Efficacy 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 efficacy 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 stratified 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 offered 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 20·0 months (IQR 15·0–25·6) in the enzalutamide group and 16·7 months (10·2–21·9) in the bicalutamide group. Patients in the enzalutamide group had significantly improved median progression-free survival (15·7 months [95% CI 11·5–19·4]) compared with patients in the bicalutamide group (5·8 months [4·8–8·1]; hazard ratio 0·44 [95% CI 0·34–0·57]; p<0·0001). 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 flush (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 (five [3%] vs three [2%]), pathological fracture (five [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 (five [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 inflammatory response syndrome) compared with none of the three deaths in the bicalutamide group.

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 1 Eventually, most patients
Prostate cancer is predominantly driven by androgen progress to castration-resistant prostate cancer, typically
receptor signalling. The initial treatment of metastatic manifested by rising concentrations of prostate-specific
prostate cancer is to reduce circulating testosterone antigen (PSA) in the presence of castrate concentrations
with luteinising hormone-releasing hormone (LHRH) of testosterone, associated with a median time until

Lancet Oncol 2016 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); King’s College London, and Guy’s, King’s 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, Queen’s 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 [email protected]

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 benefit patients with castration-resistant prostate cancer. At the time the study was initiated, no controlled clinical trial data assessing the benefit 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 significant benefit 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 first randomised
head-to-head trial of enzalutamide versus bicalutamide in
patients with metastatic castration-resistant prostate cancer. The results of TERRAIN show that enzalutamide provides a significant and clinically meaningful benefit 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 benefit in patients assigned to enzalutamide than in those assigned to bicalutamide across all endpoints assessed, including
prostate-specific 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 significant benefit 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 effect 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.

2,3 Despite continued androgen- deprivation therapy (ADT), disease progression most often occurs because of further androgen receptor signalling from both paracrine and autocrine sources of
4 and, in most cases, the androgen
5–8
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
1,9,10
Controlled clinical trial data to support bicalutamide use in patients with castration-resistant prostate cancer are sparse, with little clinical benefit shown when
11–13 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
14

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
15 Unlike bicalutamide, enzalutamide does not have agonist activity for the wild-type androgen
15,16 with only one report so far of a confirmed decrease in serum PSA of 50% or greater upon
17 In preclinical studies, enzalutamide showed a higher affinity for the androgen receptor and superior suppression of key components of the androgen
15,18
Antitumour effects 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
19 Subsequently, enzalutamide was approved for the treatment of metastatic castration-resistant prostate cancer on the basis of the results of two pivotal
2 (in men

with chemotherapy-naive metastatic castration-resistant
20(in men with progressive disease after chemotherapy).
The aims of the TERRAIN trial—to our knowledge the first and largest head-to-head trial comparing enzalutamide with bicalutamide—were to assess both the efficacy 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 confirmed adenocarcinoma of the prostate with documented metastases, testosterone concentration of 1·7 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 2·0 cm in diameter, documented by CT or MRI. We defined disease progression at study entry by

and reviewed it on an ongoing basis. Patients provided written informed consent before study enrolment. The trial protocol has been published online.

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 stratified 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

For the trial protocol see http://
astellasoncologyprotocols.com/
TERRAIN_original_and_final_ protocols_and_SAP.pdf

See Online for appendix

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 defined by Response Evaluation Criteria for
21or bone disease progression defined by at least two new lesions on bone scan. Eligible patients had asymptomatic or mildly symptomatic prostate cancer (ie, Brief Pain Inventory–Short 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 0–1, 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 significant cardiovascular disease,
and gastrointestinal disease affecting 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
Figure 1: CONSORT diagram
*Including start of new antineoplastic treatment or other treatment, unconfirmed progressive disease, prostate-specific antigen progression, worsening of metastases, and investigator decision.

Enzalutamide (n=184) Bicalutamide (n=191)

Age, years 71 (50-96) 71 (48-91)
>75 years 54 (29%) 64 (34%)
Race
White 172 (93%) 176 (92%)
Black or African American 8 (4%) 10 (5%)
Asian 3 (2%) 2 (1%)
Native Hawaiian or other Pacific Islander 1 (1%) 1 (1%)
Other 0 2 (1%)
Ethnic origin
Not Hispanic or Latino 184 (100%) 187 (98%)
Hispanic or Latino 0 4 (2%)
Geographical region
Europe 109 (59%) 112 (59%)
North America 75 (41%) 79 (41%)
Weight, kg 88·15 (57·0-184·1) 86·8 (56·0-143·5)
Body-mass index, kg/m²* 28 (18-51) 28 (18-44)
Baseline ECOG performance status
Grade 0 130 (71%) 146 (76%)
Grade 1 54 (29%) 45 (24%)
Baseline pain score†
0–1 101 (55%) 117 (61%)
2–3 69 (38%) 67 (35%)
>3 10 (5%) 3 (2%)
Missing 4 (2%) 4 (2%)
Quality-of-life scores
Physical wellbeing 23·6 (4·1) 23·9 (4·4)
Functional wellbeing 20·0 (5·2) 20·3 (6·0)
Emotional wellbeing 18·3 (3·9) 18·8 (3·6)
Social wellbeing 22·2 (5·1) 22·4 (4·3)
Prostate cancer subscale 32·4 (7·0) 33·0 (6·9)
PCSP 11·3 (4·1) 11·6 (4·2)
FAPSI 23·9 (5·2) 24·3 (5·1)
Trial Outcome Index 76·0 (14·1) 77·1 (15·3)
FACT-G 84·0 (13·3) 85·2 (13·4)
FACT-P 116·8 (18·3) 118·3 (18·8)
Disease localisation
Bone only 83 (45%) 92 (48%)
Soft tissue only 36 (20%) 29 (15%)
Bone and soft tissue 64 (35%) 69 (36%)
Missing 1 (1%) 1 (1%)
Previous antiandrogen use
Yes 99 (54%) 98 (51%)
No 85 (46%) 93 (49%)
LHRH analogue or orchiectomy
Before metastasis 87 (47%) 76 (40%)
After metastasis 97 (53%) 115 (60%)
Haemoglobin, g/L 131 (86-169) 132 (87-169)
Alkaline phosphatase, U/L 91 (34-1349) 95 (33-1163)
Lactate dehydrogenase, U/L 183 (89-1480) 185 (120-506)
Serum albumin, g/L 44 (35-49) 43 (35-51)
Serum PSA, μg/L 21 (0·6-5000) 22 (0·1-4681)
Creatinine, μmol/L 94 (65-207) 86 (57-187)

same number of capsules or tablets throughout the study. Unblinding only took place after the final data were reviewed and the database frozen.

Procedures
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
22ADT 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 (defined as confirmed 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 patient’s best interest, or patient withdrawal. For patients who had grade 3 or worse toxic effects that could not be ameliorated by the use of adequate medical intervention, their treatment was allowed to be interrupted until the toxic effects 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 offered

(Table 1 continues on next page)
after unblinding to patients who showed clinical benefit with enzalutamide.

Outcomes
The primary endpoint was progression-free survival, Enzalutamide (n=184) Bicalutamide (n=191)

defined as the time from randomisation to the first 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 first. If the patient had more than one progression event on the date of the first progression event, the first 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 defined 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 first), time to PSA progression, PSA response by week 13, and best PSA response. We defined PSA progression as a 25% or greater increase and an absolute increase of at least 2 μg/L above the nadir (or above the baseline value for patients with no decline in PSA after baseline), which was confirmed by a second consecutive PSA assessment at least 3 weeks later. We defined 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 Therapy–Prostate (FACT-P) and objective response. Definitions and associated analyses for all endpoints are detailed in the appendix (p 5).

Statistical analysis
The data analysis cutoff 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 final analysis when a minimum of 220 progression-free survival events were reported, which would provide at least 85% power to detect an HR of 0·67 for disease progression or death based on a two-sided log-rank test, an overall significance level of 0·05, 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

Table 1: Baseline demographic characteristics and disease history

A
100
90
80

Enzalutamide Bicalutamide

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.

70
HR 0·44 (95% CI 0·34–0·57); p<0·0001
We assessed the effect of enzalutamide compared

60
50
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 pre-

40
30
20
10
0

03 6 9 12 15 18 21 24 27 30 33
specified subgroup analyses to determine whether treatment effects 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

Number at risk Enzalutamide

184

159

131

107

86
Time (months)
7152

33

21

13

8

5
on Cox regression, and the Kaplan-Meier method. We summarised the proportions of patients with

Bicalutamide
191
133
85
61
44
30
13
7
4
2
2
1
improvement from baseline in FACT-P total score and its subscales at any time during the study by treatment

B
100
90

Enzalutamide Bicalutamide
group and compared them using an unstratified Cochran-Mantel-Haenszel mean score test at the two-sided 0·05 significance level. We compared the proportion of patients who had an objective response

80
70

74%
between treatment groups using a two-sided Fisher’s exact test and the proportion of patients who went from having an unfavourable to a favourable CTC

60
50
40
54%

33%
concentration using a χ² test. We provide unadjusted, nominal p values for each comparison. We did not make any adjustment for multiple comparisons. The final analysis timing was determined by the

30
25%
28% number of prespecified progression-free survival

20
10
0

C
100
90

Total number
of events

Radiographic
disease progression

11% 10%

Skeletal-related
event

14%

New antineoplastic
therapy

4% 2% Deaths

Enzalutamide Bicalutamide
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.

80
70
60
50
40
30
20
10
0

HR 0·51 (95% CI 0·36–0·74); p=0·0002

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 findings, 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

0 3 6 9 12 15 18 21 24 27 30 33 progression-free survival

Number at risk Enzalutamide

184

147

120

99

82
Time (months) 65 49

33

20

13

8

5
Progression-free survival (A), breakdown of progression events (B), and radiographic progression-free survival (C) were assessed by independent central

Bicalutamide
191
104
73
51
38
30
14
7
3
2
2
1
review. HRs are based on Cox regression models, with ratios of less than 1 favouring enzalutamide. HR=hazard ratio. PFS=progression-free survival.

Number
Enzalutamide Bicalutamide

Median PFS (95% CI), months Enzalutamide Bicalutamide

HR (95% CI)

Age (years)

<65
65–75
>75 Geographical region
North America Europe
ECOG performance status at BL 0
1
Total Gleason score at diagnosis ≤7
≥8
Disease locations at BL Bone only
Soft tissue only Bone and soft tissue
PSA BL value
At or below median* Above median*
LHRHa or orchiectomy Before metastasis After metastasis
Previous antiandrogen therapy† Yes
No
All patients
45
85
54

75
109

130
54

71
102

83
36
64

92
91

83
101

99
85
184
47
80
64

79
112

146
45

73
110

92
29
69

95
96

77
114

98
93
191
16·5 (11·3–NR) 18·0 (11·1–27·4) 11·8 (8·2–17·1)

14·9 (10·3–18·7) 16·6 (11·7–25·6)

16·5 (11·5–25·6) 15·3 (8·2–20·7)

16·6 (10·0–25·6) 15·3 (10·8–19·4)

15·3 (11·1–20·7) 25·6 (10·8–NR) 14·9 (8·2–18·0)

19·5 (14·5–NR) 11·1 (8·4–16·5)

15·9 (10·3–25·6) 15·3 (11·0–19·4)

18·7 (13·8–NR) 11·8 (9·6–15·7) 15·7 (11·5–19·4)
5·4 (3·6–8·6) 7·0 (4·2–11·1) 5·1 (3·6–10·5)

6·2 (4·0–9·1) 5·8 (4·7–8·6)

6·8 (5·1–9·1) 5·3 (3·3–7·4)

5·8 (4·1–11·1) 5·6 (4·2–8·2)

8·2 (5·3–11·2) 5·6 (2·8–11·1) 4·8 (3·2–6·4)

8·2 (6·2–12·7) 4·1 (3·3–5·6)

5·5 (3·7–8·1) 6·6 (5·3–10·2)

6·4 (4·4–10·3) 5·6 (3·8–8·1) 5·8 (4·8–8·1)
0·33 (0·19–0·57) 0·44 (0·30–0·66) 0·55 (0·35–0·87)

0·45 (0·30–0·67) 0·44 (0·31–0·61)

0·43 (0·32–0·59) 0·42 (0·25–0·71)

0·45 (0·29–0·68) 0·46 (0·32–0·65)

0·53 (0·36–0·78) 0·32 (0·16–0·63) 0·38 (0·25–0·59)

0·41 (0·28–0·60) 0·45 (0·32–0·65)

0·38 (0·26–0·58) 0·47 (0·34–0·67)

0·35 (0·24–0·52) 0·55 (0·38–0·79) 0·44 (0·34–0·57)

0·0 0·5 1·0 1·5 2·0
Favours enzalutamide Favours bicalutamide

Figure 3: Prespecified 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-specific antigen. *Overall median baseline PSA was 21 μg/L. †Before randomisation.

preparation, did additional statistical analyses when requested by authors, reviewers, or the journal, and provided clarification regarding statistical analysis and protocol-related reviewer and journal queries during manuscript revision. All of the authors and the participating institutions had confidentiality agreements in place with the funders regarding the study data. All authors had full access to all the data in the study and had final 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; figure 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
discontinuation of study treatment are listed in figure 1; reasons classified as other included start of new antineoplastic treatment or other treatment, unconfirmed progressive disease, PSA progression, worsening of metastases, and investigator decision. Baseline demo- graphic 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 (11·7 months [IQR 5·7–20·1] vs 5·8 months [3·1–11·4], respectively). The median follow-up time was 20·0 months (IQR 15·0–25·6) in the enzalutamide group and 16·7 months (10·2–21·9) 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

A
100
90
80
70
60
50
40
30
20
10
0

Enzalutamide Bicalutamide

HR 0·28 (95% CI 0·20–0·39); p<0·0001

0 3 6 9 12 15 18 21 24 27 30 33

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 flare or for antineoplastic use, we used the duration of previous bicalutamide use as a proxy, with use of 3 months or less indicative of flare protection and greater than 3 months indicative of antineoplastic use.
Enzalutamide was associated with significantly improved progression-free survival when compared with bicalutamide (HR 0·44 [95% CI 0·34–0·57]; p<0·0001;

Number at risk Enzalutamide

184

154

109

89

74
Time (months) 58 39

26

15

9

6

3
figure 2A). Median progression-free survival was 15·7 months (95% CI 11·5–19·4) in the enzalutamide

Bicalutamide
191
103
50
26
16
9
6
3
2
2
2
1
group and 5·8 months (4·8–8·1) in the bicalutamide group. 99 (54%) of 184 patients in the enzalutamide group had a progression-free survival event based on central

B
100
80
60
40
20
0
–20
–40
–60
–80
–100

Enzalutamide Bicalutamide
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 first 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; figure 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

Observation
four (2%) of 191 patients in the bicalutamide group in the primary progression-free survival analysis (figure 2B).

C
100
90
80
70
60
50
40
30
20
10
0

Enzalutamide Bicalutamide

HR 7·0 (95% CI 4·8–10·2); p<0·0001
The beneficial treatment effect of enzalutamide on progression-free survival compared with bicalutamide was consistent across all prespecified subgroups (figure 3).
Median investigator-based progression-free survival was 15·3 months (95% CI 11·8–19·4) for patients in the enzalutamide group and 5·7 months (5·4–8·1) in the bicalutamide group (HR 0·42 [95% CI 0·33-0·55]; p<0·0001). Median time to a radiographic progression event (assessed by independent central review) was not

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 efficacy endpoints including Kaplan-Meier estimates

Number at risk Enzalutamide Bicalutamide
0

184
191
3

40
107
6

13
59
9

7
37
12
Time (months) 5
23
15

2
14
18

1
7
21

0
5
24

0
2
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-specific antigen.

reached (95% CI 25·6–not reached) for patients assigned to enzalutamide and 16·4 months (11·1–18·1) for patients assigned to bicalutamide (HR 0·51 [95% CI 0·36–0·74]; p=0·0002; figure 2C). Similarly, the median time to a PSA progression event was 19·4 months (95% CI 16·6–not reached) for patients assigned to enzalutamide and 5·8 months (5·6–8·3) for patients assigned to bicalutamide (HR 0·28 [95% CI 0·20–0·39]; p<0·0001; figure 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<0·0001; figure 4B). Additionally, the median best PSA response at any point after the start of treatment was a decrease of 93% (IQR –98·4 to –74·7)

100

80

60

40

20

0

and an increase of 0·18% (–49·2 to 79·0) for the enzalutamide and bicalutamide groups, respectively
PWB
SWB EWB FWB PCS PCSP FAPSI TOI FACT-G FACT-P
QoL domain

(p<0·0001). The median time to a 50% or greater PSA decline from baseline was 2·8 months (95% CI 2·8–2·8) 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 7·01 [95% CI 4·83–10·16]; p<0·0001; figure 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 five (7%) of 71 patients in
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 figure 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 defined as equal to or greater than the minimum clinically important difference 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 Therapy–General. FACT-P=Functional Assessment of Cancer Therapy–Prostate. 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.

All adverse events Treatment-related adverse events

the bicalutamide group, all with a partial response (p<0·0001).
Time to FACT-P total score deterioration was longer for patients in the enzalutamide group than for those in the bicalutamide group (median 13·8 months [95% CI 11·1–22] for patients in the enzalutamide group vs 8·5 months [5·8–11·3] for patients in the

Adverse events leading to treatment discontinuation
Deaths
Serious adverse events Grade ≥3 adverse events
Enzalutamide (n=183)
52 (28%) 9 (5%)*
57 (31%) 73 (40%)
Bicalutamide (n=189)
44 (23%) 3 (2%)†
44 (23%)
72(38%)
Enzalutamide (n=183)
14 (8%)

1(1%)‡ 12 (7%) 17 (9%)
Bicalutamide (n=189)
10 (5%) 0
6 (3%) 15 (8%)

bicalutamide group; p=0·0067). 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 Therapy–General (FACT-G) and total FACT-P scores
Cardiac grade ≥3 adverse events§ 10 (5%)
Myocardial infarction|| 5 (3%)
Congestive heart failure 4 (2%)
Atrial fibrillation 2 (1%)
Seizure 2 (1%)
4 (2%)¶ 0
2(1%) 0
1 (1%)
1 (1%)
1(1%) 0
1(1%)
1(1%)
0
0
0
0
1(1%)

(figure 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 0·83 (SD 1·67) in 97 patients in the enzalutamide group and 1·05 (2·00) 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 7·5 mL of blood), 60 (80%) of 75 patients in the enzalutamide group had converted to a favourable status (ie, <5 cells per 7·5 mL of blood) by week 49 compared with 45 (58%) of 77 of patients in the bicalutamide group (p=0·004).
Adverse events are summarised in tables 2 and 3 and a complete list of adverse events is shown in the appendix (pp 9–17). One patient with raised concentrations of liver
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 inflammatory 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 inflammatory 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 flush, hypertension,

Enzalutamide (n=183)

Bicalutamide (n=189)

Discussion
In patients with metastatic castration-resistant prostate

Fatigue Back pain Hot flush Nausea
Hypertension Constipation Diarrhoea Weight decrease
Pain in extremity Arthralgia
Grade 1–2 49 (27%) 30 (16%) 27 (15%) 26 (14%) 13 (7%) 21 (11%) 21 (11%) 19 (10%) 18 (10%) 16 (9%)
Grade 3
2(1%) 5 (3%) 0
0
13 (7%)
2(1%) 0
1(1%)
2(1%)
2(1%)
Grade 1–2 36 (19%) 31 (16%) 21 (11%) 33 (17%) 6 (3%)
24 (13%) 15 (8%) 14 (7%)
9 (5%) 28 (15%)
Grade 3
2(1%)
3(2%) 0
0
8 (4%)
1(1%)
2(1%) 1 (1%)
1(1%)
2(1%)
cancer, enzalutamide significantly improved progression- free survival compared with bicalutamide. The superior efficacy of enzalutamide over bicalutamide with respect to progression-free survival was noted across all prespecified 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 definition 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

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 4–5 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 9–17). 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 (five [3%] vs three [2%]), pathological fracture (five [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 (five [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 inflammatory 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 cutoff 57 (31%) patients in the enzalutamide group and 19 (10%) patients in the bicalutamide group remained on treatment.
progression and death alone.
Despite the widespread use of bicalutamide, evidence of its clinical benefits is scarce in the context of metastatic castration-resistant prostate cancer. Data from the TERRAIN trial show that enzalutamide is a more effective 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
15,18 thereby continuing to show the importance of inhibiting androgen receptor signalling in patients with castration-resistant prostate
5–8 The results of the TERRAIN trial confirm and extend the results of enzalutamide activity in the phase 3 PREVAIL trial in chemotherapy-naive patients and in the
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 first 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 benefit of enzalutamide over bicalutamide on all prespecified, 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 benefit than did
23
Enzalutamide had a favourable safety profile. Common adverse events that occurred more frequently in the enzalutamide group are consistent with the known safety profile of enzalutamide reported in the phase 3 AFFIRM
2,20 Individual adverse events of grade 3 or worse largely occurred at a similar frequency (<1% difference) between treatment groups, with the exception of hypertension and back pain, which occurred

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 fibrillation).
The findings 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 specific geographical regions and that the bicalutamide dose used in this study corresponds to that used in specific regions, the findings of TERRAIN are not generalisable to patient populations in other locations or regions that use a different bicalutamide dose.
In conclusion, enzalutamide significantly 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, Sanofi, and Takeda during the conduct of the study. SC was a consultant, advisor, meeting participant, and lecturer for Astellas, J&J, Sanofi, and Dendreon during the conduct of the study. AV was a consultant for and advisor to Astellas and Takeda, and was involved in scientific 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 scientific 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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