Enzalutamide Antitumour Activity Against Metastatic Castration-resistant Prostate Cancer Previously Treated with Docetaxel and Abiraterone: A Multicentre Analysis

EURURO-5754; No. of Pages 8

Prostate Cancer

Enzalutamide Antitumour Activity Against Metastatic

Castration-resistant Prostate Cancer Previously Treated with

Docetaxel and Abiraterone: A Multicentre Analysis

Klaus Brasso a,*, Frederik B. Thomsen a, Andres J. Schrader b, Sebastian C. Schmid c,David Lorente d, Margitta Retz c, Axel S. Merseburger e, Christoph A. von Klot e,Martin Boegemann f, Johann de Bono d

a Copenhagen Prostate Cancer Centre, Department of Urology, Rigshospitalet, University of Copenhagen, Denmark; b Department of Urology, Ulm University

Medical Centre, Ulm, Germany; c Urologische Klinik und Poliklinik, Technische Universitat Munchen, Munich, Germany; d Royal Marsden NHS Foundation

Trust and The Institute of Cancer Research, Sutton, United Kingdom; e Department of Urology and Urological Oncology, Hannover Medical School, Hannover,

Germany; f Department of Urology, Muenster University Medical Centre, Muenster, Germany

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Article info

Article history:Accepted July 21, 2014

Keywords:

Castration-resistant prostate

cancer

Enzalutamide

Abiraterone

Docetaxel

Survival

PSA

Abstract

Background: The degree of antitumour activity of enzalutamide following diseaseprogression on docetaxel and abiraterone remains controversial.Objective: To examine the effect of enzalutamide in patients progressing followingtaxane-based chemotherapy and abiraterone.Design, setting, and participants: Metastatic castration-resistant prostate cancer patientsentering one of four European compassionate use programmes of enzalutamide.Outcome measurements and statistical analysis: The primary end point was overallsurvival (OS). Secondary end points were association between OS and posttreatmentprostate-specific antigen (PSA) kinetics, patient characteristics, and progression-freesurvival, respectively. Kaplan-Meier survival analysis and Cox proportional hazardanalysis were performed.Results and limitations: We identified 137 patients who prior to enzalutamide hadprogressed following a median of eight cycles of docetaxel and seven courses ofabiraterone. The median time on enzalutamide was 3.2 mo; median OS from the timepatients started enzalutamide was 8.3 mo (95% confidence interval, 6.8–9.8). Only 45(38%) and 22 (18%) patients had PSA declines (unconfirmed) >30% and 50%, respectively.Patients who had more than 30% or 50% falls in PSA had improved survival comparedwith patients who had no such PSA fall (11.4 mo vs 7.1 mo; p = 0.001 and 12.6 vs 7.4 mo;p = 0.007, respectively). Poor performance status and low haemoglobin was negativelyassociated with OS.Conclusions: Median OS on enzalutamide following disease progression on taxane-based chemotherapy and abiraterone was modest, but patients who experience a PSAdecline >30% or 50%, respectively, with enzalutamide in this setting had longer survival.Patient summary: Enzalutamide produces modest prostate-specific antigen (PSA)responses in patients progressing following chemotherapy and abiraterone. Despite amodest PSA response, survival may still be improved.

soc

. Copenhagen Prostate Cancer Centre, Rigshospitalet, Tagensvej 20,n N, DK-2200, Denmark. Tel. +45 35 457 125; Fax: +45 35 452 [email protected] (K. Brasso).

# 2014 European As

* Corresponding authorAfsnit 7521, CopenhageE-mail address: klausbr

Please cite this article in press as: Brasso K, et al. EnzalutamideProstate Cancer Previously Treated with Docetaxel and Abiratero10.1016/j.eururo.2014.07.028

http://dx.doi.org/10.1016/j.eururo.2014.07.0280302-2838/# 2014 European Association of Urology. Published by Elsevier

iation of Urology. Published by Elsevier B.V. All rights reserved.

Antitumour Activity Against Metastatic Castration-resistantne: A Multicentre Analysis. Eur Urol (2014), http://dx.doi.org/

B.V. All rights reserved.

Fig. 1 – Consolidated Standards of Reporting Trials diagram of prostate-specific antigen and radiographic responses following abirateroneacetate and enzalutamide.mCRPC = metastatic castration-resistant prostate cancer;PFS = progression-free survival; PSA = prostate-specific antigen.

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1. Introduction

The introduction of new treatment options for patients who

have metastatic castration-resistant prostate cancer

(mCRPC) during the past decade has provided several

effective new therapeutic strategies, including two different

taxanes, a systemic alpha particle–emitting radionuclide, as

well as two novel endocrine drugs and a vaccine [1–8].

Because docetaxel had been shown to prolong survival [1,2],

first cabazitaxel [3] and more recently two new drugs—

blocking androgen synthesis through CYP17 inhibition and

the androgen receptor (AR), respectively—have been shown

to further improve survival in mCRPC patients both before

and after chemotherapy [5–8]. Abiraterone acetate, a

selective CYP17A1 inhibitor, blocks the synthesis of andro-

genic steroids, causing effective systemic and intratumoural

suppression of androgen production [9]. Enzalutamide is a

second-generation antiandrogen that binds to and blocks the

AR with higher affinity than previously available antiandro-

gens. Enzalutamide is also reported to inhibit AR nuclear

translocation and binding of the AR complex to DNA [10].

Abiraterone and enzalutamide can prolong survival by

4.6 mo and 4.8 mo, respectively, and produce significant

prostate-specific antigen (PSA) and objective responses in

mCRPC patients progressing after docetaxel [6,11].

This increasing number of new therapies has resulted in

a multiple unresolved issues regarding optimal timing,

sequencing, possible combinations, drug-resistance mech-

anisms, and cost. Recently, PSA response and survival

have been reported both in patients managed with

abiraterone following progression on docetaxel and enzalu-

tamide [12,13] and in patients managed with enzalutamide

following docetaxel and abiraterone [14–17]. All publica-

tions involve small patient numbers and retrospective case

series, and the all demonstrate modest PSA responses and

median survival compared with the randomised, placebo-

controlled COU-AA-301 and AFFIRM trials [6,11].

In this report, we present a pooled analysis of PSA

response and survival from four independent European

compassionate access programmes that provided enzaluta-

mide as third-line treatment to patients with mCRPC

following progression after docetaxel and abiraterone

treatment.

2. Materials and methods

The US Food and Drug Administration (FDA) approved enzalutamide for

postdocetaxel mCRPC patients who experienced disease progression

following publication of the AFFIRM trial [6]. In Europe, compassionate

use programmes were initiated to bridge the time between FDA and

European Medicines Agency approval. All programmes, from which we

derived the patients presented in this study, have been described in

details elsewhere [14–17]. Patients and clinical information included is

presented in the Consolidated Standards of Reporting Trials diagram

(Fig. 1). In brief, mCRPC patients progressing following chemotherapy

and subsequent abiraterone and prednisone were treated with 160 mg

enzalutamide daily in two German [14,15], one British [16], and one

Danish [17] compassionate use programme if considered candidates for

further therapy. All patients continued castration-based therapy during

enzalutamide.

Please cite this article in press as: Brasso K, et al. EnzalutamideProstate Cancer Previously Treated with Docetaxel and Abiratero10.1016/j.eururo.2014.07.028

Follow-up consisted of regular outpatient clinic visits with biochemi-

cal and clinical evaluations. Between trials, there were minor differences in

the imaging follow-up, and evaluation of progression based on

radiographic assessment or bone scans was not mandatory. For all

patients, the following pretreatment information was recorded, if

available: Gleason score at diagnosis; time from primary endocrine

treatment to CRPC; number of docetaxel cycles; time on and PSA response

to abiraterone; Eastern Cooperative Oncology Group (ECOG) performance

score; PSA; haemoglobin; albumin; lactate dehydrogenase (LDH); and

alkaline phosphatase (ALP). The primary end point was overall survival

(OS) calculated from initiation of enzalutamide; the secondary end point

was PSA response. Radiographic response and radiographic progression-

free survival (PFS) according to the Response Evaluation Criteria in Solid

Tumors (RECIST) criteria [18] were available only in a subgroup of patients.

2.1. Statistics

Continuous variables are presented as median and range. The best PSA

response was defined as percentage of change from baseline (start of

abiraterone or enzalutamide) to nadir. The first PSA measurement was

used in patients who had an increase in PSA. Patients were dichotomised

according to their best PSA response as nonresponders (continued PSA

progression) or responders (decrease or stabilised PSA). Furthermore,

patients responding were categorised according to the best PSA fall

reported: >30% and >50% falls (unconfirmed), respectively.

Survival was calculated from the date enzalutamide was initiated

using Kaplan-Meier survival analysis and presented with a 95%

confidence interval (CI). Log-rank analysis was used to compare survival

among subgroups. We used Cox proportional hazards to estimate the

effect of clinical pre-enzalutamide parameters as well as absolute and

percentage PSA response to enzalutamide on survival. No patient was

lost to follow-up. Two-sided p value <0.05 was considered significant.

Statistical analysis was performed with R (R Development Core Team,

Vienna, Austria, www.R-project.org).

Antitumour Activity Against Metastatic Castration-resistantne: A Multicentre Analysis. Eur Urol (2014), http://dx.doi.org/

Table 1 – Patient characteristics at enzalutamide initiation

No. of patients Median IQR Range No. %

Age, yr 137 71 67–74 57–85

ECOG status 96

0 12 12.5

1 56 58.3

2 28 29.2

PSA prior to enzalutamide, ng/ml 135 348 81.9–807.6 4.7–7342

Diagnostic Gleason score 106

6 11 10.4

7 30 28.3

8 18 17.0

9 43 40.6

10 4 3.8

Time from primary endocrine treatment to CRPC, yr 58 1.8 0.7–3.8 0.2–9.8

No. of docetaxel cycles received 99 8 6–10 1–39

Time on abiraterone acetate, mo 135 7 4–10.8 1.58–53.83

Best PSA response to abiraterone acetate 93

Continued PSA progression 26 28.0

Stable or decrease in PSA 67 72.0

PSA response >30% 54* 35 64.8

PSA response >50% 54* 23 45.6

Haemoglobin, mmol/l 63 6.8 6.2–7.5 5.2–11.7

Albumin, g/l 57 36 33–42 24–48

LDH, UI/l 47 246 178–377 86–897

ALP, UI/l 63 138 78–376 29–2066

ALP = alkaline phosphatase; CRPC = castration-resistant prostate cancer; ECOG = Eastern Cooperative Oncology Group; IQR = interquartile range; LDH = lactate

dehydrogenase; PSA = prostate-specific antigen.* Exact PSA response available in only 54 of 93 patients.

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3. Results

Prior to initiation of 160 mg/d of enzalutamide, the 137

patients included in this study had received a median of

eight courses of docetaxel and had subsequently received

abiraterone plus prednisone for a median of 7 mo (Table 1;

Supplemental Table 1). Of the 137 patients, information

about PSA response with prior abiraterone was available in

94 patients, of whom 32 had PSA progression and 62 were

categorised as PSA nonprogression.

Fig. 2 – Waterfall plot of best percentage change in prostate-specific antigen (Pexcluded because of unknown first PSA measurement.PSA = prostate-specific antigen.

Please cite this article in press as: Brasso K, et al. EnzalutamideProstate Cancer Previously Treated with Docetaxel and Abiratero10.1016/j.eururo.2014.07.028

The median duration of enzalutamide treatment until

clinical progression was 3.2 mo (range: 0.03–21.9). At the

time of these analyses, 14 patients were still being treated

with enzalutamide. PSA information following enzalutamide

initiation was available in 122 patients (Fig. 1). Among these

122 patients, 44 (36%) had PSA progression (nonresponders),

and the remaining 78 (64%) patients had decreased or

stabilised PSA (nonprogression, described here as responders;

Fig. 2). Forty-five (36.9%) patients had a PSA fall (uncon-

firmed) >30% and 22 (18.0%) patients >50%, respectively.

SA) from baseline. Twelve patients who had an increase in PSA were

Antitumour Activity Against Metastatic Castration-resistantne: A Multicentre Analysis. Eur Urol (2014), http://dx.doi.org/

Table 2 – Univariate Cox proportional hazard analysis between pre-enzalutamide parameters and survival

Patients who have valid information HR 95% CI p value

Age* 137 0.98 0.95–1.01 0.13

ECOG 96 0.07

0 1 (ref)

1 3.00 0.92–9.80

2 3.41 1.01–11.5

PSA** 135 1.10 0.99–1.22 0.08

Diagnostic Gleason score 104 0.77

6 1 (ref)

7 0.71 0.29–1.72

8 0.85 0.33–2.20

9 0.89 0.38–2.06

10 1.55 0.40–6.03

Time from primary endocrine treatment to CRPC* 58 0.91 0.76–1.09 0.29

No. of docetaxel series*** 99 1.02 0.98–1.07 0.36

Time on abiraterone acetatey 135 0.99 0.97–1.02 0.66

PSA response to abiraterone acetate 93

Increase in PSA 1 (ref)

Stable or decrease in PSA 0.88 0.50–1.56 0.67

Haemoglobinyy 63 1.50 1.05–2.12 0.02

Albuminyyy 57 0.74 0.38–1.43 0.37

LDHyyy 47 0.99 0.98–1.02 0.68

ALPyyy 63 1.01 1.00–1.01 0.02

ALP = alkaline phosphatase; CI = confidence interval; CRPC = castration-resistant prostate cancer; ECOG = Eastern Cooperative Oncology Group; HR = hazard

ratio; LDH = lactate dehydrogenase; PSA = prostate-specific antigen.* 1-yr increase.** A 2-fold increase.*** 1 series increase.y 1-mo increase.yy 1-mmol/l decrease.yyy 10-unit increase.

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Overall, the estimated median survival was 8.3 mo (95%

CI, 6.8–9.8) for the 137 patients. On univariate analysis,

pretreatment clinical characteristics had little or no

influence on survival (Table 2). Patients who had an ECOG

score of 2 had a higher mortality than patients who had

ECOG 0 (hazard ratio [HR]: 3.41; 95% CI, 1.01–11.5), but

Fig. 3 – Kaplan-Meier survival curves for the 110 patients who had valid perceinto quartiles. Twelve patients who had an increase in PSA were excluded becaPSA = prostate-specific antigen.

Please cite this article in press as: Brasso K, et al. EnzalutamideProstate Cancer Previously Treated with Docetaxel and Abiratero10.1016/j.eururo.2014.07.028

there was no survival difference between patients with

ECOG score 1 and ECOG score 2. A 1 mmol/l decrease in

haemoglobin was associated with an increased mortality

(HR: 1.50; 95% CI, 1.05–2.12). A 10-unit increase in ALP

concentration at enzalutamide initiation had a statistically

significant association with increased mortality (HR: 1.01;

ntage prostate-specific antigen (PSA) response to enzalutamide stratifieduse of unknown first PSA measurement.

Antitumour Activity Against Metastatic Castration-resistantne: A Multicentre Analysis. Eur Urol (2014), http://dx.doi.org/

Fig. 4 – (a) Kaplan-Meier survival curve for the 122 patients who had a prostate-specific antigen (PSA) response to enzalutamide treatment,dichotomised according to a continued PSA progression (orange line) and decline or stabilised PSA (blue line). (b) Kaplan-Meier survival curve for the122 patients who had a PSA response to enzalutamide treatment, dichotomised according to a PSA response greater than (blue line) or lower than(orange line) 30%. (c) Kaplan-Meier survival curve for the 122 patients who had a PSA response to enzalutamide treatment, dichotomised according toa PSA response greater than (blue line) or lower than (orange line) 50%.PSA = prostate-specific antigen.

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Please cite this article in press as: Brasso K, et al. Enzalutamide Antitumour Activity Against Metastatic Castration-resistantProstate Cancer Previously Treated with Docetaxel and Abiraterone: A Multicentre Analysis. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.07.028

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95% CI, 1.00–1.01), although this finding is of limited clinical

relevance. A borderline significant association between PSA

at enzalutamide initiation and survival was found (HR:

1.10; 95% CI, 0.99–1.22), although again, the clinical

relevance of this finding is uncertain. Survival was not

associated with age ( p = 0.13), albumin ( p = 0.37); LDH

( p = 0.68) at enzalutamide initiation; Gleason score at

diagnosis ( p = 0.77); time from primary endocrine treat-

ment to CRPC ( p = 0.29); number of docetaxel courses

( p = 0.36); or time on or PSA response to abiraterone

( p = 0.66 and p = 0.67, respectively). Assessment by RECIST

criteria was not performed in all compassionate use

programmes.

Responses according to RECIST criteria were reported

in 59 patients [14,16]. Overall, only seven of these patients

had a radiographic response to enzalutamide resulting in a

partial remission according to the RECIST criteria. No

patients experienced complete remissions. The median

duration of radiographic PFS in the 34 patients who

underwent regular radiographic follow-up was 3.1 mo

(95% CI, 2.3–3.9) [15,16].

In univariate analysis, a 10% lower PSA response was

associated with an increased risk of death (HR: 1.07; 95% CI,

1.03–1.10; p < 0.001). Kaplan-Meier survival curves strat-

ified into quartiles according to the best PSA response are

depicted in Figure 3. No association between the absolute

PSA decline and survival was found in univariate analysis

(HR: 1.003; 95% CI, 0.996–1.01; p = 0.37). Patients pre-

senting with stable or declining PSA following enzaluta-

mide had a median survival of 9.4 mo (95% CI, 7.5–11.3)

compared with 6.7 mo (95% CI, 5.5–7.9) in patients who had

PSA progression ( p = 0.047; Fig. 4a). Patients who had a PSA

fall >30% had a median survival of 11.4 mo (95% CI,

8.0–14.8) compared with 7.1 mo (95% CI, 5.9–8.2) in

patients who had a PSA decline <30% ( p = 0.002; Fig. 4b).

Patients who had a �50% fall in PSA had a median survival

of 12.6 mo (undefined 95% CI) compared with 7.4 mo (95%

CI, 6.1–8.6) for patients who had a PSA response <50%

( p = 0.007; Fig. 4c). Finally, there were no major differences

in pre-enzalutamide characteristics among patients who

had a PSA response >30% compared with those patients

who had a lower response (Supplemental Table 2).

4. Discussion

Since the introduction of docetaxel, mCRPC has been

artificially divided into a prechemotherapy and a post-

chemotherapy disease state for regulatory reasons. AR

signalling remains a key driver of progression during

mCRPC, despite testosterone at castration levels in both

of these disease states [19]. New therapeutic modalities

targeting the AR have been successfully developed and are

currently being introduced for both pre- and postche-

motherapy mCRPC. With the introduction of these new

treatment options, the questions of optimal timing, patient

selection, sequencing, and the development of drug

resistance have been heavily debated.

In vitro experiments have also demonstrated impaired

antitumour activity of taxanes in cell lines resistant to

Please cite this article in press as: Brasso K, et al. EnzalutamideProstate Cancer Previously Treated with Docetaxel and Abiratero10.1016/j.eururo.2014.07.028

next-generation AR-targeting drugs [20]. This finding may

reflect the taxane mode of action, which involves the AR

pathway through the role of microtubules on AR nuclear-

cytoplasmic shuttling or may be the result of up-regulation

of other antiapoptotic mechanisms [21,22]. The response to

enzalutamide has also been reported to be affected by

glucocorticoid receptor signalling in preclinical studies,

although limited clinical data are available to support this

hypothesis to date [23]. Arora et al. indicate that exposure to

enzalutamide in a preclinical model of prostate cancer

induces glucocorticoid receptor up-regulation leading to

the development of enzalutamide resistance.

Compared with the AFFIRM trial [6], the data from the

compassionate use programmes pooled in this study

indicate more modest antitumour activity for enzalutamide

in postchemotherapy mCRPC patients previously treated

with abiraterone [14–17]. The antitumour activity of

abiraterone following both docetaxel and enzalutamide

has similarly been reported to be modest compared with

COU-AA-301 [11–13]. Mezynski et al. have also shown a

lower antitumour activity for docetaxel in patients previ-

ously managed with abiraterone [24]. Nevertheless, our

results indicate that a subset of patients previously

managed with docetaxel and abiraterone who responded

with nonincreasing or decreasing PSA following enzaluta-

mide may have improved OS. In univariate analysis, PSA

declines were associated with improved survival; further

analysis stratifying by response in patients who had no PSA

increase, a 30% decrease, and a 50% decrease in PSA

following initiation of enzalutamide, respectively, demon-

strated longer survival compared with patients who

experienced increasing PSA, <30% decrease, or a 50%

decrease, respectively. Studies applying the Prostate Cancer

Working Group 2 guidelines and implementing regular

imagining should be performed to confirm these findings.

Patients benefiting from enzalutamide may therefore be

those who have a PSA response to this agent, while patients

who have a poorer PSA response could benefit from other

treatment options. Overall, the biochemical activity of

enzalutamide after abiraterone and docetaxel may be

higher than that of abiraterone following progression on

docetaxel and enzalutamide [12,13]. Randomised clinical

trials are, however, now required to address the optimal

sequences or combinations for the administration of these

novel agents.

Lower haemoglobin and ECOG score 2 were both

associated with poorer prognosis in univariate analysis.

Patients who had a PSA >30% had significantly higher

baseline haemoglobin and a trend towards better ECOG

scores (Supplemental Table 2). These differences in baseline

parameters may partly explain the survival benefit seen in

patients who have a better PSA response. Survival following

initiation of enzalutamide was not associated with evalu-

ated pretreatment characteristics—time to CRPC, the PSA

response, and duration of prior chemotherapy and abir-

aterone or age.

This preliminary report of PSA response to enzalutamide

treatment in mCRPC patients progressing after postche-

motherapy abiraterone has obvious limitations. First, it is a

Antitumour Activity Against Metastatic Castration-resistantne: A Multicentre Analysis. Eur Urol (2014), http://dx.doi.org/

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retrospective study; baseline characteristics are incom-

pletely recorded, with differences among the four centres;

and the patients have not been followed systematically by

protocol. The number of patients is limited, and the study

lacks information about PSA kinetics and parameters other

than PSA to monitor the response of enzalutamide

treatment. Bone scans and radiographic evaluation was

performed only if clinically indicated; radiographic re-

sponse in accordance with the RECIST criteria was recorded

only in a subset of patients [18]. Of the patients included in

the present study, only 36.9% and 18.0% responded with a

PSA decline of 30% and 50%, respectively. However, the

combined analyses demonstrate that despite a modest PSA

response, with only a limited number of patients reaching a

PSA response �30%, a survival benefit was demonstrated in

patients who did not have a rising PSA following the

introduction of enzalutamide.

5. Conclusions

This study presents data from four European studies on

compassionate-access enzalutamide for mCRPC patients

progressing following docetaxel and abiraterone. We

demonstrate that enzalutamide, when administered as a

third-line treatment, has more modest antitumour activity

than that reported in the AFFIRM trial. Nonetheless, patients

who had a PSA decline >30% and 50% have superior survival

and may benefit from this agent. With the increasing

number of treatment options available for patients who

have mCRPC, well-conducted studies determining the

optimal treatment sequence or combination of these drugs

are urgently needed to base future treatment algorithms on

solid evidence.

Author contributions: Klaus Brasso had full access to all the data in the

study and takes responsibility for the integrity of the data and the

accuracy of the data analysis.

Study concept and design: Brasso, Thomsen, Schmid, Merseburger,

de Bono.

Acquisition of data: Brasso, Thomsen, Schrader, Schmid, Lorente, Retz,

Merseburger, von Klot, Boegemann, de Bono.

Analysis and interpretation of data: Brasso, Thomsen, Schrader, Schmid,

Lorente, Retz, Merseburger, von Klot, Boegemann, de Bono.

Drafting of the manuscript: Brasso, Thomsen.

Critical revision of the manuscript for important intellectual content:

Schrader, Schmid, Lorente, Retz, Merseburger, von Klot, Boegemann,

de Bono.

Statistical analysis: Brasso, Thomsen.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Brasso.

Other (specify): None.

Financial disclosures: Klaus Brasso certifies that all conflicts of interest,

including specific financial interests and relationships and affiliations

relevant to the subject matter or materials discussed in the manuscript

(eg, employment/affiliation, grants or funding, consultancies, honoraria,

stock ownership or options, expert testimony, royalties, or patents filed,

received, or pending), are the following: Klaus Brasso received

consulting fees from Astellas, Bayer AG, and Sanofi-Aventis as well as

lecture fees from Ferring and Sanofi-Aventis. Andres J. Schrader received

Please cite this article in press as: Brasso K, et al. EnzalutamideProstate Cancer Previously Treated with Docetaxel and Abiratero10.1016/j.eururo.2014.07.028

consulting and lecture fees from Astellas Pharma GmbH, Janssen-Cilag

GmbH, Pfizer GmbH, Bayer AG, GlaxoSmithKline, Novartis, Medac, Ipsen

Pharma, and Sanofi-Aventis. Sebastian Schmid received lecture fees from

Astellas Pharma GmbH and travel grants from GlaxoSmithKline GmbH &

Co. KG. Margitta Retz received lecture fees and honoraria from Astellas

Pharma GmbH, Janssen-Cilag GmbH, Pfizer GmbH, Bayer AG, and

GlaxoSmithKline GmbH & Co. KG. Alex Merseburger received lecture fees

and honoraria from Astellas Pharma GmbH, Janssen-Cilag GmbH, Novartis

Pharma, Pfizer GmbH, Bayer AG, and GlaxoSmithKline GmbH & Co. KG.

Martin Boegemann received lecture fees and honoraria from Astellas

Pharma GmbH, Janssen-Cilag GmbH, Pfizer GmbH, Bayer AG, Teva GmbH,

and GlaxoSmithKline GmbH & Co. KG. Johann de Bono received consulting

fees from Ortho Biotech Oncology Research and Development (a unit of

Cougar Biotechnology); consulting fees and travel support from Amgen,

Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb,

Dendreon, Enzon, Exelixis, Genentech, GlaxoSmithKline, Medivation,

Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Supergen, and Takeda;

and grant support from AstraZeneca and Genentech.

Funding/Support and role of the sponsor: None.

Appendix A. On behalf of national enzalutamide study

groups

Denmark: M.A. Røder 1, P. Rathenborg 2, M. Borre 3,

P. Iversen 1

Germany: C.H. Ohlmann 5, T.J. Schnoeller 6, L.M. Krabbe 4,

T. Hajili 7, F. Jentzmik 6, M. Stoeckle 5, M. Schrader 6,

E. Hermann 4, M.V. Cronauer 6, A. Geith 7, A. Boker 8,

R. Tauber 7, A.K. Seitz 7, M. Kuczyk 8, J.E. Gschwend 7

United Kingdom: D. Bianchini 9, A. Rodriquez-Vida 10,

A. Omlin 9, C. Pezaro 9, R. Ferraldeschi 9, A. Zivi 9, G. Attard 9,

S. Chowdhury 10

1 Copenhagen Prostate Cancer Center, Department

of Urology, Rigshospitalet, University of Copenhagen,

Copenhagen, Denmark2 Department of Urology, Herlev Hospital, Copenhagen

University Hospital, Copenhagen, Denmark3 Department of Urology, Aarhus University Hospital,

Skejby, Denmark4 Department of Urology, Muenster University Medical

Center, Muenster, Germany5 Department of Urology, Saarland University Medical

Center, Hamburg/Saar, Germany6 Department of Urology, Ulm University Medical Center,

Ulm, Germany7 Urologische Klinik und Poliklinik, Technischen Universitat

Munchen, Munich, Germany8 Department of Urology and Urological Oncology, Hann-

over Medical School, Hannover, Germany9 Royal Marsden NHS Foundation Trust and The Institute of

Cancer Research, Sutton, United Kingdom10 Guy’s and St Thomas’ NHS Foundation Trust, London,

United Kingdom

Appendix B. Supplementary data

Supplementary data associated with this article can be

found, in the online version, at http://dx.doi.org/10.1016/

j.eururo.2014.07.028.

Antitumour Activity Against Metastatic Castration-resistantne: A Multicentre Analysis. Eur Urol (2014), http://dx.doi.org/

E U R O P E A N U R O L O G Y X X X ( 2 0 1 4 ) X X X – X X X8

EURURO-5754; No. of Pages 8

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