favorable baseline CTC
count who converted to an unfavorable count worsened
(>26 months to 9.3 months). Based on these data, CTCs
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Treatment paradigm in 2011 and beyond
2011
Beyond 2011
Gonadotropin-releasing hormone agonist
Gonadotropin-releasing hormone agonist
Gonadotropin-releasing hormone agonist
+ bicalutamide
Sipuleucel-T?
Sipuleucel-T?
Gonadotropin-releasing hormone agonist
+ abiraterone + low-dose steroids
Low-dose steroids
Stilbestrol?
Stilbestrol?
Docetaxel
Docetaxel
Cabazitaxel
Abiraterone
■ Reassessment with conventional imaging
and intermediate end point biomarkers
(e.g. CTCs and functional imaging)
■ Patient molecular stratification with
analytically validated biomarkers
Cabazitaxel
■ Reassessment with PSA and CT
or bone scans
Figure 2 | Treatment paradigm for CRPC in 2011 and beyond. The gold standard for
CRPC remains docetaxel; however, positive results with cabazitaxel, sipuleucel‑T and
abiraterone provide a range of agents, and stilbestrol and low-dose steroids should
also be considered. In the current treatment pathway, cabazitaxel and abiraterone
are in the post-docetaxel setting and sipuleucel‑T is in the pre-docetaxel setting in
line with FDA approval. In the future, this pathway will inevitably change substantially,
as factors including resistance to prior therapies and drug availability determine the
sequence of drugs. In addition, efforts should be made to molecularly stratify
patients to match targeted therapies (Figure 1 and Table 3). The decision for
treatment transition should incorporate standard clinicopathological measures, novel
biomarkers (such as CTCs and circulating plasma DNA) and imaging modalities (such
as diffusion weighted-MRI and F18 PET). Abbreviations: CRPC, castration-resistant
prostate cancer; CTCs, circulating tumor cells; PSA, prostate-specific antigen.
are an accurate and independent predictor of overall survival in CRPC and are likely to predict prognosis and
monitor the antitumor effects of treatment in CRPC in
the future (Figure 2).98 Using CTCs as an intermediate
end point for overall survival is being assessed in ongoing
clinical trials (NCT00638690; NCT01084655).33
New CRPC therapeutic landscape
First-line therapy for CRPC is docetaxel; however, with
positive results now available from phase III trials of
cabazitaxel, sipuleucel‑T and abiraterone, and data for
MDV‑3100 expected soon, we now have a cocktail of
agents to choose from. Although survival gains are measured in months for each agent, careful deliberation must
be given to the rational use of these agents to optimize
their administration (Figure 2).
Factors such as drug-related toxicities and the acquired
cross resistance to individual agents after exposure to a
prior therapy have to be considered. For example, it was
606 | OCTOBER 2011 | VOLUME 8
recently shown that chemotherapies such as doce­taxel
not only inhibit cell division, but also impair AR signaling through significant AR translocation.62,105 Therefore,
it might be possible that by affecting the AR with docetaxel, cross resistance to other AR antagonists may arise.
It is likely that the novel agents currently approved or
being assessed for use following docetaxel treatment will
have an eventual role in the pre-docetaxel setting. Since
taxanes modulate AR signaling, it will be important to
consider if taxanes are as active in patients with CRPC
following treatment with agents such as abiraterone or
MDV‑3100, or if these agents will negatively impact
taxane benefit.
Transition from one treatment to the next should be
initiated based not just on a combination of clinical, biochemical and radiological measures, but also on novel
biomarkers and functional imaging modalities.87,96 It is
crucial that such biomarkers are analytically validated
and clinically qualified, before their wider use as decision
end points.87 Key questions about the biology of prostate
cancer remain; for example, does advanced-stage CRPC
ever truly become nuclear-steroid receptor independent?
The reality is that unless we start seeing patients developing disease progression without a rising PSA, we should
not assume this to be the case.
Conclusions
These are exciting times for the treatment of advancedstage prostate cancer, but much remains to be done,
particu­larly in the introduction of novel treatments in
the adjuvant setting where it is envisioned higher cure
rates may be achievable. Overall, we are entering a new
era in CRPC management surrounded by a very different treatment landscape. In 2010 and 2011, there
were four positive phase III trials for CRPC—although
the alpharadin data have not yet been fully reported;
along with docetaxel, these therapeutics have demonstrated survival benefits in CRPC, with three obtaining
FDA approval (Figure 2). It is now critical that these
agents are appropriately applied to the CRPC treatment pathway to maximize benefits for patients with
advanced-stage prostate cancer. Such an approach will
require the incorporation of novel functional imaging
modalities and predictive and inter­mediate end point
biomarkers. Despite these recent advances, efforts
should continue to develop novel agents through intelli­
gent trial designs that involve molecular therapeutics in
selected patient populations.
Review criteria
Data for this review was compiled using the PubMed, ASCO
abstract and ESMO abstract databases published before
30 June 2011. The search terms included “castration
resistant prostate cancer”, “docetaxel”, “abiraterone”,
“CYP17”, “androgen receptor”, “cabazitaxel”,
“sipuleucel‑T”, “alpharadin”, “MDV‑3100”, “circulating
tumor cells” and “biomarkers”. Data on clinical trials were
obtained from: http://www.clinicaltrials.gov. Only articles
published in English were considered.
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1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
Jemal, A., Siegel, R., Xu, J. & Ward, E. Cancer
statistics, 2010. CA Cancer J. Clin. 60,
277–300 (2010).
Ferlay, J., Parkin, D. M. & Steliarova-Foucher, E.
Estimates of cancer incidence and mortality in
Europe in 2008. Eur. J. Cancer 46, 765–781
(2010).
Pienta, K. J. & Bradley, D. Mechanisms
underlying the development of androgenindependent prostate cancer. Clin. Cancer Res.
12, 1665–1671 (2006).
Yap, T. A., Carden, C. P., Attard, G. & de
Bono, J. S. Targeting CYP17: established and
novel approaches in prostate cancer. Curr. Opin.
Pharmacol. 8, 449–457 (2008).
[No authors listed]. Maximum androgen
blockade in advanced prostate cancer: an
overview of the randomised trials. Prostate
Cancer Trialists’ Collaborative Group. Lancet
355, 1491–1498 (2000).
Figg, W. D. et al. Prostate specific antigen
decline following the discontinuation of
flutamide in patients with stage D2 prostate
cancer. Am. J. Med. 98, 412–414 (1995).
Nishimura, K. et al. Low doses of oral
dexamethasone for hormone-refractory prostate
carcinoma. Cancer 89, 2570–2576 (2000).
Small, E. J. et al. Antiandrogen withdrawal alone
or in combination with ketoconazole in
androgen-independent prostate cancer
patients: a phase III trial (CALGB 9583). J. Clin.
Oncol. 22, 1025–1033 (2004).
Tannock, I. F. et al. Docetaxel plus prednisone
or mitoxantrone plus prednisone for advanced
prostate cancer. N. Engl. J. Med. 351,
1502–1512 (2004).
Petrylak, D. P. et al. Docetaxel and estramustine
compared with mitoxantrone and prednisone
for advanced refractory prostate cancer.
N. Engl. J. Med. 351, 1513–1520 (2004).
Attard, G. et al. Improving the outcome of
patients with castration-resistant prostate
cancer through rational drug development. Br. J.
Cancer 95, 767–774 (2006).
Chen, Y., Clegg, N. J. & Scher, H. I.
Anti‑androgens and androgen-depleting
therapies in prostate cancer: new agents for an
established target. Lancet Oncol. 10, 981–991
(2009).
Yamaoka, M., Hara, T. & Kusaka, M.
Overcoming persistent dependency on
androgen signaling after progression to
castration-resistant prostate cancer.
Clin. Cancer Res. 16, 4319–4324 (2010).
Bruno, R. D. & Njar, V. C. Targeting cytochrome
P450 enzymes: a new approach in anti-cancer
drug development. Bioorg. Med. Chem. 15,
5047–5060 (2007).
Labrie, C., Cusan, L., Plante, M., Lapointe, S. &
Labrie, F. Analysis of the androgenic activity of
synthetic “progestins” currently used for the
treatment of prostate cancer. J. Steroid
Biochem. 28, 379–384 (1987).
Titus, M. A., Schell, M. J., Lih, F. B., Tomer, K. B.
& Mohler, J. L. Testosterone and
dihydrotestosterone tissue levels in recurrent
prostate cancer. Clin. Cancer Res. 11,
4653–4657 (2005).
He, B. et al. Structural basis for androgen
receptor interdomain and coactivator
interactions suggests a transition in nuclear
receptor activation function dominance.
Mol. Cell 16, 425–438 (2004).
Taplin, M. E. et al. A phase II study of
mifepristone (RU‑486) in castration-resistant
prostate cancer, with a correlative assessment
of androgen-related hormones. BJU Int. 101,
1084–1089 (2008).
19. Chen, C. D. et al. Molecular determinants of
resistance to antiandrogen therapy. Nat. Med.
10, 33–39 (2004).
20. Harris, W. P., Mostaghel, E. A., Nelson, P. S. &
Montgomery, B. Androgen deprivation therapy:
progress in understanding mechanisms of
resistance and optimizing androgen depletion.
Nat. Clin. Pract. Urol. 6, 76–85 (2009).
21. Venkitaraman, R. et al. Efficacy of low-dose
dexamethasone in castration-refractory prostate
cancer. BJU Int. 101, 440–443 (2008).
22. Tannock, I. F. et al. Chemotherapy with
mitoxantrone plus prednisone or prednisone
alone for symptomatic hormone-resistant
prostate cancer: a Canadian randomized trial
with palliative end points. J. Clin. Oncol. 14,
1756–1764 (1996).
23. Kantoff, P. W. et al. Hydrocortisone with or
without mitoxantrone in men with hormonerefractory prostate cancer: results of the cancer
and leukemia group B 9182 study. J. Clin. Oncol.
17, 2506–2513 (1999).
24. Nishimura, K. et al. Potential mechanism for the
effects of dexamethasone on growth of
androgen-independent prostate cancer. J. Natl
Cancer Inst. 93, 1739–1746 (2001).
25. Morioka, M. et al. Prostate-specific antigen
levels and prognosis in patients with hormonerefractory prostate cancer treated with low-dose
dexamethasone. Urol. Int. 68, 10–15 (2002).
26. Saika, T. et al. Treatment of androgenindependent prostate cancer with
dexamethasone: a prospective study in stage D2
patients. Int. J. Urol. 8, 290–294 (2001).
27. Berry, W., Dakhil, S., Modiano, M., Gregurich, M.
& Asmar, L. Phase III study of mitoxantrone plus
low dose prednisone versus low dose
prednisone alone in patients with asymptomatic
hormone refractory prostate cancer. J. Urol. 168,
2439–2443 (2002).
28. Fossa, S. D. et al. Weekly docetaxel and
prednisolone versus prednisolone alone in
androgen-independent prostate cancer:
a randomized phase II study. Eur. Urol. 52,
1691–1698 (2007).
29. Chang, C. Y., Walther, P. J. & McDonnell, D. P.
Glucocorticoids manifest androgenic activity in a
cell line derived from a metastatic prostate
cancer. Cancer Res. 61, 8712–8717 (2001).
30. Fousteris, M. A. et al. 20-Aminosteroids as a
novel class of selective and complete androgen
receptor antagonists and inhibitors of prostate
cancer cell growth. Bioorg. Med. Chem. 18,
6960–6969 (2010).
31. Tran, C. et al. Development of a secondgeneration antiandrogen for treatment of
advanced prostate cancer. Science 324,
787–790 (2009).
32. Scher, H. I. et al. Antitumour activity of MDV3100
in castration-resistant prostate cancer: a
phase 1–2 study. Lancet 375, 1437–1446
(2010).
33. US National Library of Medicine. ClinicalTrials.gov
[online], www.ClinicalTrials.gov (2011).
34. Jarman, M., Barrie, S. E. & Llera, J. M.
The 16, 17-double bond is needed for
irreversible inhibition of human cytochrome
p45017alpha by abiraterone (17‑(3-pyridyl)
androsta‑5, 16‑dien‑3beta-ol) and related
steroidal inhibitors. J. Med. Chem. 41,
5375–5381 (1998).
35. Rowlands, M. G. et al. Esters of 3‑pyridylacetic
acid that combine potent inhibition of 17 alphahydroxylase/C17, 20-lyase (cytochrome P45017
alpha) with resistance to esterase hydrolysis.
J. Med. Chem. 38, 4191–4197 (1995).
36. Potter, G. A., Barrie, S. E., Jarman, M. &
Rowlands, M. G. Novel steroidal inhibitors of
NATURE REVIEWS | CLINICAL ONCOLOGY human cytochrome P45017 alpha
(17 alpha‑hydroxylase‑C17, 20-lyase): potential
agents for the treatment of prostatic cancer.
J. Med. Chem. 38, 2463–2471 (1995).
37. Barrie, S. E. et al. Pharmacology of novel
steroidal inhibitors of cytochrome P450(17)
alpha (17 alpha-hydroxylase/C17–20 lyase).
J. Steroid Biochem. Mol. Biol. 50, 267–273
(1994).
38. Bianchini, D., Zivi, A., Sandhu, S. & de Bono, J. S.
Horizon scanning for novel therapeutics for the
treatment of prostate cancer. Expert Opin.
Investig. Drugs 19, 1487–1502 (2010).
39. O’Donnell, A. et al. Hormonal impact of the
17alpha-hydroxylase/C(17, 20)-lyase inhibitor
abiraterone acetate (CB7630) in patients with
prostate cancer. Br. J. Cancer 90, 2317–2325
(2004).
40. Attard, G. et al. Phase I clinical trial of a selective
inhibitor of CYP17, abiraterone acetate,
confirms that castration-resistant prostate
cancer commonly remains hormone driven.
J. Clin. Oncol. 26, 4563–4571 (2008).
41. Attard, G. et al. Selective inhibition of CYP17
with abiraterone acetate is highly active in the
treatment of castration-resistant prostate
cancer. J. Clin. Oncol. 27, 3742–3748 (2009).
42. Reid, A. H. et al. Significant and sustained
antitumor activity in post-docetaxel, castrationresistant prostate cancer with the CYP17
inhibitor abiraterone acetate. J. Clin. Oncol. 28,
1489–1495 (2010).
43. Ryan, C. J. et al. Phase I clinical trial of the
CYP17 inhibitor abiraterone acetate
demonstrating clinical activity in patients with
castration-resistant prostate cancer who
received prior ketoconazole therapy. J. Clin.
Oncol. 28, 1481–1488 (2010).
44. Danila, D. C. et al. Phase II multicenter study
of abiraterone acetate plus prednisone therapy
in patients with docetaxel-treated castrationresistant prostate cancer. J. Clin. Oncol. 28,
1496–1501 (2010).
45. de Bono, J. S. et al. Abiraterone and increased
survival in metastatic prostate cancer. N. Engl. J.
Med. 364, 1995–2005 (2011).
46.FDA. Abiraterone Acetate [online], http://
www.fda.gov/AboutFDA/CentersOffices/CDER/
ucm253139.htm (2011).
47. Dreicer, R. et al. Safety, pharmacokinetics, and
efficacy of TAK‑700 in metastatic castrationresistant prostrate cancer: A phase I/II, openlabel study [abstract]. J. Clin. Oncol.
28 (15 Suppl.), a3084 (2010).
48. Handratta, V. D. et al. Novel C‑17‑heteroaryl
steroidal CYP17 inhibitors/antiandrogens:
synthesis, in vitro biological activity,
pharmacokinetics, and antitumor activity in the
LAPC4 human prostate cancer xenograft model.
J. Med. Chem. 48, 2972–2984 (2005).
49. Tokai Pharmaceuticals. Tokai pharmaceuticals
initiates ARMOR clinical development program for
TOK-001; first ever multi-target investigational
drug for prostate cancer [online], http://
www.tokaipharmaceuticals.com/pdfs/
ARMORClinicalDevelopment.pdf (2009).
50. Berthold, D. R. et al. Docetaxel plus prednisone
or mitoxantrone plus prednisone for advanced
prostate cancer: updated survival in the TAX 327
study. J. Clin. Oncol. 26, 242–245 (2008).
51. Scher, H. I. et al. Docetaxel (D) plus high-dose
calcitriol versus D plus prednisone (P) for
patients (Pts) with progressive castrationresistant prostate cancer (CRPC): Results from
the phase III ASCENT2 trial [abstract]. J. Clin.
Oncol. 28, (15 Suppl.), a4509 (2010).
52. Small, E. et al. A phase III trial of GVAX
immunotherapy for prostate cancer in
VOLUME 8 | OCTOBER 2011 | 607
© 2011 Macmillan Publishers Limited. All rights reserved
REVIEWS
combination with docetaxel versus docetaxel plus
prednisone in symptomatic, castration-resistant
prostate cancer (CRPC) [abstract]. Genitourinary
Cancers Symp. a7 (2009).
53. Kelly, W. K. et al. A randomized, double-blind,
placebo-controlled phase III trial comparing
docetaxel, prednisone, and placebo with
docetaxel, prednisone, and bevacizumab in men
with metastatic castration-resistant prostate
cancer (mCRPC): Survival results of CALGB
90401 [abstract]. J. Clin. Oncol. 28 (18 Suppl.),
LBA4511 (2010).
54. Franke, R. M., Carducci, M. A., Rudek, M. A.,
Baker, S. D. & Sparreboom, A. Castrationdependent pharmacokinetics of docetaxel in
patients with prostate cancer. J. Clin. Oncol. 28,
4562–4567 (2010).
55. Ansari, J. et al. Docetaxel chemotherapy for
metastatic hormone refractory prostate cancer as
first-line palliative chemotherapy and subsequent
re-treatment: Birmingham experience. Oncol. Rep.
20, 891–896 (2008).
56. Eymard, J. C. et al. Docetaxel reintroduction in
patients with metastatic castration-resistant
docetaxel-sensitive prostate cancer: a
retrospective multicentre study. BJU Int. 106,
974–978 (2010).
57. Bracarda, S., Logothetis, C., Sternberg, C. N.
& Oudard, S. Current and emerging treatment
modalities for metastatic castration-resistant
prostate cancer. BJU Int. 107 (Suppl. 2), 13–20
(2011).
58. Sartor, A. O. et al. Satraplatin in patients with
advanced hormone-refractory prostate cancer
(HRPC): Overall survival (OS) results from the
phase III satraplatin and prednisone against
refractory cancer (SPARC) trial [abstract]. J. Clin.
Oncol. 26, a5003 (2008).
59. Kelland, L. R. et al. Preclinical antitumor
evaluation of bis‑acetato‑ammine‑dichloro‑
cyclohexylamine platinum(IV): an orally active
platinum drug. Cancer Res. 53, 2581–2586
(1993).
60. Yap, T. A., Sandhu, S. K., Carden, C. P. &
de Bono, J. S. Poly(ADP-Ribose) polymerase (PARP)
inhibitors: Exploiting a synthetic lethal strategy in
the clinic. CA Cancer J. Clin. 61, 31–49 (2011).
61. de Bono, J. S. et al. Prednisone plus cabazitaxel
or mitoxantrone for metastatic castrationresistant prostate cancer progressing after
docetaxel treatment: a randomised open-label
trial. Lancet 376, 1147–1154 (2010).
62. Attard, G., Greystoke, A., Kaye, S. & De Bono, J.
Update on tubulin-binding agents. Pathol. Biol.
(Paris) 54, 72–84 (2006).
63. Aller, A. W., Kraus, L. A. & Bissery, M.‑C. In vitro
activity of TXD258 in chemotherapeutic resistant
tumor cell lines [abstract 1923]. Proc. Am. Assoc.
Cancer Res. 41, 303 (2000).
64. Bissery, M.‑C. et al. Preclinical evaluation of
TXD258, a new taxoid [abstract 1364]. Proc. Am.
Assoc. Cancer Res. 41, 214 (2000).
65. Mita, A. C. et al. Phase I and pharmacokinetic
study of XRP6258 (RPR 116258A), a novel
taxane, administered as a 1‑hour infusion every
3 weeks in patients with advanced solid tumors.
Clin. Cancer Res. 15, 723–730 (2009).
66. Pivot, X. et al. A multicenter phase II study of
XRP6258 administered as a 1‑h i.v. infusion every
3 weeks in taxane-resistant metastatic breast
cancer patients. Ann. Oncol. 19, 1547–1552
(2008).
67.FDA. Cabazitaxel [online], http://www.fda.gov/
AboutFDA/CentersOffices/CDER/ucm216214.htm
(2010).
68. Rosenberg, J. E. et al. Activity of second-line
chemotherapy in docetaxel-refractory hormonerefractory prostate cancer patients: randomized
608 | OCTOBER 2011 | VOLUME 8
phase 2 study of ixabepilone or mitoxantrone and
prednisone. Cancer 110, 556–563 (2007).
69. Beardsley, E. K. et al. A phase II study of
patupilone in patients (pts) with metastatic
castration- resistant prostate cancer (CRPC) who
have progressed after docetaxel [abstract 5139].
J. Clin. Oncol. 27 (15 Suppl.), a5139 (2009).
70. Ribas, A. & Flaherty, K. T. BRAF targeted therapy
changes the treatment paradigm in melanoma.
Nat. Rev. Clin. Oncol. 8, 426–433 (2011).
71. Sanda, M. G. et al. Demonstration of a rational
strategy for human prostate cancer gene therapy.
J. Urol. 151, 622–628 (1994).
72. Wang, X. et al. Autoantibody signatures in
prostate cancer. N. Engl. J. Med. 353, 1224–1235
(2005).
73. Drake, C. G. Prostate cancer as a model for
tumour immunotherapy. Nat. Rev. Immunol. 10,
580–93 (2010).
74. Di Lorenzo, G., Buonerba, C. & Kantoff, P. W.
Immunotherapy for the treatment of prostate
cancer. Nat. Rev. Clin. Oncol. doi:10.1038/
nrclinonc.2011.72.
75. Brahmer, J. R. et al. Phase I study of single-agent
anti-programmed death‑1 (MDX‑1106) in
refractory solid tumors: safety, clinical activity,
pharmacodynamics, and immunologic correlates.
J. Clin. Oncol. 28, 3167–3175 (2010).
76. Small, E. J. et al. Placebo-controlled phase III trial
of immunologic therapy with sipuleucel‑T
(APC8015) in patients with metastatic,
asymptomatic hormone refractory prostate
cancer. J. Clin. Oncol. 24, 3089–3094 (2006).
77. Higano, C. S. et al. 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 (2009).
78. Kantoff, P. W. et al. Sipuleucel‑T immunotherapy
for castration-resistant prostate cancer. N. Engl. J.
Med. 363, 411–422 (2010).
79. Higano, C. S. et al. Sipuleucel‑T. Nat. Rev. Drug
Discov. 9, 513–514 (2010).
80. Nilsson, S., O’Bryan-Tear, C. G., Bolstad, B.,
Lokna, A. & Parker, C. C. Alkaline phosphatase
(ALP) normalization and overall survival in
patients with bone metastases from castrationresistant prostate cancer (CRPC) treated with
radium‑223 [abstract]. J. Clin. Oncol. 29 (Suppl.),
a4620 (2011).
81.Bayer. Alpharadin significantly improves overall
survival in phase III trial in patients with castrationresistant prostate cancer that has spread to the
bone [online], http://www.bayer.com/en/
news-detail.aspx?newsid=14775 (2011).
82. James, N. D. et al. Final safety and efficacy
analysis of the specific endothelin A receptor
antagonist zibotentan (ZD4054) in patients with
metastatic castration-resistant prostate cancer
and bone metastases who were pain-free or
mildly symptomatic for pain: a double-blind,
placebo-controlled, randomized phase II trial.
BJU Int. 106, 966–973 (2010).
83. Nelson, J. B. et al. Phase 3, randomized,
controlled trial of atrasentan in patients with
nonmetastatic, hormone-refractory prostate
cancer. Cancer 113, 2478–2487 (2008).
84. Carducci, M. A. et al. A phase 3 randomized
controlled trial of the efficacy and safety of
atrasentan in men with metastatic hormonerefractory prostate cancer. Cancer 110,
1959–1966 (2007).
85. Kummar, S., Gutierrez, M., Doroshow, J. H. &
Murgo, A. J. Drug development in oncology:
classical cytotoxics and molecularly targeted
agents. Br. J. Clin. Pharmacol. 62, 15–26 (2006).
86. Biomarkers Definitions Working Group.
Biomarkers and surrogate endpoints: preferred
definitions and conceptual framework.
Clin. Pharmacol. Ther. 69, 89–95 (2001).
87. Yap, T. A., Sandhu, S. K., Workman, P. &
de Bono, J. S. Envisioning the future of early
anticancer drug development. Nat. Rev. Cancer
10, 514–523 (2010).
88. Attard, G. et al. Characterization of ERG, AR and
PTEN gene status in circulating tumor cells from
patients with castration-resistant prostate cancer.
Cancer Res. 69, 2912–2918 (2009).
89. Petrovics, G. et al. Frequent overexpression of
ETS-related gene‑1 (ERG1) in prostate cancer
transcriptome. Oncogene 24, 3847–3852
(2005).
90. Tomlins, S. A. et al. Recurrent fusion of TMPRSS2
and ETS transcription factor genes in prostate
cancer. Science 310, 644–648 (2005).
91. Attard, G. et al. Duplication of the fusion of
TMPRSS2 to ERG sequences identifies fatal
human prostate cancer. Oncogene 27, 253–263
(2008).
92. Narod, S. A., Seth, A. & Nam, R. Fusion in the ETS
gene family and prostate cancer. Br. J. Cancer 99,
847–851 (2008).
93. Bubley, G. J. et al. Eligibility and response
guidelines for phase II clinical trials in androgenindependent prostate cancer: recommendations
from the Prostate-Specific Antigen Working Group.
J. Clin. Oncol. 17, 3461–3467 (1999).
94. Therasse, P. et al. New guidelines to evaluate the
response to treatment in solid tumors. European
Organization for Research and Treatment of
Cancer, National Cancer Institute of the United
States, National Cancer Institute of Canada.
J. Natl Cancer Inst. 92, 205–216 (2000).
95. Scher, H. I. et al. Design and end points of clinical
trials for patients with progressive prostate
cancer and castrate levels of testosterone:
recommendations of the Prostate Cancer Clinical
Trials Working Group. J. Clin. Oncol. 26,
1148–1159 (2008).
96. Yap, T. A., Sarker, D., Kaye, S. B. & de Bono, J. S
in Imaging in Oncology 3rd edn Ch. 61
(eds Husband, J. E. & Reznek, R. H.) 1366–1383
(Informa Healthcare, New York, USA 2010).
97. Scher, H. I., Warren, M. & Heller, G. The
association between measures of progression
and survival in castrate-metastatic prostate
cancer. Clin. Cancer Res. 13, 1488–1492 (2007).
98. de Bono, J. S. et al. Circulating tumor cells predict
survival benefit from treatment in metastatic
castration-resistant prostate cancer. Clin. Cancer
Res. 14, 6302–6309 (2008).
99. Lilja, H., Ulmert, D. & Vickers, A. J.
Prostate‑specific antigen and prostate cancer:
prediction, detection and monitoring. Nat. Rev.
Cancer 8, 268–278 (2008).
100.D’Amico, A. V. et al. Predictors of mortality after
prostate-specific antigen failure. Int. J. Radiat.
Oncol. Biol. Phys. 65, 656–660 (2006).
101.Attard, G. & de Bono, J. S. Prostate cancer:
PSA as an intermediate end point in clinical trials.
Nat. Rev. Urol. 6, 473–475 (2009).
102.Attard, G. & de Bono, J. S. Utilizing circulating
tumor cells: challenges and pitfalls. Curr. Opin.
Genet. Dev. 21, 50–58 (2010).
103.Defeo, E. M., Wu, C. L., McDougal, W. S. &
Cheng, L. L. A decade in prostate cancer:
from NMR to metabolomics. Nat. Rev. Urol. 8,
301–311 (2011).
104.FDA. CellSearchTM Epithelial Cell Kit/ CellSpotterTM
Analyzer—K031588 [online], http://www.fda.gov/
MedicalDevices/ProductsandMedicalProcedures/
DeviceApprovalsandClearances/RecentlyApprovedDevices/ucm081239.htm (2009).
105.Zhu, M. L. et al. Tubulin-targeting chemotherapy
impairs androgen receptor activity in prostate
cancer. Cancer Res. 70, 7992–8002 (2010).
www.nature.com/nrclinonc
© 2011 Macmillan Publishers Limited. All rights reserved
REVIEWS
106.Sternberg, C. N. et al. Multinational, doubleblind, phase III study of prednisone and either
satraplatin or placebo in patients with castraterefractory prostate cancer progressing after prior
chemotherapy: the SPARC trial. J. Clin. Oncol. 27,
5431–5438 (2009).
107.Sternberg, C. N. et al. Docetaxel plus oblimersen
sodium (Bcl‑2 antisense oligonucleotide): an
EORTC multicenter, randomized phase II study in
patients with castration-resistant prostate
cancer. Ann. Oncol. 20, 1264–1269 (2009).
108.Sonpavde, G. et al. Sunitinib malate for
metastatic castration-resistant prostate cancer
following docetaxel-based chemotherapy.
Ann. Oncol. 21, 319–324 (2009).
109.Cathomas, R. et al. Cetuximab in combination
with docetaxel in patients (pts) with metastatic
castration resistant (mCRPC) and docetaxelrefractory prostate cancer: A multicenter
phase II trial (SAKK 08/07) [abstract]. J. Clin.
Oncol. 28 (15 Suppl.), a4666 (2010).
110.Small, E. et al. Randomized phase II study
comparing 4 monthly doses of ipilimumab
(MDX‑010) as a single agent or in combination
with a single dose of docetaxel in patients with
hormone-refractory prostate cancer [abstract].
J. Clin. Oncol. 24 (18 Suppl.), a4609 (2006).
111.Beer, T. M. et al. Randomized, double-blind,
phase III trial to compare the efficacy of
ipilimumab (Ipi) versus placebo in asymptomatic
or minimally symptomatic patients (pts) with
metastatic chemotherapy-naïve castrationresistant prostate cancer (CRPC) [abstract].
J Clin. Oncol. 29 (Suppl.), TPS182 (2011).
112.Drake, C. G. et al. A randomized, double-blind,
phase III trial comparing ipilimumab versus
placebo following radiotherapy (RT) in patients
(pts) with castration-resistant prostate cancer
(CRPC) who have received prior treatment with
docetaxel (D) [abstract]. J. Clin. Oncol.
29 (Suppl.), TPS181 (2011).
113.Tollefson, M. K. et al. A randomized phase II
study of ipilimumab with androgen ablation
compared with androgen ablation alone in
patients with advanced prostate cancer
[abstract]. Genitourinary Cancers Symp. a168
(2010).
114.Granberg, C. F. et al. Conversion of advanced
prostate cancer to organ-confined minimal
residual disease using CTLA‑4 blockade
(ipilimumab) immunotherapy [abstract].
Genitourinary Cancers Symp. a33 (2010).
115.Mohebtash, M. et al. Phase I trial of targeted
therapy with PSA-TRICOM vaccine (V) and
ipilimumab (ipi) in patients (pts) with metastatic
castration-resistant prostate cancer (mCRPC)
[abstract]. J. Clin. Oncol. 27 (15 Suppl.), a5144
(2009).
116.Madan, R. A. et al. Overall survival (OS) analysis
of a phase l trial of a vector-based vaccine (PSATRICOM) and ipilimumab (Ipi) in the treatment of
metastatic castration-resistant prostate cancer
(mCRPC) [abstract]. Genitourinary Cancers
Symp. a38 (2010).
117.Fong, L. et al. Potentiating endogenous antitumor
immunity to prostate cancer through combination
immunotherapy with CTLA4 blockade and
GM‑CSF. Cancer Res. 69, 609–615 (2009).
118.Kantoff, P. W. et al. Overall survival analysis of a
phase II randomized controlled trial of a Poxviralbased PSA-targeted immunotherapy in
metastatic castration-resistant prostate cancer.
J. Clin. Oncol. 28, 1099–1105 (2010).
119.Heath, E. I. et al. A phase II trial of
17‑allylamino‑17-demethoxygeldanamycin in
patients with hormone-refractory metastatic
prostate cancer. Clin. Prostate Cancer 4,
138–141 (2005).
120.Heath, E. I. et al. A phase II trial of
17‑allylamino‑17-demethoxygeldanamycin in
patients with hormone-refractory metastatic
prostate cancer. Clin. Cancer Res. 14,
7940–7946 (2008).
121.Chi, K. N. et al. Randomized phase II study of
docetaxel and prednisone with or without
OGX‑011 in patients with metastatic castrationresistant prostate cancer. J. Clin. Oncol. 28,
4247–4254 (2010).
122.Chi, K. N. et al. A phase I dose-finding study of
combined treatment with an antisense Bcl‑2
oligonucleotide (Genasense) and mitoxantrone
in patients with metastatic hormone-refractory
prostate cancer. Clin. Cancer Res. 7, 3920–3927
(2001).
123.Tolcher, A. W. Preliminary phase I results of
G3139 (bcl‑2 antisense oligonucleotide) therapy
in combination with docetaxel in hormonerefractory prostate cancer. Semin. Oncol. 28,
67–70 (2001).
124.Liu, G. et al. An open-label, multicenter, phase I/II
study of single-agent AT‑101 in men with
castrate-resistant prostate cancer. Clin. Cancer
Res. 15, 3172–3176 (2009).
125.Tolcher, A. W. et al. Phase I and pharmacokinetic
study of YM155, a small-molecule inhibitor of
survivin. J. Clin. Oncol. 26, 5198–5203 (2008).
126.Tolcher, A. W. et al. Phase I/II open-label study of
YM155 plus docetaxel and prednisone in men
with hormone refractory prostate cancer (HRPC)
[abstract]. Genitourinary Cancers Symp. a214
(2009).
127.Fong, P. C. et al. Inhibition of poly(ADP-ribose)
polymerase in tumors from BRCA mutation
carriers. N. Engl. J. Med. 361, 123–134 (2009).
128.Sonpavde, G. et al. Azacitidine favorably
modulates PSA kinetics correlating with plasma
DNA LINE‑1 hypomethylation in men with
chemonaive castration-resistant prostate
cancer. Urol. Oncol. doi:10.1016/
j.urolonc.2009.09.015.
129.Sonpavde, G. et al. Phase II study of azacitidine
to restore responsiveness of prostate cancer to
hormonal therapy. Clin. Genitourin. Cancer 5,
457–459 (2007).
130.Bradley, D. et al. Vorinostat in advanced prostate
cancer patients progressing on prior
chemotherapy (National Cancer Institute Trial
6862): trial results and interleukin‑6 analysis:
a study by the Department of Defense Prostate
Cancer Clinical Trial Consortium and University
of Chicago Phase 2 Consortium. Cancer 115,
5541–5549 (2009).
131.Schneider, B. J. et al. Phase I study of vorinostat
(suberoylanilide hydroxamic acid, NSC 701852)
in combination with docetaxel in patients with
advanced and relapsed solid malignancies.
Invest. New Drugs doi:10.1007/
s10637-010-9503-6.
132.Molife, L. R. et al. Phase II, two-stage, single-arm
trial of the histone deacetylase inhibitor (HDACi)
romidepsin in metastatic castration-resistant
prostate cancer (CRPC). Ann. Oncol. 21,
109–113 (2009).
133.Picus, J. et al. A phase 2 study of estramustine,
docetaxel, and bevacizumab in men with
castrate-resistant prostate cancer: results from
Cancer and Leukemia Group B Study 90006.
Cancer 117, 525–533 (2011).
134.Ning, Y. M. et al. Phase II trial of bevacizumab,
thalidomide, docetaxel, and prednisone in
patients with metastatic castration-resistant
prostate cancer. J. Clin. Oncol. 28, 2070–2076
(2010).
135.Dahut, W. L. et al. A phase II clinical trial of
sorafenib in androgen-independent prostate
cancer. Clin. Cancer Res. 14, 209–214 (2008).
NATURE REVIEWS | CLINICAL ONCOLOGY 136.Chi, K. N. et al. A phase II study of sorafenib in
patients with chemo-naive castration-resistant
prostate cancer. Ann. Oncol. 19, 746–751
(2008).
137.Steinbild, S. et al. A clinical phase II study with
sorafenib in patients with progressive hormonerefractory prostate cancer: a study of the CESAR
Central European Society for Anticancer Drug
Research-EWIV. Br. J. Cancer 97, 1480–1485
(2007).
138.Sonpavde, G. et al. Sunitinib malate for
metastatic castration-resistant prostate cancer
following docetaxel-based chemotherapy.
Ann. Oncol. 21, 319–324 (2010).
139.Tew, W. P. et al. Phase 1 study of aflibercept
administered subcutaneously to patients with
advanced solid tumors. Clin. Cancer Res. 16,
358–366 (2010).
140.Adelberg, D. et al. A phase II study of cediranib in
post-docetaxel, castration-resistant prostate
cancer (CRPC) [abstract]. Genitourinary Cancers
Symp. a63 (2010).
141.Horti, J. et al. A randomized, double-blind,
placebo-controlled phase II study of vandetanib
plus docetaxel/prednisolone in patients with
hormone-refractory prostate cancer. Cancer
Biother. Radiopharm. 24, 175–180 (2009).
142.Tiffany, N. M., Wersinger, E. M., Garzotto, M. &
Beer, T. M. Imatinib mesylate and zoledronic acid
in androgen-independent prostate cancer.
Urology 63, 934–939 (2004).
143.Mathew, P. et al. Platelet-derived growth factor
receptor inhibition and chemotherapy for
castration-resistant prostate cancer with bone
metastases. Clin. Cancer Res. 13, 5816–5824
(2007).
144.Baselga, J. et al. Phase I safety,
pharmacokinetics, and inhibition of SRC activity
study of saracatinib in patients with solid tumors.
Clin. Cancer Res. 16, 4876–4883 (2010).
145.Yu, E. Y. et al. Once-daily dasatinib: expansion of
phase II study evaluating safety and efficacy of
dasatinib in patients with metastatic castrationresistant prostate cancer. Urology 77,
1166–1171 (2011).
146.Armstrong, A. J. et al. A phase I-II study of
docetaxel and atrasentan in men with castrationresistant metastatic prostate cancer.
Clin. Cancer Res. 14, 6270–6276 (2008).
147.James, N. D. et al. Safety and efficacy of the
specific endothelin‑A receptor antagonist
ZD4054 in patients with hormone-resistant
prostate cancer and bone metastases who were
pain free or mildly symptomatic: a double-blind,
placebo-controlled, randomised, phase 2 trial.
Eur. Urol. 55, 1112–1123 (2009).
148.Slovin, S. F. et al. Anti-epidermal growth factor
receptor monoclonal antibody cetuximab plus
Doxorubicin in the treatment of metastatic
castration-resistant prostate cancer. Clin.
Genitourin. Cancer 7, E77–E82 (2009).
149.Boccardo, F. et al. Prednisone plus gefitinib
versus prednisone plus placebo in the treatment
of hormone-refractory prostate cancer:
a randomized phase II trial. Oncology 74,
223–228 (2008).
150.Small, E. J. et al. A phase II trial of gefitinib in
patients with non-metastatic hormone-refractory
prostate cancer. BJU Int. 100, 765–769 (2007).
151.Canil, C. M. et al. Randomized phase II study of
two doses of gefitinib in hormone-refractory
prostate cancer: a trial of the National Cancer
Institute of Canada-Clinical Trials Group. J. Clin.
Oncol. 23, 455–460 (2005).
152.Salzberg, M. et al. An open-label,
noncomparative phase II trial to evaluate the
efficacy and safety of docetaxel in combination
with gefitinib in patients with hormone-refractory
VOLUME 8 | OCTOBER 2011 | 609
© 2011 Macmillan Publishers Limited. All rights reserved
REVIEWS
metastatic prostate cancer. Onkologie 30,
355–360 (2007).
153.Ziada, A. et al. The use of trastuzumab in the
treatment of hormone refractory prostate
cancer; phase II trial. Prostate 60, 332–337
(2004).
154.Small, E. J., Bok, R., Reese, D. M., Sudilovsky, D.
& Frohlich, M. Docetaxel, estramustine, plus
trastuzumab in patients with metastatic
androgen-independent prostate cancer. Semin.
Oncol. 28, 71–76 (2001).
155.Sridhar, S. S. et al. A multicenter phase II clinical
trial of lapatinib (GW572016) in hormonally
untreated advanced prostate cancer. Am. J. Clin.
Oncol. 33, 609–613 (2010).
156.Dreicer, R. et al. Oral enzastaurin in prostate
cancer: A two-cohort phase II trial in patients
with PSA progression in the non-metastatic
castrate state and following docetaxel-based
chemotherapy for castrate metastatic disease.
Invest. New Drugs doi:10.1007/
s10637-010-9428-0.
157.Higano, C. et al. A phase II study evaluating the
efficacy and safety of single agent IMC A12, a
monoclonal antibody (MAb), against the insulinlike growth factor‑1 receptor (IGF-IR), as
monotherapy in patients with metastastic,
asymptomatic castration-resistant prostate
cancer (CRPC) [abstract]. J. Clin. Oncol.
27 (15 Suppl.), a5142 (2009).
158.Chi, K. N. et al. A phase II study of preoperative
figitumumab (F) in patients (pts) with localized
prostate cancer (PCa) [abstract]. J. Clin. Oncol.
28 (15 Suppl.), a4662 (2010).
159.Molife, L. R. et al. The insulin-like growth factor‑I
receptor inhibitor figitumumab (CP‑751,871) in
combination with docetaxel in patients with
advanced solid tumours: results of a phase Ib
dose-escalation, open-label study. Br. J. Cancer
103, 332–339 (2010).
160.Dorff, T. B. et al. Clinical and correlative results
of SWOG S0354: a phase II trial of CNTO328
(siltuximab), a monoclonal antibody against
interleukin‑6, in chemotherapy-pretreated
patients with castration-resistant prostate
cancer. Clin. Cancer Res. 16, 3028–3034
(2010).
161.Hussain, M. et al. Cabozantinib (XL184) in
metastatic castration-resistant prostate cancer
(mCRPC): Results from a phase II randomized
discontinuation trial [abstract]. J. Clin. Oncol.
29 (Suppl.) a4516 (2011).
162.Yap, T. A. et al. Phase I trial of a selective c‑MET
inhibitor ARQ 197 incorporating proof of
mechanism pharmacodynamic studies. J. Clin.
Oncol. 29, 1271–1279 (2011).
163.Mekhail, T. et al. Final results: A dose escalation
phase I study of ARQ 197, a selective c‑Met
inhibitor, in patients with metastatic solid tumors
[abstract]. J. Clin. Oncol. 27 (15 Suppl.), a3548
(2009).
164.Holzbeierlein, J. et al. Gene expression analysis
of human prostate carcinoma during hormonal
therapy identifies androgen-responsive genes
and mechanisms of therapy resistance. Am. J.
Pathol. 164, 217–227 (2004).
610 | OCTOBER 2011 | VOLUME 8
165.Stanbrough, M. et al. Increased expression of
genes converting adrenal androgens to
testosterone in androgen-independent prostate
cancer. Cancer Res. 66, 2815–2825 (2006).
166.Edwards, J., Krishna, N. S., Grigor, K. M. &
Bartlett, J. M. Androgen receptor gene
amplification and protein expression in hormone
refractory prostate cancer. Br. J. Cancer 89,
552–556 (2003).
167.Brooke, G. N., Parker, M. G. & Bevan, C. L.
Mechanisms of androgen receptor activation
in advanced prostate cancer: differential
co‑activator recruitment and gene expression.
Oncogene 27, 2941–2950 (2008).
168.Hara, T. et al. Novel mutations of androgen
receptor: a possible mechanism of bicalutamide
withdrawal syndrome. Cancer Res. 63, 149–153
(2003).
169.Elo, J. P. et al. Mutated human androgen receptor
gene detected in a prostatic cancer patient is
also activated by estradiol. J. Clin. Endocrinol.
Metab. 80, 3494–3500 (1995).
170.Tan, J. et al. Dehydroepiandrosterone activates
mutant androgen receptors expressed in the
androgen-dependent human prostate cancer
xenograft CWR22 and LNCaP cells. Mol.
Endocrinol. 11, 450–459 (1997).
171.Schweizer, L. et al. The androgen receptor can
signal through Wnt/beta-catenin in prostate
cancer cells as an adaptation mechanism to
castration levels of androgens. BMC Cell Biol.
9, 4 (2008).
172.Marcelli, M. et al. Androgen receptor mutations
in prostate cancer. Cancer Res. 60, 944–949
(2000).
173.Taplin, M. E. et al. Mutation of the androgenreceptor gene in metastatic androgenindependent prostate cancer. N. Engl. J. Med.
332, 1393–1398 (1995).
174.Fenton, M. A. et al. Functional characterization
of mutant androgen receptors from androgenindependent prostate cancer. Clin. Cancer Res.
3, 1383–1388 (1997).
175.Sartor, A. O. et al. Antiandrogen withdrawal in
castrate-refractory prostate cancer: a Southwest
Oncology Group trial (SWOG 9426). Cancer 112,
2393–2400 (2008).
176.Small, E. J. & Srinivas, S. The antiandrogen
withdrawal syndrome. Experience in a large
cohort of unselected patients with advanced
prostate cancer. Cancer 76, 1428–1434 (1995).
177.Nadiminty, N. et al. Aberrant activation of the
androgen receptor by NF‑kappaB2/p52 in
prostate cancer cells. Cancer Res. 70,
3309–3319 (2010).
178.Kim, H. J. & Lee, W. J. Ligand-independent
activation of the androgen receptor by insulinlike growth factor‑I and the role of the MAPK
pathway in skeletal muscle cells. Mol. Cells 28,
589–593 (2009).
179.Wegiel, B. et al. Molecular pathways in the
progression of hormone-independent and
metastatic prostate cancer. Curr. Cancer Drug
Targets 10, 392–401 (2010).
180.Mahajan, N. P. et al. Activated Cdc42-associated
kinase Ack1 promotes prostate cancer
progression via androgen receptor tyrosine
phosphorylation. Proc. Natl Acad. Sci. USA 104,
8438–8443 (2007).
181.Gao, S., Liu, G. Z. & Wang, Z. Modulation of
androgen receptor-dependent transcription by
resveratrol and genistein in prostate cancer
cells. Prostate 59, 214–225 (2004).
182.Whitaker, H. C. & Neal, D. E. RAS pathways in
prostate cancer—mediators of hormone
resistance? Curr. Cancer Drug Targets 10,
834–839 (2010).
183.Carver, B. S. et al. Reciprocal feedback
regulation of PI3K and androgen receptor
signaling in PTEN-deficient prostate cancer.
Cancer Cell 19, 575–586 (2011).
184.Chandarlapaty, S. et al. AKT inhibition relieves
feedback suppression of receptor tyrosine
kinase expression and activity. Cancer Cell 19,
58–71 (2011).
185.Mulholland, D. J. et al. Cell autonomous role of
PTEN in regulating castration-resistant prostate
cancer growth. Cancer Cell 19, 792–804 (2011).
186.Wu, J. D. et al. Interaction of IGF signaling and
the androgen receptor in prostate cancer
progression. J. Cell Biochem. 99, 392–401
(2006).
187.Wen, Y. et al. HER‑2/neu promotes androgenindependent survival and growth of prostate
cancer cells through the Akt pathway. Cancer
Res. 60, 6841–6845 (2000).
188.Verras, M. et al. The androgen receptor
negatively regulates the expression of c‑Met:
implications for a novel mechanism of prostate
cancer progression. Cancer Res. 67, 967–975
(2007).
189.Leotoing, L. et al. Influence of nucleophosmin/
B23 on DNA binding and transcriptional activity
of the androgen receptor in prostate cancer cell.
Oncogene 27, 2858–2867 (2008).
190.Desai, S. J., Ma, A. H., Tepper, C. G., Chen, H. W.
& Kung, H. J. Inappropriate activation of the
androgen receptor by nonsteroids: involvement
of the Src kinase pathway and its therapeutic
implications. Cancer Res. 66, 10449–10459
(2006).
191.Comuzzi, B. et al. The transcriptional co-activator
cAMP response element-binding protein-binding
protein is expressed in prostate cancer and
enhances androgen- and anti‑androgen‑induced
androgen receptor function. Am. J. Pathol. 162,
233–241 (2003).
192.Zhou, X. E. et al. Identification of SRC3/AIB1 as
a preferred coactivator for hormone-activated
androgen receptor. J. Biol. Chem. 285,
9161–9171 (2010).
193.Sadar, M. D. Small molecule inhibitors targeting
the “achilles’ heel” of androgen receptor activity.
Cancer Res 71, 1208–1213 (2011).
Author contributions
All authors contributed to the research, discussion of
content, writing, editing and reviewing of this
manuscript.
Supplementary information is linked to the online
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