Articles

Ecacy and safety of enzalutamide versus bicalutamide

for patients with metastatic prostate cancer (TERRAIN):
a randomised, double-blind, phase 2 study
Neal D Shore, Simon Chowdhury, Arnauld Villers, Laurence Klotz, D Robert Siemens, De Phung, Steve van Os, Nahla Hasabou, Fong Wang,
Suman Bhattacharya, Axel Heidenreich

Summary
Background Enzalutamide is an oral androgen-receptor inhibitor that has been shown to improve survival in
two placebo-controlled phase 3 trials, and is approved for patients with metastatic castration-resistant prostate cancer.
The objective of the TERRAIN study was to compare the ecacy and safety of enzalutamide with bicalutamide in
patients with metastatic castration-resistant prostate cancer.
Methods TERRAIN was a double-blind, randomised phase 2 study, that recruited asymptomatic or minimally
symptomatic men with prostate cancer progression on androgen-deprivation therapy (ADT) from academic,
community, and private health-care provision sites across North America and Europe. Eligible patients were randomly
assigned (1:1) via an interactive voice response system to receive enzalutamide 160 mg/day or bicalutamide 50 mg/day,
both taken orally, in addition to ADT, until disease progression. Patients were stratied by a permutated block method
(block size of four), by whether bilateral orchiectomy or receipt of luteinising hormone-releasing hormone agonist or
antagonist therapy started before or after the diagnosis of metastases, and by study site. Participants, investigators,
and those assessing outcomes were masked to group assignment. The primary endpoint was progression-free
survival, analysed in all randomised patients. Safety outcomes were analysed in all patients who received at least one
dose of study drug. The open-label period of the trial is in progress, wherein patients still on treatment at the end of
the double-blind treatment period were oered open-label enzalutamide at the discretion of the patient and study
investigator. This trial is registered with ClinicalTrials.gov, number NCT01288911.
Findings Between March 22, 2011, and July 11, 2013, 375 patients were randomly assigned, 184 to enzalutamide and
191 to bicalutamide. 126 (68%) and 168 (88%) patients, respectively, discontinued their assigned treatment before
study end, mainly due to progressive disease. Median follow-up time was 200 months (IQR 150256) in the
enzalutamide group and 167 months (102219) in the bicalutamide group. Patients in the enzalutamide group had
signicantly improved median progression-free survival (157 months [95% CI 115194]) compared with patients
in the bicalutamide group (58 months [4881]; hazard ratio 044 [95% CI 034057]; p<00001). Of the most
common adverse events, those occurring more frequently with enzalutamide than with bicalutamide were fatigue
(51 [28%] of 183 patients in the enzalutamide group vs 38 [20%] of 189 in the bicalutamide group), back pain (35 [19%]
vs 34 [18%]), and hot ush (27 [15%] vs 21 [11%]); those occurring more frequently with bicalutamide were nausea
(26 [14%] vs 33 [17%]), constipation (23 [13%] vs 25 [13%]), and arthralgia (18 [10%] vs 30 [16%]). The most common
grade 3 or worse adverse events in the enzalutamide or bicalutamide treatment groups, respectively, were hypertension
(13 [7%] vs eight [4%]), hydronephrosis (three [2%] vs seven [4%]), back pain (ve [3%] vs three [2%]), pathological
fracture (ve [3%] vs two [1%]), dyspnoea (four [2%] vs one [1%]), bone pain (one [1%] vs four [2%]), congestive cardiac
failure (four [2%] vs two [1%]), myocardial infarction (ve [3%] vs none), and anaemia (four [2%] vs none]). Serious
adverse events were reported by 57 (31%) of 183 patients and 44 (23%) of 189 patients in the enzalutamide and
bicalutamide groups, respectively. One of the nine deaths in the enzalutamide group was thought to be possibly
related to treatment (due to systemic inammatory response syndrome) compared with none of the three deaths in
the bicalutamide group.

Lancet Oncol 2016; 17: 15363

Published Online
January 13, 2016
http://dx.doi.org/10.1016/
S1470-2045(15)00518-5
Carolina Urologic Research
Center, Myrtle Beach, SC, USA
(N D Shore MD); Kings College
London, and Guys, Kings and
St Thomas Hospitals, London,
UK (S Chowdhury MD);
Department of Urology, Lille
University, Lille, France
(Prof A Villers MD); Sunnybrook
Health Sciences Centre,
University of Toronto, Toronto,
ON, Canada (L Klotz MD); Centre
for Applied Urological
Research, Queens University,
Kingston, ON, Canada
(Prof D R Siemens MD); Astellas
Pharma, Leiden, Netherlands
(D Phung BSc, S van Os MD);
Astellas Pharma, Northbrook,
IL, USA (N Hasabou MD);
Medivation, San Francisco, CA,
USA (F Wang MD,
S Bhattacharya PhD); and
Department of Urology,
Aachen University, Aachen,
Germany
(Prof A Heidenreich MD)
Correspondence to:
Dr Neal Shore, Carolina Urologic
Research Center, Myrtle Beach,
SC 29572, USA
nshore@gsuro.com

Interpretation The data from the TERRAIN trial support the use of enzalutamide rather than bicalutamide in patients
with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer.
Funding Astellas Pharma, Inc and Medivation, Inc.

Introduction
Prostate cancer is predominantly driven by androgen
receptor signalling. The initial treatment of metastatic
prostate cancer is to reduce circulating testosterone
with luteinising hormone-releasing hormone (LHRH)
www.thelancet.com/oncology Vol 17 February 2016

analogues or by orchiectomy.1 Eventually, most patients

progress to castration-resistant prostate cancer, typically
manifested by rising concentrations of prostate-specic
antigen (PSA) in the presence of castrate concentrations
of testosterone, associated with a median time until
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Research in context
Evidence before the study
We reviewed the preclinical and clinical literature for evidence
suggesting that androgen receptor signalling continues to play
a part in the progression of castration-resistant prostate cancer,
even in patients who have disease progression while on
androgen-deprivation therapy including luteinising
hormone-releasing hormone analogues and antiandrogen
therapy. We searched PubMed between January, 2000, and
April, 2015, using the terms prostate cancer, metastatic, and
androgen receptor signalling. Articles published in languages
other than English were excluded. Preclinical data in models of
castration-resistant prostate cancer and phase 1 clinical data of
androgen signalling inhibitors in patients with metastatic
castration-resistant prostate cancer suggested that the disease
was still driven by the androgen receptor and that more potent
inhibitors of androgen signalling might benet patients with
castration-resistant prostate cancer. At the time the study was
initiated, no controlled clinical trial data assessing the benet of
more potent androgen receptor inhibition had been published;
however, phase 3 clinical trials were in progress. Data from both
the AFFIRM and PREVAIL trials of enzalutamide, published in
2012 and 2014, respectively, have subsequently shown that
enzalutamide has a signicant benet over placebo in terms of
overall survival and radiographic progression-free survival, as
well as objective tumour response in patients with measurable
soft tissue disease.
Added value of this study
TERRAIN is, to our knowledge, the rst randomised
head-to-head trial of enzalutamide versus bicalutamide in

death of about 30 months.2,3 Despite continued androgendeprivation therapy (ADT), disease progression most
often occurs because of further androgen receptor
signalling from both paracrine and autocrine sources of
androgenic ligands4 and, in most cases, the androgen
receptor is overexpressed.58
Bicalutamide, a non-steroidal oral antiandrogen, is
approved for use in conjunction with LHRH analogues in
men with hormone-treatment-naive prostate cancer, and
is often used in clinical practice. In the castration-resistant
setting, bicalutamide has been recommended as
second-line therapy by clinical guidelines, although this
recommendation is based on low levels of evidence.1,9,10
Controlled clinical trial data to support bicalutamide use
in patients with castration-resistant prostate cancer are
sparse, with little clinical benet shown when
bicalutamide was added to ongoing ADT.1113 Furthermore,
non-steroidal antiandrogens, such as bicalutamide, might
function as androgen receptor agonists in the setting
of androgen receptor overexpression or mutation, as
manifested by the antiandrogen withdrawal syndrome, a
reduction in serum PSA, and clinical improvement
observed upon antiandrogen discontinuation.14
154

patients with metastatic castration-resistant prostate cancer.

The results of TERRAIN show that enzalutamide provides a
signicant and clinically meaningful benet compared with
bicalutamide in reducing the risk of disease progression or
death in men with metastatic castration-resistant prostate
cancer. Additionally, we noted a greater benet in patients
assigned to enzalutamide than in those assigned to
bicalutamide across all endpoints assessed, including
prostate-specic antigen (PSA) progression, PSA response,
objective tumour response, and quality of life. Similar results
were also reported in the recently completed STRIVE trial of
enzalutamide versus bicalutamide in patients with metastatic
or non-metastatic castration-resistant prostate cancer.
Implications of all the available evidence
In both the TERRAIN study reported here and the STRIVE study,
enzalutamide provided a signicant benet compared with
bicalutamide with respect to radiographic progression-free
survival, objective tumour response, time to PSA progression,
and PSA response. Even though bicalutamide is not approved
for the treatment of metastatic castration-resistant prostate
cancer, it is widely used in this setting despite evidence of only a
short-lived eect in a minority of patients. Bicalutamide might
also accelerate prostate cancer progression by functioning as a
partial agonist of the androgen receptor in the setting of
androgen receptor overexpression, as occurs in metastatic
castration-resistant prostate cancer. The data from the TERRAIN
trial support the use of enzalutamide instead of bicalutamide in
patients with asymptomatic or mildly symptomatic metastatic
castration-resistant prostate cancer.

Enzalutamide is an androgen receptor inhibitor that

targets several steps in the androgen receptor signalling
pathway; its mechanism of action is distinct from that
of antiandrogens. It inhibits binding of androgens
to the androgen receptor, androgen-receptor nuclear
translocation, and androgen-receptor-mediated DNA
binding.15 Unlike bicalutamide, enzalutamide does not
have agonist activity for the wild-type androgen
receptor,15,16 with only one report so far of a conrmed
decrease in serum PSA of 50% or greater upon
discontinuation.17 In preclinical studies, enzalutamide
showed a higher anity for the androgen receptor and
superior suppression of key components of the androgen
receptor signalling pathway than bicalutamide.15,18
Antitumour eects in patients with castration-resistant
prostate cancer were reported, including decreased
serum PSA concentrations, stabilised metastatic bone
disease, and conversion from an unfavourable to a
favourable concentration of circulating tumour cells
(CTCs).19 Subsequently, enzalutamide was approved for
the treatment of metastatic castration-resistant prostate
cancer on the basis of the results of two pivotal
placebo-controlled phase 3 trials: PREVAIL2 (in men
www.thelancet.com/oncology Vol 17 February 2016

Articles

with chemotherapy-naive metastatic castration-resistant

prostate cancer) and AFFIRM20 (in men with progressive
disease after chemotherapy).
The aims of the TERRAIN trialto our knowledge the
rst and largest head-to-head trial comparing
enzalutamide with bicalutamidewere to assess both
the ecacy and safety of these agents in the treatment of
men with metastatic castration-resistant prostate cancer.

Methods
Study design and participants
TERRAIN was a multinational, randomised, double-blind,
phase 2 trial of enzalutamide versus bicalutamide in
patients with metastatic castration-resistant prostate
cancer recruited from academic, community, and private
health-care provision sites in North America and Europe
(appendix, p 1). Patients were eligible if they had
histologically conrmed adenocarcinoma of the prostate
with documented metastases, testosterone concentration
of 17 nmol/L (50 ng/dL) or lower, and disease
progression on ADT. Patients were regarded as having
metastatic disease at screening if they had at least one of
the following criteria: at least two bone lesions on bone
scans; soft tissue disease documented by CT or MRI; or
unequivocal pelvic lymphadenopathy with the short axis
greater than 20 cm in diameter, documented by CT or
MRI. We dened disease progression at study entry by
the presence of one or more of the following three criteria:
PSA progression (ie, three or more measurements of
rising PSA concentrations with an interval of at least
1 week between determinations); soft tissue disease
progression dened by Response Evaluation Criteria for
Solid Tumors (RECIST), version 11;21 or bone disease
progression dened by at least two new lesions on
bone scan. Eligible patients had asymptomatic or
mildly symptomatic prostate cancer (ie, Brief Pain
InventoryShort Form [BPI-SF], question 3, score <4),
were not using opiate analgesics for prostate
cancer-related pain, had an Eastern Cooperative Oncology
Group performance status of 01, and had a life
expectancy of at least 12 months. Key exclusion criteria
included previous progression on antiandrogen
therapy, previous chemotherapy, brain metastasis, and a
history of seizure. Patients were also excluded for
severe concurrent disease, active epidural disease, other
malignancy, clinically signicant cardiovascular disease,
and gastrointestinal disease aecting absorption.
Previous antiandrogen use was permitted, provided that
previous treatment was not administered within 6 weeks
before randomisation. We did not apply any age
restrictions for study inclusion. Full details of all
inclusion and exclusion criteria can be found in the
trial protocol.
The review boards of participating institutions approved
the study protocol, and the trial was done in accordance
with the Declaration of Helsinki. A data monitoring
committee was charged with reviewing the safety data
www.thelancet.com/oncology Vol 17 February 2016

and reviewed it on an ongoing basis. Patients provided

written informed consent before study enrolment. The trial
protocol has been published online.

For the trial protocol see http://

astellasoncologyprotocols.com/
TERRAIN_original_and_final_
protocols_and_SAP.pdf

Randomisation and masking

Enrolled patients were randomly assigned to receive
enzalutamide (Astellas Pharma, Inc, Northbrook, IL,
USA) or bicalutamide (Zydus Cadila Healthcare Ltd,
Moraiya, India), using a 1:1 randomisation schedule,
which was coordinated by an independent third party
(Bracket Global, PA, USA) via an interactive voice
response system. The designated contract research
organisation (ICON Clinical Research, Dublin, Ireland)
generated the randomisation schedule and then the
study site (investigator or designee) contacted the
interactive web response system to randomly assign a
patient to a study treatment. The permuted block
method (block size of four) was used to generate the
random allocation sequence. Patients were stratied
according to whether bilateral orchiectomy or receipt of
LHRH agonist or antagonist therapy started before or
after the diagnosis of metastases, and by study site.
To maintain the double-blind nature of this study, the
appearance of placebo capsules and tablets were identical
to enzalutamide capsules and bicalutamide tablets,
respectively, with patients in both groups ingesting the

See Online for appendix

559 patients enrolled

184 excluded
165 met exclusion criteria or did not meet
inclusion criteria
8 withdrew consent
2 had pretreatment adverse events
9 other

375 patients randomised

184 allocated to enzalutamide

183 received allocated
intervention
1 did not receive allocated
intervention

0 lost to follow-up
126 discontinued intervention
75 progressive disease
14 adverse event
10 withdrawal by patient
6 protocol violation
6 death
15 other*

184 in full analysis set

183 in safety analysis set

191 allocated to bicalutamide

189 received allocated
intervention
2 did not receive allocated
intervention

2 lost to follow-up
168 discontinued intervention
105 progressive disease
12 adverse event
20 withdrawal by patient
2 protocol violation
1 death
28 other*

191 in full analysis set

189 in safety analysis set

Figure 1: CONSORT diagram

*Including start of new antineoplastic treatment or other treatment, unconrmed progressive disease,
prostate-specic antigen progression, worsening of metastases, and investigator decision.

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Enzalutamide (n=184)
Age, years

Bicalutamide (n=191)

71 (5096)

71 (4891)

54 (29%)

64 (34%)

172 (93%)

176 (92%)

Black or African American

8 (4%)

10 (5%)

Asian

3 (2%)

2 (1%)

Native Hawaiian or other Pacic Islander

1 (1%)

1 (1%)

Other

2 (1%)

>75 years
Race
White

Procedures

Ethnic origin
Not Hispanic or Latino
Hispanic or Latino

184 (100%)

187 (98%)

4 (2%)

Geographical region
Europe
North America

109 (59%)

112 (59%)

75 (41%)

79 (41%)

Weight, kg

8815 (5701841)

868 (5601435)

Body-mass index, kg/m*

28 (1851)

28 (1844)

Baseline ECOG performance status

Grade 0

130 (71%)

146 (76%)

Grade 1

54 (29%)

45 (24%)

Baseline pain score

01

101 (55%)

117 (61%)

23

69 (38%)

67 (35%)

>3

10 (5%)

3 (2%)

4 (2%)

4 (2%)

Missing
Quality-of-life scores
Physical wellbeing

236 (41)

239 (44)

Functional wellbeing

200 (52)

203 (60)

Emotional wellbeing

183 (39)

188 (36)

Social wellbeing

222 (51)

224 (43)

Prostate cancer subscale

324 (70)

330 (69)

PCSP

113 (41)

116 (42)

FAPSI

239 (52)

243 (51)

Trial Outcome Index

760 (141)

771 (153)

FACT-G

840 (133)

852 (134)

FACT-P

1168 (183)

1183 (188)

Disease localisation
Bone only

83 (45%)

92 (48%)

Soft tissue only

36 (20%)

29 (15%)

Bone and soft tissue

64 (35%)

69 (36%)

1 (1%)

1 (1%)

Yes

99 (54%)

98 (51%)

No

85 (46%)

93 (49%)

Missing
Previous antiandrogen use

LHRH analogue or orchiectomy

Before metastasis

87 (47%)

76 (40%)

After metastasis

97 (53%)

115 (60%)

Haemoglobin, g/L
Alkaline phosphatase, U/L
Lactate dehydrogenase, U/L

131 (86169)

132 (87169)

91 (341349)

95 (331163)

183 (891480)

185 (120506)

Serum albumin, g/L

44 (3549)

Serum PSA, g/L

21 (065000)

22 (014681)

Creatinine, mol/L

94 (65207)

86 (57187)

43 (3551)

(Table 1 continues on next page)

156

same number of capsules or tablets throughout the

study. Unblinding only took place after the nal data
were reviewed and the database frozen.

Patients randomly assigned to enzalutamide received

160 mg/day as four capsules, plus one placebo tablet, and
those assigned to bicalutamide received 50 mg/day as
one tablet, plus four placebo capsules. The bicalutamide
dose selected for this study, 50 mg/day, is indicated for
use in combination with LHRH analogues.22 ADT with an
LHRH agonist or antagonist was to be maintained
throughout the study. We permitted concurrent use of
bisphosphonates and denosumab, provided the dose was
stable throughout the study.
Study treatment was continued until occurrence of a
progression event (dened as conrmed radiographic
disease progression, a skeletal-related event, or initiation
of a new antineoplastic therapy), or an adverse event
whereby continued administration of the study drug
was not deemed to be in the patients best interest, or
patient withdrawal. For patients who had grade 3 or
worse toxic eects that could not be ameliorated by the
use of adequate medical intervention, their treatment
was allowed to be interrupted until the toxic eects
improved to grade 2 or better severity. Treatment
could subsequently be restarted with enzalutamide
(or enzalutamide and placebo) at the same or a reduced
dose (120 mg or 80 mg) concurrent with restarting of
bicalutamide (or bicalutamide and placebo) with the
written approval of the medical monitor. Patient
screening for detailed medical history of prostate cancer,
concomitant medication usage, cardiovascular disease,
haematological laboratory values, and PSA and
testosterone concentrations was done over 28 days
(weeks 4 to 1). Study assessments were then done at
weeks 1, 2, 5, 9, 13, 17, 21, and 25, and then every
subsequent 12 weeks. Radiographic assessments (CT or
MRI and bone scans) were done at screening, weeks 13
and 25, and then every 12 weeks subsequently.
Radiographic results were submitted for independent
central review.
Clinical laboratory assessments (haematology and
chemistry) were obtained at every scheduled visit before
the administration of the study drug and analysed at a
central laboratory. Adverse events were collected from
the time of informed consent until 30 days after last dose
of study drug, and their severity was graded according to
the Cancer Therapy and Evaluation Program Common
Terminology Criteria for Adverse Events, version 4.0.
Other safety assessments included liver function tests,
physical examinations, and electrocardiogram readings.
Further details on safety assessments are described in
the trial protocol.
Open-label treatment with enzalutamide was oered
after unblinding to patients who showed clinical benet
with enzalutamide.
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Outcomes
The primary endpoint was progression-free survival,
dened as the time from randomisation to the rst
progression event (ie, the earliest incidence of
centrally determined radiographic disease progression, a
skeletal-related event, or initiation of a new antineoplastic
therapy) or death from any cause, whichever occurred rst.
If the patient had more than one progression event on
the date of the rst progression event, the rst event
was selected from among those events according to
the following order: radiographic disease progression,
skeletal-related event, the initiation of a new antineoplastic
therapy, and death. Secondary endpoints included safety,
investigator-review-based progression-free survival (where
a progression event was dened as objective evidence
of radiographic disease progression based on the
assessments made by the investigators and not by
independent central review, a skeletal-related event,
initiation of new antineoplastic therapy, or death by any
cause, whichever occurred rst), time to PSA progression,
PSA response by week 13, and best PSA response.
We dened PSA progression as a 25% or greater increase
and an absolute increase of at least 2 g/L above the nadir
(or above the baseline value for patients with no decline in
PSA after baseline), which was conrmed by a second
consecutive PSA assessment at least 3 weeks later.
We dened PSA response as the percentage change in
PSA from baseline to the smallest PSA value after baseline,
on or before day 99 (ie, the upper boundary of the week 13
visit window). For patients with no decrease in PSA
between baseline and week 13, the PSA response by
week 13 was the smallest increase in PSA up to day 99. For
patients with no post-baseline PSA values up to day 99, we
set the PSA response by week 13 to missing. Exploratory
and other endpoints included assessments of Functional
Assessment of Cancer TherapyProstate (FACT-P) and
objective response. Denitions and associated analyses for
all endpoints are detailed in the appendix (p 5).

Enzalutamide (n=184)

Duration of prostate cancer, years

The data analysis cuto date was Oct 19, 2014. Analysis
of the primary endpoint was a between-group
comparison of progression-free survival in the full
analysis set (all randomly assigned patients), with the
null hypothesis that progression-free survival would be
the same for patients in the enzalutamide group and
those in the bicalutamide group (ie, a hazard ratio [HR]
equal to 1).
We planned to do the nal analysis when a minimum
of 220 progression-free survival events were reported,
which would provide at least 85% power to detect an HR
of 067 for disease progression or death based on a
two-sided log-rank test, an overall signicance level of
005, and an expected median progression-free survival
of 6 months for the bicalutamide group. We aimed for a
study duration of 2 years (18 months of enrolment and
6 additional months of follow-up) to observe the required
www.thelancet.com/oncology Vol 17 February 2016

29 (04228)

33 (03230)

Total Gleason score at initial diagnosis

7

71 (39%)

73 (38%)

102 (55%)

110 (58%)

11 (6%)

8 (4%)

M0

67 (36%)

64 (34%)

M1

64 (35%)

74 (39%)

MX or unknown

53 (29%)

53 (28%)

Missing
Distant metastasis at initial diagnosis

Time since diagnosis of metastases, days

382 (108243)

411 (177901)

Number of bone lesions at screening

0

1 (1%)

15

69 (38%)

76 (40%)
37 (19%)

610

29 (16%)

1115

10 (5%)

11 (6%)

>15

12 (7%)

12 (6%)

Too many to count

26 (14%)

22 (12%)

1 (1%)

2 (1%)

No

105 (57%)

109 (57%)

Yes

79 (43%)

82 (43%)

Missing
Previous radiation therapy

Number of previous radiation therapies

1

53 (29%)

63 (33%)

22 (12%)

17 (9%)

3 (2%)

1 (1%)

1 (1%)

1 (1%)

Reason for radiation therapy

Primary disease

53 (29%)

52 (27%)

Metastatic disease

21 (11%)

19 (10%)

9 (5%)

9 (5%)
47 (25%)

Other
Previous surgeries or procedures of interest
Prostatectomy

43 (23%)

Orchiectomy

13 (7%)

11 (6%)

TURP

18 (10%)

22 (12%)

Cryoablation

Statistical analysis

Bicalutamide (n=191)

(Continued from previous page)

Pelvic lymph node dissection

6 (3%)

4 (2%)

10 (5%)

9 (5%)

HIFU

2 (1%)

Other

13 (7%)

10 (5%)

10 (5%)

Medical history of cardiac disorders of interest

Atrial brillation

17 (9%)

Coronary artery disease

15 (8%)

9 (5%)

Myocardial infarction

9 (5%)

13 (7%)

Cardiac heart failure

4 (2%)

4 (2%)

Data are median (range), number (%), and mean (SD). ECOG=Eastern Cooperative Oncology Group. PCSP=prostate
cancer subscale pain-related score. FAPSI=Functional Assessment of Cancer Therapy Advanced Prostate Symptom
Index. FACT-G=Functional Assessment of Cancer TherapyGeneral. FACT-P=Functional Assessment of Cancer
TherapyProstate. LHRH=luteinising hormone-releasing hormone. TURP=transurethral resection of the prostate.
HIFU=high-intensity focused ultrasound. *Out of 180 patients in the enzalutamide group and 190 patients in the
bicalutamide group. Brief Pain Inventory-Short Form, question 3; higher scores indicate a higher degree of pain.
In patients with bone metastases (147 and 161 patients in the enzalutamide and bicalutamide groups, respectively).
Patients could have had more than one reason for radiation therapy, more than one surgery or procedure, or more
than one previous cardiac disorder. Includes acute myocardial infarction.

Table 1: Baseline demographic characteristics and disease history

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Enzalutamide
Bicalutamide

100
90

Progression-free survival (%)

80
HR 044 (95% CI 034057); p<00001
70
60
50
40
30
20
10
0
0
Number at risk
Enzalutamide 184
Bicalutamide 191

12

15

18

21

24

27

30

33

33
7

21
4

13
2

8
2

5
1

Time (months)
159
133

131
85

107
61

86
44

71
30

52
13

B
100

Enzalutamide
Bicalutamide

Patients with progression events (%)

90
80

74%

70
60

54%

50
40

33%

30

28%

25%

20
11%
10

10%

14%
4%

2%

0
Total number
of events

Radiographic
disease
progression

Skeletal-related
event

New
antineoplastic
therapy

Deaths

Enzalutamide
Bicalutamide

100

Radiographic progression-free survival (%)

90
80
HR 051 (95% CI 036074); p=00002

70
60
50
40
30
20
10
0
0

Number at risk
Enzalutamide 184
Bicalutamide 191

158

12

15

18

21

24

27

30

33

33
7

20
3

13
2

8
2

5
1

Time (months)
147
104

120
73

99
51

82
38

65
30

49
14

220 progression-free survival events. Assuming that 4%

of patients would be lost to follow-up, we calculated a
target sample size of 370 patients (185 per treatment
group). We did the sample size calculations using the
software package nQuery Advisor Version 7.0.
We assessed the eect of enzalutamide compared
with bicalutamide using a two-sided log-rank test and
HR with a 95% CI based on a Cox regression model,
displayed using Kaplan-Meier plots. We did prespecied subgroup analyses to determine whether
treatment eects were consistent across subgroups.
We assessed time to PSA progression, radiographic
progression-free survival, and time to FACT-P total
score deterioration (ie, a decrease from baseline in the
FACT-P total score by 10 points or more) using a
two-sided log-rank test, HR with a 95% CI based
on Cox regression, and the Kaplan-Meier method.
We summarised the proportions of patients with
improvement from baseline in FACT-P total score and
its subscales at any time during the study by treatment
group and compared them using an unstratied
Cochran-Mantel-Haenszel mean score test at the
two-sided 005 signicance level. We compared the
proportion of patients who had an objective response
between treatment groups using a two-sided Fishers
exact test and the proportion of patients who went
from having an unfavourable to a favourable CTC
concentration using a test. We provide unadjusted,
nominal p values for each comparison. We did not
make any adjustment for multiple comparisons.
The nal analysis timing was determined by the
number of prespecied progression-free survival
events. We did all analyses using SAS version 9.3.
We analysed safety data in all patients who received at
least one dose of study drug and summarised the
analyses descriptively by treatment group. The adverse
event reporting period was during treatment plus
30 days after treatment discontinuation or until initiation
of a new therapy. We did not adjust the data presented
here for time on study drug. TERRAIN is registered with
ClinicalTrials.gov, number NCT01288911.

Role of the funding source

Astellas Pharma, Inc and Medivation, Inc, the codevelopers
of enzalutamide, funded the study. The authors, Astellas,
and Medivation contributed to the study design,
interpretation of the ndings, and development of the
report. Astellas contributed to data collection and both
companies contributed to the data analysis. The funders
provided funding for editorial assistance with manuscript
Figure 2: Kaplan-Meier estimates of progression-free survival, breakdown of
progression events, and Kaplan-Meier estimates of radiographic
progression-free survival
Progression-free survival (A), breakdown of progression events (B), and
radiographic progression-free survival (C) were assessed by independent central
review. HRs are based on Cox regression models, with ratios of less than 1
favouring enzalutamide. HR=hazard ratio. PFS=progression-free survival.

www.thelancet.com/oncology Vol 17 February 2016

Articles

Number

Median PFS (95% CI), months

Enzalutamide Bicalutamide

Enzalutamide

Bicalutamide

HR (95% CI)

Age (years)
<65

45

47

165 (113NR)

54 (3686)

033 (019057)

6575

85

80

180 (111274) 70 (42111)

044 (030066)

>75

54

64

118 (82171)

51 (36105)

055 (035087)

75

79

149 (103187) 62 (4091)

045 (030067)

109

112

166 (117256) 58 (4786)

044 (031061)

130

146

165 (115256) 68 (5191)

043 (032059)

54

45

153 (82207)

53 (3374)

042 (025071)

Geographical region
North America
Europe
ECOG performance status at BL

Total Gleason score at diagnosis

7

71

73

166 (100256) 58 (41111)

045 (029068)

102

110

153 (108194) 56 (4282)

046 (032065)

Bone only

83

92

153 (111207) 82 (53112)

053 (036078)

Soft tissue only

36

29

256 (108NR)

56 (28111)

032 (016063)

Bone and soft tissue

64

69

149 (82180)

48 (3264)

038 (025059)

At or below median*

92

95

195 (145NR)

82 (62127)

041 (028060)

Above median*

91

96

111 (84165)

41 (3356)

045 (032065)

159 (103256) 55 (3781)

038 (026058)

153 (110194) 66 (53102)

047 (034067)

Disease locations at BL

PSA BL value

LHRHa or orchiectomy
Before metastasis

83

77

After metastasis

101

114

Yes

99

98

187 (138NR)

64 (44103)

035 (024052)

No

85

93

118 (96157)

56 (3881)

055 (038079)

184

191

Previous antiandrogen therapy

All patients

044 (034057)

157 (115194) 58 (4881)

00

05
Favours enzalutamide

10

15

20

Favours bicalutamide

Figure 3: Prespecied subgroup analysis of progression-free survival

BL=baseline. ECOG=Eastern Cooperative Oncology Group. HR=hazard ratio. LHRHa=luteinising hormone-releasing hormone analogues. NR=not reached.
PFS=progression-free survival. PSA=prostate-specic antigen. *Overall median baseline PSA was 21 g/L. Before randomisation.

preparation, did additional statistical analyses when

requested by authors, reviewers, or the journal, and
provided clarication regarding statistical analysis and
protocol-related reviewer and journal queries during
manuscript revision. All of the authors and the
participating institutions had condentiality agreements
in place with the funders regarding the study data.
All authors had full access to all the data in the study and
had nal responsibility for the decision to submit for
publication. All authors agreed on the submitted version of
the manuscript.

Results
From March 22, 2011, to July 11, 2013, 375 patients were
randomly assigned from 84 sites in eight countries in
North America and Europe (184 to enzalutamide and
191 to bicalutamide; gure 1; appendix p 1), and were
included in the full analysis set. 372 (99%) patients
received at least one dose of the study treatment
(183 [99%] of 184 in the enzalutamide group and
189 [99%] of 191 in the bicalutamide group) and were
included in the safety analyses. The reasons for
www.thelancet.com/oncology Vol 17 February 2016

discontinuation of study treatment are listed in gure 1;

reasons classied as other included start of new
antineoplastic treatment or other treatment, unconrmed
progressive disease, PSA progression, worsening of
metastases, and investigator decision. Baseline demographic and disease characteristics were well balanced
between the two treatment groups, although a larger
proportion of patients in the enzalutamide group had a
history of cardiac disorders than did those in the
bicalutamide group (table 1).
The median time on study drug was longer in the
enzalutamide group than in the bicalutamide group
(117 months [IQR 57201] vs 58 months [31114],
respectively). The median follow-up time was 200 months
(IQR 150256) in the enzalutamide group and
167 months (102219) in the bicalutamide group.
167 (45%) of 375 patients had at least one previous
period of bicalutamide use for which duration of use was
calculable (86 [45%] of 191 patients in the bicalutamide
group and 81 [44%] of 184 patients in the enzalutamide
group). For those in the enzalutamide group, 21 (11%),
14 (8%), and 12 (7%) patients received previous
159

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Enzalutamide
Bicalutamide

100
Patients without PSA progression event (%)

90
80
70
60

HR 028 (95% CI 020039); p<00001

50
40
30
20
10
0
0

Number at risk
Enzalutamide 184
Bicalutamide 191

12

15

18

21

24

27

30

33

26
3

15
2

9
2

6
2

3
1

Time (months)
154
103

109
50

89
26

74
16

58
9

39
6

B
Enzalutamide
Bicalutamide

100
80
Change in PSA from baseline (%)

60
40
20
0
20
40
60
80
100
Observation

Enzalutamide
Bicalutamide

100

Patients without 50% decrease in PSA (%)

90
80

HR 70 (95% CI 48102); p<00001

70
60
50
40
30
20
10
0
0

Number at risk
Enzalutamide 184
Bicalutamide 191

160

bicalutamide treatment for a total of more than

3 months, more than 6 months, and more than
12 months, respectively. For the 191 patients in the
bicalutamide group, 24 (13%), 18 (9%), and 13 (7%)
patients had previously received bicalutamide for a total
of more than 3 months, more than 6 months, and more
than 12 months, respectively. Since we did not obtain the
reasons for bicalutamide use, such as for protection
against antiandrogen are or for antineoplastic use, we
used the duration of previous bicalutamide use as a
proxy, with use of 3 months or less indicative of are
protection and greater than 3 months indicative of
antineoplastic use.
Enzalutamide was associated with signicantly
improved progression-free survival when compared with
bicalutamide (HR 044 [95% CI 034057]; p<00001;
gure 2A). Median progression-free survival was
157 months (95% CI 115194) in the enzalutamide
group and 58 months (4881) in the bicalutamide
group. 99 (54%) of 184 patients in the enzalutamide group
had a progression-free survival event based on central
radiographic assessments during the study compared
with 141 (74%) of 191 patients in the bicalutamide group.
Centrally assessed radiographic disease progression and
initiation of new antineoplastic therapy were the most
prevalent rst progression events included in the centrally
assessed progression-free survival endpoint in both
groups (46 [25%] of 184 patients in the enzalutamide
group vs 63 [33%] of 191 in the bicalutamide group had
radiographic disease progression, and 25 [14%] vs 54 [28%]
had initiation of new antineoplastic therapy; gure 2B).
Skeletal-related events were noted in 21 (11%) patients in
the enzalutamide group versus 20 (10%) patients in the
bicalutamide group. Death occurred in seven (4%) of
184 patients in the enzalutamide group (one of which
was thought to be treatment related) compared with
four (2%) of 191 patients in the bicalutamide group in the
primary progression-free survival analysis (gure 2B).
The benecial treatment eect of enzalutamide on
progression-free survival compared with bicalutamide
was consistent across all prespecied subgroups
(gure 3).
Median investigator-based progression-free survival was
153 months (95% CI 118194) for patients in the
enzalutamide group and 57 months (5481) in the
bicalutamide group (HR 042 [95% CI 033055];
p<00001). Median time to a radiographic progression
event (assessed by independent central review) was not

12

15

18

21

24

2
14

1
7

0
5

0
2

Time (months)
40
107

13
59

7
37

5
23

Figure 4: Kaplan-Meier estimates of time to PSA progression, PSA change

from baseline by week 13, and Kaplan-Meier estimates of time to 50%
decrease in PSA
Data shown for secondary ecacy endpoints including Kaplan-Meier estimates
for time to PSA progression (A), greatest percentage PSA change from baseline
by week 13, presented as waterfall plot (B), and Kaplan-Meier estimates for time
to 50% or greater decrease in PSA (C). HRs are based on Cox regression models,
with HR <1 favouring enzalutamide for (A) and HR >1 favouring enzalutamide
for (C). HR=hazard ratio. PSA=prostate-specic antigen.

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www.thelancet.com/oncology Vol 17 February 2016

100

Patients with improvement in QoL domain (%)

reached (95% CI 256not reached) for patients assigned

to enzalutamide and 164 months (111181) for patients
assigned to bicalutamide (HR 051 [95% CI 036074];
p=00002; gure 2C). Similarly, the median time to a
PSA progression event was 194 months (95% CI
166not reached) for patients assigned to enzalutamide
and 58 months (5683) for patients assigned to
bicalutamide (HR 028 [95% CI 020039]; p<00001;
gure 4A). Declines in PSA of at least 50% were noted in
151 (82%) of 184 patients in the enzalutamide group
compared with 40 (21%) of 191 in the bicalutamide group.
The median change in PSA concentration from baseline
by week 13 was greater in the enzalutamide group than in
the bicalutamide group (p<00001; gure 4B). Additionally,
the median best PSA response at any point after the start
of treatment was a decrease of 93% (IQR 984 to 747)
and an increase of 018% (492 to 790) for the
enzalutamide and bicalutamide groups, respectively
(p<00001). The median time to a 50% or greater PSA
decline from baseline was 28 months (95% CI 2828)
in the enzalutamide group; the estimate was not reached
in the bicalutamide group as too few patients in this group
had such a PSA decrease during the study (HR 701
[95% CI 4831016]; p<00001; gure 4C).
Post-hoc analysis showed that of patients with
measurable soft tissue disease at baseline, 26 (37%) of
70 patients in the enzalutamide group had an objective
response (two [3%] had a complete response, 24 [34%]
had a partial response), as reported by independent
central review, compared with ve (7%) of 71 patients in
the bicalutamide group, all with a partial response
(p<00001).
Time to FACT-P total score deterioration was longer
for patients in the enzalutamide group than for those
in the bicalutamide group (median 138 months
[95% CI 11122] for patients in the enzalutamide
group vs 85 months [58113] for patients in the
bicalutamide group; p=00067). Compared with
bicalutamide, a higher proportion of patients assigned
to enzalutamide had improvement in various FACT-P
domains as well as in Functional Assessment of Cancer
TherapyGeneral (FACT-G) and total FACT-P scores
(gure 5). In patients with both a baseline and week 49
BPI-SF composite pain score, the mean change in
BPI-SF pain score from baseline to week 49 was 083
(SD 167) in 97 patients in the enzalutamide group and
105 (200) in 48 patients in the bicalutamide group;
lower scores on the BPI-SF correlated with less pain.
Of the patients with an unfavourable CTC status at
baseline (ie, 5 cells per 75 mL of blood), 60 (80%) of
75 patients in the enzalutamide group had converted to a
favourable status (ie, <5 cells per 75 mL of blood) by
week 49 compared with 45 (58%) of 77 of patients in the
bicalutamide group (p=0004).
Adverse events are summarised in tables 2 and 3 and a
complete list of adverse events is shown in the appendix
(pp 917). One patient with raised concentrations of liver

Enzalutamide
Bicalutamide

80

60 p=00039 p=01502 p=00102 p=00575 p=00676 p=00011 p=00055 p=00428 p=00264 p=00260
51
42
40

34
27

43

41

37

34
28

25

25

21

20

36
26

23

33

25

22

FACT-G

FACT-P

17
9

0
PWB

SWB

EWB

FWB

PCS

PCSP

FAPSI

TOI

QoL domain

Figure 5: Patients with FACT-P improvement at any time during the study
The FACT-P instrument consists of 27 core items for assessing patient function, and the subscales reported in this
gure are all derived from these items (appendix p 6). Data are the proportion of patients with FACT-P improvement
at any time during the study. Improvement was dened as equal to or greater than the minimum clinically important
dierence from baseline (3 points for FACT-P subscales PWB, FWB, EWB, SWB, and PCS; 9 points for TOI; 7 points for
FACT-G; and 10 points for FACT-P; appendix p 6). EWB=emotional wellbeing. FACT-G=Functional Assessment of
Cancer TherapyGeneral. FACT-P=Functional Assessment of Cancer TherapyProstate. FAPSI=Functional Assessment
of Cancer Therapy Advanced Prostate Symptom Index. FWB=functional wellbeing. PCS=prostate cancer subscale.
PCSP=PCS pain-related score. PWB=physical wellbeing. QoL=quality-of-life. SWB=social wellbeing. TOI=Trial
Outcome Index.

Adverse events leading to treatment

discontinuation
Deaths
Serious adverse events
Grade 3 adverse events
Cardiac grade 3 adverse events

All adverse events

Treatment-related adverse
events

Enzalutamide
(n=183)

Bicalutamide
(n=189)

Enzalutamide
(n=183)

Bicalutamide
(n=189)

52 (28%)

44 (23%)

14 (8%)

10 (5%)

9 (5%)*

3 (2%)

57 (31%)

44 (23%)

12 (7%)

1 (1%)

6 (3%)

73 (40%)

72 (38%)

17 (9%)

15 (8%)

10 (5%)

4 (2%)

1 (1%)

0
0

Myocardial infarction||

5 (3%)

1 (1%)

Congestive heart failure

4 (2%)

2 (1%)

Atrial brillation

2 (1%)

1 (1%)

2 (1%)

1 (1%)

1 (1%)

1 (1%)

Seizure

Data are number of patients with at least one event (% of all patients). *Due to anaemia (n=1), renal failure (n=1),
paraplegia/spinal cord compression (n=1), systemic inammatory response syndrome (n=1), aspiration pneumonia
(n=1), paraneoplastic syndrome (n=1), and fatal cardiac events (n=3). Due to aspiration pneumonia (n=1), gastric
cancer (n=1), and disease progression (n=1). Due to systemic inammatory response syndrome. Patients could have
more than one cardiac event (not mutually exclusive). One patient had mitral valve incompetence and one had
supraventricular tachycardia (neither of these events occurred in patients in the enzalutamide group), and two had
congestive heart failure. ||Includes acute myocardial infarction.

Table 2: Safety overview

enzymes and active and newly diagnosed hepatitis C

reduced his dose of enzalutamide to 80 mg/day.
Of the most common adverse events, those occurring
in a higher proportion of patients who received
enzalutamide than in those who received bicalutamide
were fatigue, back pain, hot ush, hypertension,
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Enzalutamide (n=183)

Bicalutamide (n=189)

Grade 12

Grade 12

Grade 3
2 (1%)

Grade 3

Fatigue

49 (27%)

2 (1%)

36 (19%)

Back pain

30 (16%)

5 (3%)

31 (16%)

3 (2%)

Hot ush

27 (15%)

21 (11%)

Nausea

26 (14%)

33 (17%)

Hypertension

13 (7%)

Constipation
Diarrhoea

13 (7%)

6 (3%)

8 (4%)

21 (11%)

2 (1%)

24 (13%)

1 (1%)

21 (11%)

15 (8%)

2 (1%)
1 (1%)

Weight decrease

19 (10%)

1 (1%)

14 (7%)

Pain in extremity

18 (10%)

2 (1%)

9 (5%)

1 (1%)

Arthralgia

16 (9%)

2 (1%)

28 (15%)

2 (1%)

Data are number of patients with at least one event (% of all patients). Only adverse events that occurred in at least 10% of
patients in either group are presented. No grade 45 of the adverse events presented in this table were reported.

Table 3: Summary of common adverse events

diarrhoea, weight decrease, and pain in the extremities;

those occurring more frequently in the bicalutamide
group were nausea, constipation, and arthralgia (table 3).
A grade 3 or worse adverse event was reported in 73 (40%)
of 183 patients who received enzalutamide and 72 (38%)
of 189 patients who received bicalutamide (appendix
pp 917). The most common grade 3 or worse adverse
events (occurring in 2% or more patients in either group)
in the enzalutamide or bicalutamide treatment groups,
respectively, were hypertension (13 [7%] vs eight [4%]),
hydronephrosis (three [2%] vs seven [4%]), back pain
(ve [3%] vs three [2%]), pathological fracture (ve [3%] vs
two [1%]), dyspnoea (four [2%] vs one [1%]), bone pain
(one [1%] vs four [2%]), congestive cardiac failure
(four [2%] vs two [1%]), myocardial infarction (ve [3%] vs
none), and anaemia (four [2%] vs none]). Grade 3 or
worse cardiac adverse events were reported in ten (5%)
patients in the enzalutamide group and four (2%)
patients in the bicalutamide group during the course of
the study. An increased incidence of grade 3 or worse
cardiac adverse events in the enzalutamide group
compared with the bicalutamide group was noted later in
the study (after 6 months on the study drug; appendix,
p 8) when there was a greater imbalance in exposure by
treatment group. Of the nine deaths in the enzalutamide
group, one was reported as being possibly related to the
study drug (systemic inammatory response syndrome)
compared with none of three deaths in the bicalutamide
group. Two patients in the enzalutamide group had
seizures; one was diagnosed with a brain tumour after
presenting with seizure, and the other had an undisclosed
childhood and family history of seizures and had his
event after a traumatic head injury. One patient in the
bicalutamide group had a hypoglycaemic seizure.
89 (48%) of 184 patients in the enzalutamide group and
44 (23%) of 191 patients in the bicalutamide group were
on treatment at 12 months, and at study cuto 57 (31%)
patients in the enzalutamide group and 19 (10%) patients
in the bicalutamide group remained on treatment.
162

Discussion
In patients with metastatic castration-resistant prostate
cancer, enzalutamide signicantly improved progressionfree survival compared with bicalutamide. The superior
ecacy of enzalutamide over bicalutamide with respect
to progression-free survival was noted across all
prespecied subgroups, including age, geographical
location, baseline performance status, baseline PSA,
whether ADT was initiated before or after the diagnosis
of metastatic disease, and previous use of antiandrogens.
The denition of progression-free survival in this study
also included skeletal-related events or change of
antineoplastic therapy, and so it might be a more
clinically meaningful outcome than radiographic disease
progression and death alone.
Despite the widespread use of bicalutamide, evidence
of its clinical benets is scarce in the context of metastatic
castration-resistant prostate cancer. Data from the
TERRAIN trial show that enzalutamide is a more
eective treatment than bicalutamide for patients with
metastatic prostate cancer who progress on ADT, and are
consistent with the superior activity of enzalutamide
versus bicalutamide in preclinical models of metastatic
castration-resistant prostate cancer,15,18 thereby continuing
to show the importance of inhibiting androgen receptor
signalling in patients with castration-resistant prostate
cancer.58 The results of the TERRAIN trial conrm and
extend the results of enzalutamide activity in the phase 3
PREVAIL trial in chemotherapy-naive patients and in the
AFFIRM trial in patients who had received docetaxel.2,20
These data support the role of enzalutamide use in
patients with asymptomatic or minimally symptomatic
metastatic castration-resistant prostate cancer who had
disease progression while on ADT with an LHRH agonist
or antagonist, or after bilateral orchiectomy.
To our knowledge, the TERRAIN trial is the rst study
in men with metastatic castration-resistant prostate
cancer who had not had disease progression while on
previous antiandrogen treatment, with results that show
a consistent benet of enzalutamide over bicalutamide
on all prespecied, exploratory, and post-hoc endpoints.
Furthermore, results from the recently completed
STRIVE trial (NCT01664923), in which patients with
non-metastatic castration-resistant prostate cancer (M0)
were included in addition to patients with metastatic
cancer, suggest that patients assigned to enzalutamide
either early in their disease or after development of
metastatic disease derived more clinical benet than did
those assigned to bicalutamide.23
Enzalutamide had a favourable safety prole. Common
adverse events that occurred more frequently in the
enzalutamide group are consistent with the known safety
prole of enzalutamide reported in the phase 3 AFFIRM
and PREVAIL trials.2,20 Individual adverse events of
grade 3 or worse largely occurred at a similar frequency
(<1% dierence) between treatment groups, with the
exception of hypertension and back pain, which occurred
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Articles

more frequently with enzalutamide. An increased

incidence of grade 3 or worse cardiac adverse events in
the enzalutamide group compared with the bicalutamide
group was noted later in the study when there was a
greater imbalance in exposure between treatment groups
(appendix, p 8). Most patients with these events in both
treatment groups had a history of cardiac disorders at
baseline. Notably, a slightly larger proportion of the
enzalutamide group had a history of cardiac disorders
compared with patients in the bicalutamide group
(table 1). Only one patient (in the enzalutamide group)
reported grade 3 or worse cardiac events that were
regarded by the investigator to be related to the study
drug (myocardial infarction and atrial brillation).
The ndings of the TERRAIN trial should be
interpreted in light of the study limitations. The primary
endpoint included death, but we did not investigate
overall survival. Additionally, given that patients
included in this study are from specic geographical
regions and that the bicalutamide dose used in this
study corresponds to that used in specic regions, the
ndings of TERRAIN are not generalisable to patient
populations in other locations or regions that use a
dierent bicalutamide dose.
In conclusion, enzalutamide signicantly reduced
the risk of disease progression or death in men
with metastatic castration-resistant prostate cancer
compared with bicalutamide in this double-blind,
randomised trial.
Contributors
All authors contributed to the development of the report through study
design, data analysis, data interpretation, writing, reviewing, and
approvals of every development stage.
Declaration of interests
NDS was a consultant to Astellas, Bayer, Ferring, Dendreon, Janssen,
Sano, and Takeda during the conduct of the study. SC was a
consultant, advisor, meeting participant, and lecturer for Astellas, J&J,
Sano, and Dendreon during the conduct of the study. AV was a
consultant for and advisor to Astellas and Takeda, and was involved in
scientic studies and trials with Astellas and Ipsen, during the conduct
of the study. LK reports honoraria for advisory board participation from
Astellas, Medivation, Janssen, Amgen, Genomic Health, and Abbvie,
outside the submitted work. DRS reports involvement in scientic
studies and trials with Astellas, BN ImmunoTherapeutics, and Janssen
during the conduct of the study. DP, SvO, and NH are employees of
Astellas. FW and SB are employees of Medivation. AH declares no
competing interests.
Acknowledgments
We, the authors, meet the criteria for authorship as recommended by the
International Committee of Medical Journal Editors. We take full
responsibility for the scope, direction, and content of the manuscript
and have approved the submitted manuscript. We received no
compensation related to the development of the manuscript, and would
like to thank David McMinn, of Complete HealthVizion, for assistance
in drafting and revising the manuscript on the basis of detailed
discussion and feedback from all the authors; this assistance was funded
by Astellas Pharma, Inc and Medivation, Inc.
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Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on
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Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic
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