P os a e
Cance
Sa e y
and
An i umou
Ac i i y
o
ODM-201
(BAY-1841788)
in
Chemo he apy-naï e
and
CYP17
Inhibi o -naï e
Pa ien s:
Follow-up
om
he
ARADES
and
ARAFOR
T ials
Neal
D.
Sho e
a,
*,
Teu o
L.
Tammela
b
,
Ch is ophe
Massa d
c
,
Pe i
Bono
d
,
John
Aspeg en
e
,
Mika
Mus onen
e
,
Ka im
Fizazi
c
a
Ca olina
U ologic
Resea ch
Cen e ,
My le
Beach,
SC,
USA;
b
Tampe e
Uni e si y
Hospi al,
Depa men
o
U ology,
Tampe e,
Finland;
c
Ins i u
Gus a e
Roussy,
Uni e si y
o
Pa is
Sud,
Villejui ,
F ance;
d
Comp ehensi e
Cance
Cen e ,
Helsinki
Uni e si y
Hospi al
and
Uni e si y
o
Helsinki,
Helsinki,
Finland;
e
O ion
Co po a ion,
O ion
Pha ma,
Espoo,
Finland
E
U
R
O
P
E
A
N
U
R
O
L
O
G
Y
F
O
C
U
S
4
(
2
0
18
)
5
4
7
–
5
5
3
a a
ilable
a
www.sciencedi ec .com
jou na
l
homepage:
www.eu opea
nu ology.com/eu ocus
A icle
in o
A icle
his o y:
Accep ed
Janua y
24,
2017
Associa e
Edi o :
James
Ca o
Keywo ds:
And ogen
ecep o
And ogen
ecep o
an agonis
Me as a ic
cas a ion- esis an
p os a e
cance
ODM-201
Abs ac
Backg ound:
ODM-201,
a
new
and ogen
ecep o
an agonis
o
ea men
o
me as a ic
cas a ion- esis an
p os a e
cance
(mCRPC),
demons a ed
an i umou
ac i i y
and
accep -
able
ole abili y
in
phase
1/2
ials.
Objec i e:
To
de e mine
he
an i umou
ac i i y
and
sa e y
p ofile
o
ex ended
ea men
wi h
ODM-201
in
men
wi h
mCRPC.
Design,
se ing,
and
pa icipan s:
ARADES
and
ARAFOR
ials
wi h
ODM-201
en olled
chemo-
he apy-naï e
and
CYP17
inhibi o
(CYP17i)-naï e
mCRPC
pa ien s.
Bo h
ials
had
ex ended
ollow-up.
He e
we
epo
esul s
o
chemo he apy-naï e
and
CYP17i-naï e
pa ien s
om
bo h
ials
(da a
cu o
Oc obe
2014
o
ARADES
and
Ap il
2015
o
ARAFOR)
a e
ex ended
ollow-up.
In e en ion:
A
o al
o
41
chemo he apy-naï e
and
CYP17i-naï e
pa ien s
ecei ed
o al
ODM-
201
wice
daily
( o al
daily
dose
o
1200,
1400
o
1800
mg).
Ou come
measu emen s
and
s a is ical
analysis:
An i umou
ac i i y
was
assessed
in
e ms
o
p os a e-specific
an igen
(PSA)
declines
and
PSA/ adiog aphic
p og ession.
Sa e y
was
assessed
un il
disease
p og ession
and/o
d ug
discon inua ion
due
o
any
in ole able
ad e se
e en
(AE).
Resul s
and
limi a ions:
ODM-201
sa e y
da a
a e
a
median
ea men
ime
o
13.5
mo
(95%
confidence
in e al
[CI]
9.7–15.6,
in e qua ile
ange
[IQR]
7.5–22.0)
we e
simila
o
hose
epo ed
in
he
main
ARADES
and
ARAFOR
ials.
The
o e all
AE
incidence
was
80.5%
(n
=
33/41),
wi h
58.5%
(n
=
24/41)
o
pa ien s
expe iencing
only
g ade
1–2
AEs.
The
mos
common
AEs
we e
a igue,
back
pain,
dia hoea,
nausea,
and
pain
in
ex emi y.
The
median
imes
o
PSA
and
adiological
p og ession
we e
12.4
mo
(95%
CI
6.3–18.2,
IQR
5.5–22.0)
and
15.3
mo
(95%
CI
9.5–no
eached
[NR],
IQR
6.3–NR),
espec i ely.
Conclusions:
Ex ended
ea men
wi h
ODM-201
(1200–1800
mg/d)
was
well
ole a ed,
wi h
no
new
sa e y
conce ns,
and
p o ided
e idence
o
sus ained
an i umou
ac i i y
in
chemo he apy-
naï e
and
CYP17i-naï e
pa ien s
wi h
mCRPC.
Pa ien
summa y:
P olonged
ea men
wi h
high
doses
o
ODM-201
was
well
ole a ed
and
p o ided
long-las ing
disease
con ol
in
pa ien s
wi h
mCRPC.
ODM-201
ep esen s
a
he a-
peu ic
ea men
op ion
o
mCRPC.
The
ARAFOR
ial
(including
he
ollow-up
s age)
and
he
ollow-up
componen
o
he
ARADES
ial
a e
egis e ed
wi h
ClinicalT ials.go
as
ial
numbe s
NCT01784757
and
NCT01429064.
©
2017
Eu opean
Associa ion
o
U ology.
Published
by
Else ie
B.V.
This
is
an
open
access
a icle
unde
he
CC
BY-NC-ND
license
(h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/).
* Co esponding
au ho .
Ca olina
U ologic
Resea ch
Cen e ,
A lan ic
U ology
Clinics,
My le
Beach,
SC,
USA.
Tel:
+1
843
449
1010,
Fax:
+1
843
286
0119.
E-mail
add ess:
[email p o ec ed]
(N.D.
Sho e).
h p://dx.doi.o g/10.1016/j.eu .2017.01.015
2405-4569/©
2017
Eu opean
Associa ion
o
U ology.
Published
by
Else ie
B.V.
This
is
an
open
access
a icle
unde
he
CC
BY-NC-ND
license
(h p://
c ea i ecommons.o g/licenses/by-nc-nd/4.0/).
1.
In oduc ion
P os a e
cance
(PCa)
is
he
hi d
mos
common
cause
o
cance - ela ed
dea h
in
men
in
he
EU,
wi h
an
es ima ed
92
000
dea hs
in
2012
[1].
And ogen
dep i a ion
he apy
(ADT),
ia
ei he
o chiec omy
o
ea men
wi h
a
lu einis-
ing
ho mone– eleasing
ho mone
agonis /an agonis ,
is
he
s anda d
o
ca e
o
pa ien s
wi h
ho mone-sensi i e
ad anced
PCa
[2,3].
Despi e
an
ini ial
esponse
o
ea men ,
mos
pa ien s
p og ess
o
me as a ic
cas a ion- esis an
PCa
(mCRPC),
which
has
a
poo
p ognosis
[2,4,5]
and
equi es
subsequen
he apeu ic
in e en ion
[6,7].
Al e a ions
in
he
and ogen
ecep o
(AR)
signalling
pa hway
a e
he
main
unde lying
molecula
mechanism
d i ing
mCRPC
[8–10].
As
umou
g ow h
o
PCa
cells
in
he
cas a ion- esis an
disease
s age
is
dependen
on
pe -
sis en
AR
signalling,
he
AR
axis
is
conside ed
an
e ec i e
he apeu ic
a ge
in
mCRPC
[11,12].
Speci ic
and ogen
axis-
and
AR- a ge ing
agen s—abi a e one
and
enzalu amide—
ha e
been
app o ed
in
he
EU
and
he
USA
o
mCRPC
ea men .
Bo h
compounds
imp o ed
o e all
su i al
and
adiog aphic
p og ession- ee
su i al
and
had
a
bene-
icial
impac
on
quali y
o
li e
(QoL)
in
phase
3
ials
includ-
ing
pos -chemo he apy
[13–15]
and
p e-chemo he apy
[16,17]
mCRPC
pa ien s.
New
AR
inhibi o s
a e
being
de el-
oped
o
ea men
o
mCRPC,
including
ODM-201,
an
in es-
iga ional
nons e oidal
o al
AR
an agonis
ha
is
s uc u -
ally
di e en
om
any
o he
an iand ogen
compound,
including
enzalu amide
and
apalu amide
[18].
A
p eclinical
s udy
showed
ha
ODM-201
has
an i umou
ac i i y
in
i o,
as
i
inhibi ed
umou
g ow h
in
a
mu ine
VCap
CRPC
xenog a
model,
wi h
highe
ac i i y
han
enzalu amide
[18].
In
wo
phase
1/2
ials,
ODM-201
exhibi ed
an i umou
ac i i y
and
was
well
ole a ed
in
men
wi h
mCRPC.
In
he
open-label
mul icen e
ARADES
ial
(NCT01429064),
a
non- andomised,
i s -in-man,
dose
escala ion
phase
1
(n
=
24)
showed
ha
an i umou
ac i i y
was
achie ed
a
all
doses
es ed
(200–1800
mg/d)
and
no
dose-limi ing
oxici y
was
obse ed
[19].
In
he
phase
2
ex ension
(n
=
110),
a
p os a e-speci ic
an igen
(PSA)
decline
was
obse ed
wi h
all
ODM-201
doses
es ed
(200–1400
mg/d),
and
he
1400-mg/d
dose
led
o
he
g ea es
PSA
esponse
in
chemo he apy-naï e
and
CYP17
inhibi o
(CYP17i)-naï e
pa ien s.
Fu he mo e,
ODM-201
was
well
ole a ed,
wi h
>99%
o
ad e se
e en s
(AEs)
being
g ade
1–2
[19].
ARAFOR
(NCT01784757)
was
an
open-label
mul icen e
ial
ha
included
a
pha macokine ic
componen
(n
=
30)
and
an
open-label
ex ension
s udy
(n
=
30)
[20].
ODM-201
demons a ed
an i umou
ac i i y
and
was
well
ole a ed
in
chemo he apy-naï e
pa ien s:
a
PSA
esponse
(50%
dec ease
in
PSA
le els
om
baseline
a
week
12)
was
obse ed
in
25/30
pa ien s
(83%),
and
91%
o
ea men -
eme gen
AEs
we e
o
g ade
1–2
[20].
Wi h
he
p e ious
indings
om
he
ARADES
and
ARAFOR
ials,
he
sa e y
and
umou -supp ession
ac i i y
o
ex ended
ODM-201
dosing
in
men
wi h
mCRPC
a e
o
clinical
in e es ,
as
hese
pa ien s
usually
bene i
om
p olonged
ea men .
He e
we
epo
da a
om
he
ollow-up
o
he
ARADES
and
ARAFOR
ials
on
he
sa e y
and
an i umou
ac i i y
o
ODM-201
in
pa ien s
wi h
mCRPC,
who
did
no
ecei e
p io
chemo he apy
o
CYP17i.
2.
Pa ien s
and
me hods
2.1.
S udy
design
and
pa ien s
The
da a
p esen ed
he e
om
he
ARADES
(cu o
da e
Oc obe
31,
2014)
[19]
and
ARAFOR
(cu o
da e
Ap il
30,
2015)
ials
[20]
include
hose
pa ien s
who
we e
chemo he apy-
and
CYP17i-naï e
and
ecei ed
1200,
1400
o
1800
mg/d
o
ODM-201.
The
comple e
s udy
design
was
published
p e iously
[19,20].
In
b ie ,
male
pa ien s
we e
aged
18
y ,
had
p og essi e
mCRPC,
an
Eas e n
Coope a i e
Oncology
G oup
pe o -
mance
s a us
(ECOG-PS)
sco e
o
0–1,
and
se um
es os e one
le els
<1.7
nmol/l.
Pa ien s
we e
included
i
hey
we e
mildly
symp oma ic
o
asymp oma ic
and
hose
wi h
a
his o y
o
isk
o
seizu es
could
be
included.
Pa ien s
wi hou
bila e al
o chidec omy
had
o
con inue
app o ed
ADT
du ing
he
ial.
In
he
ARADES
and
ARAFOR
ials,
disease
p og ession
was
defined
by:
ising
PSA
( wo
consecu i e
inc eases
in
PSA
le els
1
wk
apa ,
wi h
he
lowes
alue
being
2
ng/ml);
adiog aphic
disease
p og ession
(assessed
using
he
modified
Response
E alua ion
C i e ia
in
Solid
Tumou s
e sion
1.1);
o
he
p esence
o
wo
o
mo e
new
bone
lesions.
Exclusion
c i e ia
we e
he
p esence
o
b ain
me as ases
and
p io
ea men
wi h
AR
an agonis s,
CYP17i
o
chemo he apy.
2.2.
E hics
Pa ien s
ga e
w i en
in o med
consen
and
he
ials
we e
app o ed
by
an
independen
e hics
commi ee
a
each
cen e
o
by
he
in es iga ional
e iew
boa d.
The
ials
we e
conduc ed
acco ding
o
he
p inciples
o
he
Decla a ion
o
Helsinki
and
he
guidelines
o
Good
Clinical
P ac ice.
2.3.
T ea men
Pa ien s
ecei ed
ODM-201
wice
daily
wi h
ood
( o al
daily
dose
o
1200,
1400
o
1800
mg).
T ea men
con inued
un il
disease
p og ession
o
an
in ole able
AE.
2.4.
An i umou
ac i i y
assessmen s
In
he
ARADES
and
ARAFOR
ials,
PSA
concen a ions
we e
measu ed
a
baseline,
e e y
4
wk
un il
he
9-mo
isi ,
e e y
3
mo
he ea e ,
and
a
he
end-o -s udy
isi .
The
pe cen age
change
in
se um
PSA
was
calcu-
la ed
om
baseline
un il
pa ien s
discon inued
he
s udy.
Baseline
PSA
was
defined
as
he
PSA
le el
be o e
he
fi s
ODM-201
dose.
The
median
ime
o
PSA
p og ession
was
defined
as
he
ime
om
ODM-201
ea men
ini ia ion
un il
documen a ion
o
a
25%
inc ease
and
an
absolu e
inc ease
o
2
ng/ml
in
PSA
om
nadi ,
acco ding
o
P os a e
Cance
Wo king
G oup
2
c i e ia
[21];
his
had
o
be
confi med
by
an
addi ional
PSA
measu emen
3
wk
la e .
A
minimum
pe iod
o
12
wk
was
equi ed
be o e
PSA
p og ession
could
be
decla ed.
Time
o
adiog aphic
p og ession
was
defined
as
he
ime
be ween
he
s a
o
ea men
and
he
occu ence
o
he
fi s
p og ession
(so
issue
o
bone)
as
assessed
using
compu ed
omog aphy/magne ic
esonance
imaging
o
a
bone
scan.
2.5.
Sa e y
and
ole abili y
AEs
we e
classified
by
sys em
o gan
classes
and
p e e ed
e ms
(Medical
Dic iona y
o
Regula o y
Ac i i ies
coding
sys em,
e sion
17.1
in
he
ARADES
ial,
and
18.0
in
he
ARAFOR
ial)
and
g aded
by
he
Na ional
E
U
R
O
P
E
A
N
U
R
O
L
O
G
Y
F
O
C
U
S
4
(
2
0
1
8
)
5
4
7
–
5
5
3
548
Cance
Ins i u e
o
Common
Te minology
C i e ia
o
AEs
( e sion
4.03).
Labo a o y
assessmen s
(haema ology,
se um
biochemis y,
ho mones
and
u ine
analysis)
we e
pe o med:
a
baseline,
once
a
week
o
he
fi s
28
d,
e e y
4
wk
un il
he
9-mo
isi ,
e e y
3
mo
he ea e ,
and
a
he
end-o -s udy
isi .
Ho mone
measu emen s
we e
pe o med
up
o
week
12.
2.6.
S a is ical
analysis
An i umou
ac i i y
and
sa e y
analyses
included
all
pa ien s
who
ecei ed
a
leas
one
dose
o
ODM-201.
Time
o
PSA
and
adiog aphic
p og ession
we e
calcula ed
using
Kaplan-Meie
es ima es;
he
median
alues
wi h
associa ed
95%
confidence
in e als
(CIs)
and
in e qua ile
anges
(IQRs)
a e
epo ed.
All
measu emen s
a e
summa ised
using
desc ip i e
s a is ics.
Analyses
we e
pe o med
using
da a
collec ed
up
o
he
cu o
da es
o
Oc obe
31,
2014
o
ARADES
and
Ap il
30,
2015
o
ARAFOR.
3.
Resul s
3.1.
Pa ien s
A
o al
o
41
pa ien s
wi h
p og essi e
mCRPC
we e
included
in
he
analyses;
hey
we e
all
chemo he apy-naï e
and
CYP17i-naï e.
O
hese,
30
(73.2%)
we e
om
he
ARAFOR
ial
and
11
(26.8%)
om
he
ARADES
ial.
Baseline
demog aphic
and
clinical
cha ac e is ics
o
he
pa ien s
we e
well
balanced
in
he
wo
ials
(Table
1).
The
median
age
was
69.0
y
( ange
54.0–86.0)
and
mos
pa ien s
(73.2%)
we e
classi ied
as
ECOG-PS
sco e
0.
The
o e all
baseline
median
PSA
was
27.7
ng/ml
( ange
3.5–1293.8);
mos
pa ien s
had
bone
disease
a
sc eening
(n
=
36,
87.8%),
whe eas
16
pa ien s
(39.0%)
had
disease
localised
in
he
lymph
nodes
and
h ee
pa ien s
(7.3%)
had
isce al
disease.
Da a
o
pa ien s
om
he
ARADES
ial
we e
collec ed
un il
Oc obe
31,
2014;
he
ini ial
esul s
we e
epo ed
in
2014
using
a
cu o
da e
o
Oc obe
3,
2013
[19].
Pa ien
da a
om
he
ARAFOR
ial
we e
collec ed
h ough
o
Ap il
30,
2015
and
he
ini ial
esul s
we e
published
in
2015
wi h
a
cu o
da e
o
Oc obe
31,
2014
[20].
The
di e ence
in
cu o
da es
be ween
he
wo
s udies
p esen ed
he e
e lec s
he
di e en
s udy
ini ia ion
da es
[19,20].
All
pa ien s
om
he
ARAFOR
ial
(30/41,
73.2%)
ecei ed
1200
mg/d
o
ODM-201,
while
ARADES
pa ien s
ecei ed
1400
mg/d
(n
=
9/41,
22.0%)
o
1800
mg/d
(n
=
2,
4.9%).
O e all,
30/41
pa ien s
(73.2%)
discon inued
he
s udy;
he
mos
common
cause
o
discon inua ion
was
Table
1
–
Baseline
demog aphics
and
clinical
cha ac e is ics.
ARADES
ial
(n
=
11)
ARAFOR
ial
(n
=
30)
To al
(n
=
41)
Age
(y )
73.0
(62.0–82.0)
68.0
(54.0–86.0)
69.0
(54.0–86.0)
PSA
(ng/ml)
219.2
(14.9–1293.8)
a
18.2
(3.5–554.8)
27.7
(3.5–1293.8)
b
Tes os e one
(ng/dl)
0.7
(0.4–1.7)
0.8
(0.4–1.6)
0.8
(0.4–1.7)
LDH
(U/l)
193.0
(159.6–515.0)
a
323.5
(163.0–559.0)
287.0
(159.6–559.0)
b
Gleason
sco e
a
diagnosis
2–6
1
(9.1)
6
(20.0)
7
(17.1)
7
4
(36.4)
12
(40.0)
16
(39.0)
8–10
5
(45.5)
12
(40.0)
17
(41.5)
Missing
c
1
(9.1)
0
(0.0)
1
(2.4)
ECOG-PS
0
10
(90.9)
20
(66.7)
30
(73.2)
1
1
(9.1)
10
(33.3)
11
(26.8)
Time
om
diagnosis
o
SS
(mo)
64.1
(10.9–165.7)
39.7
(7.6–133.7)
50.0
(7.6–165.7)
P io
an iand ogen
he apy
11
(100.0)
22
(73.3)
33
(80.5)
LHRH
he apy
10
(90.9)
30
(100.0)
40
(97.6)
Time
om
LHRH
he apy
o
SS
(mo)
40.7
(6.6–153.3)
d
22.5
(0.9–126.6)
e
22.5
(0.9–153.3)
Disease
localisa ion
Lymph
node
4
(36.4)
12
(40.0)
16
(39.0)
Bone
disease
9
(81.8)
27
(90.0)
36
(87.8)
Bone
only
7
(63.6)
15
(50.0)
22
(53.7)
Bone
and
so
issue
2
(18.2)
12
(40.0)
14
(34.1)
So
issue
only
2
(18.2)
3
(10.0)
5
(12.2)
Visce al
1
(9.1)
2
(6.7)
3
(7.3)
Bone
me as ases
a
sc eening
0
2
(18.2)
3
(10.0)
5
(12.2)
1–4
3
(27.3)
9
(30.0)
12
(29.3)
5–20
3
(27.3)
4
(13.3)
7
(17.1)
>20
o
non-coun able
3
(27.3)
14
(46.7)
17
(41.5)
ECOG-PS
=
Eas e n
Coope a i e
Oncology
G oup
pe o mance
s a us;
LDH
=
lac a e
dehyd ogenase;
LHRH
=
lu einising
ho mone- eleasing
ho mone;
PSA
=
p os a e-specific
an igen;
SS
=
s udy
s a .
Da a
a e
p esen ed
as
median
( ange)
o
con inuous
a iables
and
as
n
(%)
o
ca ego ical
a iables.
a
n
=
10.
b
n
=
40.
c
Gleason
sco e
no
a ailable.
d
n
=
8.
e
n
=
29.
n
=
37.
E
U
R
O
P
E
A
N
U
R
O
L
O
G
Y
F
O
C
U
S
4
(
2
0
1
8
)
5
4
7
–
5
5
3
549
disease
p og ession
(90%
o
pa ien s),
wi h
only
wo
pa ien s
(6.7%)
discon inuing
due
o
AEs
and
one
(3.3%)
o
pe sonal
easons.
Fou
ARADES
pa ien s
whose
ea -
men
was
ongoing
a e
he
o iginal
da a
cu o
o
Oc obe
3,
2013
[19]
discon inued
he
ex ension
s udy
be o e
he
new
cu o
da e
o
Oc obe
31,
2014.
O
he
en
pa ien s
who
we e
ongoing
by
Oc obe
31,
2014
in
he
main
ARAFOR
ial
[20],
one
discon inued
he
ex ension
ollow-up
be o e
he
new
cu o
da e
o
Ap il
30,
2015
and
one
discon inued
s udy
ea men ,
bu
no
he
s udy,
be o e
he
ex ended
da a
cu o .
Al hough
he
median
ollow-up
ime
was
15.3
mo
(95%
CI
10.4–16.5,
IQR
7.9–25.7;
Fig.
1)
and
he
median
on- ea men
ime
was
13.5
mo
(95%
CI
9.7–15.6,
IQR
7.5–22.0),
11
pa ien s
(n
=
10
ARAFOR
and
n
=
1
ARADES)
con inued
he
s udy
a e
he
da a
cu o .
O
hese,
en
pa ien s
(n
=
9
ARAFOR
and
n
=
1
ARADES)
con inued
ODM-201
ea men
a e
he
da a
cu o :
wo
pa ien s
we e
on
a
named
pa ien
(compassiona e)
use
basis,
wi h
one
pa ien
ecei ing
ea men
un il
he
end
o
Augus
2016,
o
a
o al
on- ea men
ime
o
41
mo.
3.2.
Sa e y
An
AE
was
expe ienced
by
80.5%
(n
=
33/41)
o
pa ien s,
and
29
pa ien s
(70.7%)
had
mo e
han
one
AE.
The
mos
com-
mon
AEs
o
any
g ade
we e:
a igue
(g ade
1)
in
eigh
pa ien s
(19.5%);
nausea
(g ade
1–3),
pain
in
ex emi y
(g ade
1–2),
back
pain
(g ade
2–3)
and
dia hoea
(g ade
1–2)
in
i e
pa ien s
(12.2%);
and
a h algia
(g ade
1–2)
in
ou
pa ien s
(9.8%)
(Table
2).
O e all,
24
pa ien s
(58.5%)
had
only
g ade
1–2
AEs
and
se en
pa ien s
(17.1%)
expe i-
enced
g ade
3
AEs,
including:
PCa
p og ession,
back
pain,
nausea,
bone
pain,
inc ease
in
blood
alkaline
phospha ase,
hype ension,
hypona aemia,
lung
adenoca cinoma,
all
and
emo al
neck
ac u e
(Table
2).
G ade
4
AEs
we e
obse ed
only
in
he
ARAFOR
ial
and
included
espi a o y
ailu e
and
neu oendoc ine
ca cinoma
( wo
pa ien s),
and
one
pa ien
died
due
o
gene al
physical
heal h
de e io a-
ion
and
PCa
p og ession
(Table
2).
The
pa e n
o
AEs
epo ed
du ing
his
s udy
in
chemo he apy-naï e
and
CYP17i-naï e
pa ien s
is
simila
o
ha
epo ed
in
he
same
pa ien
popula ion
du ing
he
main
ARADES
and
ARAFOR
ials:
a
he
ime
o
he
o iginal
cu o
da es
(Oc obe
3,
2013
o
ARADES
and
Oc obe
31,
2014
o
ARAFOR),
he
mos
common
AEs
o
any
g ade
included
g ade
1
a igue/
as henia
(8
pa ien s,
19.5%);
dia hoea
and
pain
in
ex emi y
(g ade
1–2)
and
g ade
1–3
nausea
(5
pa ien s,
12.2%);
and
g ade
2–3
back
pain
and
g ade
1–2
pe iphe al
oedema
(4
pa ien s,
9.8%).
Fu he mo e,
du ing
he
main
ARADES
and
ARAFOR
ials
he
incidence
o
g ade
3
AEs
(4
pa ien s,
9.8%)
was
simila
o
ha
epo ed
du ing
he
ollow-up
(7
pa ien s,
17.1%);
o e all,
no
new
AEs
(any
g ade)
we e
obse ed
in
he
ollow-up.
Du ing
his
s udy,
ea men - ela ed
AEs
occu ed
in
en
pa ien s
(24.4%):
ou
pa ien s
(36.4%)
we e
om
he
ARADES
ial
and
six
(20.0%)
om
ARAFOR
(Table
3).
All
ea men - ela ed
AEs
we e
g ade
1;
he
mos
common
we e
a igue
(3
pa ien s,
7.3%)
and
ho
lush
(2
pa ien s,
4.9%).
3.3.
An i umou
ac i i y
The
pe cen age
PSA
change
om
baseline
o
each
pa ien
du ing
ea men
wi h
1200,
1400,
and
1800
mg/d
o
ODM-201
is
shown
in
Fig.
2A.
The
maximum
PSA
esponse
a e
(50%
PSA
educ ion
om
baseline
a
any
ime
du ing
he
s udy)
was
85%
(n
=
34/40);
his
was
80%
(n
=
8/10)
and
87%
(n
=
26/30)
in
he
ARADES
and
ARAFOR
ials,
espec-
i ely
(Fig.
2B).
The
median
ime
o
PSA
p og ession
was
12.4
mo
(95%
CI
6.3–18.2,
IQR
5.5–22.0)
o
all
pa ien s
(Fig.
2C).
This
was
sligh ly
longe
in
he
ARAFOR
ial
(12.5
mo,
95%
CI
5.4–no
eached
[NR],
IQR
4.6–NR)
han
in
he
ARADES
ial
(9.9
mo,
95%
CI
5.5–22.0,
IQR
7.6–19.6).
Simila
da a
we e
ob ained
o
he
ime
o
adiological
p og ession;
his
was
15.3
mo
(95%
CI
9.5–NR,
IQR
6.3–NR)
in
he
ARAFOR
ial,
bu
was
no
eached
in
he
ARADES
ial
(95%
CI
2.6–NR,
IQR
14.0–NR).
4.
Discussion
Analysis
o
he
ex ended
ollow-up
o
pa ien s
om
he
ARADES
and
ARAFOR
ials
indica ed
ha
o
up
o
25.7
mo
(median
15.3),
ea men
wi h
high
doses
o
ODM-201
(1200,
1400
and
1800
mg/d)
was
well
ole a ed
and
p o-
ided
du able
an i umou
ac i i y
in
chemo he apy-naï e
and
CYP17i-naï e
pa ien s
wi h
mCRPC.
These
esul s
a e
consis en
wi h
he
indings
epo ed
o
he
ea lie
s ages
Fig.
1
–
Kaplan-Meie
es ima e
o
(A)
ollow-up
and
(B)
ime
on
ea men .
CI
=
con idence
in e al.
E
U
R
O
P
E
A
N
U
R
O
L
O
G
Y
F
O
C
U
S
4
(
2
0
1
8
)
5
4
7
–
5
5
3
550
o
he
wo
ials
[19,20]:
in
he
ARADES
ial,
pa ien s
wi hou
p io
chemo he apy
and
CYP17i
ea men
who
ecei ed
1400
mg/d
o
ODM-201
we e
hose
who
showed
he
g ea es
PSA
supp ession
[19].
ODM-201
dose
le els
used
in
his
s udy
we e
based
on
he
e icacy
obse ed
in
he
main
ARADES
[19]
and
ARAFOR
[20]
ials
in
pa ien s
ecei ing
highe
doses
o
s udy
medica ion,
and
a e
consis en
wi h
he
s udy
design
o
wo
planned
phase
3
ODM-201
ials,
ARAMIS
(NCT02200614)
and
ARASENS
(NCT02799602),
in
which
pa ien s
will
ecei e
he
1200
mg
daily
dose
o
ODM-201.
The
ODM-201
sa e y
p o ile
a e
ex ended
use
is
consis-
en
wi h
da a
p e iously
epo ed
o
he
ARADES
and
ARAFOR
ials
[19,20]
and
no
addi ional
sa e y
conce ns
we e
obse ed.
Mos
pa ien s
analysed
he e
(n
=
32/41,
78.0%)
expe ienced
AEs
o
g ade
1–2;
likewise,
in
he
main
ARAFOR
and
ARADES
ials,
mos
AEs
(116/129,
90%,
and
82/83,
99%,
espec i ely)
we e
o
g ade
1–2
among
all
he
AEs
epo ed.
O
hese,
he
mos
common
e en s
we e
a igue
(g ade
1
in
8/41,
19.5%)
and
nausea
(g ade
1–3
in
5/41,
12.2%),
which
a e
clinically
ele an
AEs
in
mCRPC
and
a e
commonly
obse ed
du ing
ea men
wi h
AR
an ago-
nis s
[13,16,22–25].
The
incidence
o
AEs
in
chemo he apy-
naï e
and
CYP17i-naï e
pa ien s
analysed
he e
is
simila
o
ha
epo ed
in
he
same
pa ien
popula ion
du ing
he
main
ARADES
and
ARAFOR
ials
a
he
ime
o
he
o iginal
cu o
da es,
demons a ing
ha
ex ended
ODM-201
ea -
men
is
no
associa ed
wi h
any
new
sa e y
conce ns.
On
he
basis
o
hese
da a,
he
sa e y
o
ODM-201
com-
pa es
a ou ably
wi h
ha
epo ed
o
o he
AR
an ago-
nis s,
such
as
enzalu amide,
whose
long- e m
sa e y
p o ile
was
es ablished
in
chemo he apy-naï e
pa ien s
in
a
phase
1/2
ial
[23]
om
which
pa ien s
wi h
a
known
isk
o
seizu e
we e
excluded.
Fo
bo h
AR
an agonis s,
he
mos
commonly
epo ed
ea men -eme gen
AEs
ollowing
ex ended
ea men
we e
a igue
and
nausea,
obse ed
in
19.5%
(g ade
1
a igue)
and
12.2%
(g ade
1–3
nausea)
o
Table
2
–
Ad e se
e en s
(AEs).
Pa ien s
epo ing
AEs,
n
(%)
G ade
1–2
G ade
3
G ade
4
G ade
5
Any
AEs
ARADES
(n
=
11)
11
(100.0)
1
(9.1)
0
(0.0)
0
(0.0)
ARAFOR
(n
=
30)
21
(70.0)
6
(20.0)
2
(6.7)
1
(3.3)
To al
(n
=
41)
32
(78.0)
7
(17.1)
2
(4.9)
1
(2.4)
G ade
1
G ade
2
G ade
3
G ade
4
G ade
5
G ades
1–5
Common
AEs
a
(n
=
41)
Fa igue
8
(19.5)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
8
(19.5)
Nausea
4
(9.8)
1
(2.4)
1
(2.4)
0
(0.0)
0
(0.0)
5
(12.2)
Pain
in
ex emi y
5
(12.2)
1
(2.4)
0
(0.0)
0
(0.0)
0
(0.0)
5
(12.2)
Back
pain
0
(0.0)
4
(9.8)
1
(2.4)
0
(0.0)
0
(0.0)
5
(12.2)
Dia hoea
4
(9.8)
1
(2.4)
0
(0.0)
0
(0.0)
0
(0.0)
5
(12.2)
A h algia
2
(4.9)
2
(4.9)
0
(0.0)
0
(0.0)
0
(0.0)
4
(9.8)
Bone
pain
1
(2.4)
2
(4.9)
1
(2.4)
0
(0.0)
0
(0.0)
3
(7.3)
Haema u ia
3
(7.3)
1
(2.4)
0
(0.0)
0
(0.0)
0
(0.0)
3
(7.3)
Influenza
2
(4.9)
2
(4.9)
0
(0.0)
0
(0.0)
0
(0.0)
3
(7.3)
Abdominal
pain
2
(4.9)
1
(2.4)
0
(0.0)
0
(0.0)
0
(0.0)
3
(7.3)
Dysu ia
3
(7.3)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
3
(7.3)
Headache
3
(7.3)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
3
(7.3)
Ho
flush
3
(7.3)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
3
(7.3)
Hype ension
0
(0.0)
2
(4.9)
1
(2.4)
0
(0.0)
0
(0.0)
3
(7.3)
Rash
2
(4.9)
1
(2.4)
0
(0.0)
0
(0.0)
0
(0.0)
3
(7.3)
Rhino hoea
3
(7.3)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
3
(7.3)
Vomi ing
2
(4.9)
1
(2.4)
0
(0.0)
0
(0.0)
0
(0.0)
3
(7.3)
P os a e
cance
0
(0.0)
1
(2.4)
1
(2.4)
0
(0.0)
1
(2.4)
3
(7.3)
a
AEs
occu ing
in
5%
o
pa ien s.
Table
3
–
T ea men - ela ed
ad e se
e en s
(TRAEs)
a
.
Pa ien s
epo ing
g ade
1
TRAEs,
n
(%)
Any
TRAE
ARADES
(n
=
11)
4
(36.4)
ARAFOR
(n
=
30)
6
(20.0)
To al
(n
=
41)
10
(24.4)
All
TRAEs
(n
=
41)
Fa igue
3
(7.3)
Ho
flush
2
(4.9)
Abdominal
pain
1
(2.4)
Cons ipa ion
1
(2.4)
Dec eased
appe i e
1
(2.4)
Dia hoea
1
(2.4)
Dizziness
1
(2.4)
Dysgeusia
1
(2.4)
Fla ulence
1
(2.4)
Gynaecomas ia
1
(2.4)
Headache
1
(2.4)
Nasopha yngi is
1
(2.4)
Nausea
1
(2.4)
Poo
pe iphe al
ci cula ion
1
(2.4)
Sola
de ma i is
1
(2.4)
Somnolence
1
(2.4)
Tinni us
1
(2.4)
U ina y
incon inence
1
(2.4)
a
All
TRAEs
we e
o
g ade
1.
E
U
R
O
P
E
A
N
U
R
O
L
O
G
Y
F
O
C
U
S
4
(
2
0
1
8
)
5
4
7
–
5
5
3
551

pa ien s
ea ed
wi h
ODM-201;
in
enzalu amide- ea ed
men,
a igue
occu ed
in
72%
(any
g ade)
o
pa ien s,
wi h
15%
expe iencing
g ade
3/4,
whe eas
nausea
(any
g ade)
was
epo ed
by
31%
o
pa ien s
[23].
The
incidence
o
a igue
du ing
ex ended
ODM-201
ea men
epo ed
he e
is
also
lowe
han
ha
seen
in
phase
3
ials
o
enzalu amide
(36%
all
g ades
and
2%
g ade
3)
[16]
and
abi a e one
ace a e
(39%
all
g ades
and
2%
g ade
3)
[17]
in
pa ien s
who
had
no
ecei ed
chemo he apy.
Impo an ly,
no
seizu es
we e
epo ed
a e
ex ended
ea men
wi h
ODM-201.
This
may
be
explained
by
he
lowe
likelihood
o
ODM-201
c ossing
he
blood-b ain
ba ie ,
as
shown
in
p eclinical
s udies,
and
may
be
ela ed
o
he
unique
chem-
ical
s uc u e
o
ODM-201;
addi ional
ials
a e
needed
o
con i m
hese
indings
[18,26].
P io
enzalu amide
ials
epo ed
ea men - ela ed
seizu es
[13,23,24],
and
p eclinical
s udies
sugges ed
ha
enzalu amide
may
c oss
he
blood-b ain
ba ie
and
bind
o
GABA
ecep o s
[13,24,27,28],
he eby
inc easing
he
isk
o
seizu es.
In
addi ion
o
a
a ou able
ole abili y
p o ile,
p olonged
ea men
wi h
ODM-201
p o ided
sus ained
an i umou
ac i i y:
a
dec ease
in
PSA
le els
om
baseline
was
main-
ained
o e
ime
in
mos
chemo he apy-naï e
and
CYP17i-
naï e
pa ien s
a
all
doses
es ed
(Fig.
2A,B),
simila
o
he
ARADES
and
ARAFOR
ials.
The
median
imes
o
PSA
p o-
g ession
(12.4
mo,
95%
CI
6.3–18.2)
and
adiological
p og ession
(15.3
mo,
95%
CI
9.5–NR)
we e
simila
o
da a
om
he
main
ARAFOR
ial
(12.4
mo,
95%
CI
5.3–NR;
and
15.2
mo,
95%
CI
9.4–18.2)
bu
we e
sho e
han
hose
epo ed
o
chemo he apy-naï e
and
CYP17i-naï e
pa ien s
om
he
ARADES
main
ial
(16.6
mo,
95%
CI
5.6–NR;
and
NR,
95%
CI
8.4–NR).
A
limi a ion
o
his
analysis
is
ha ,
being
a
non- andom-
ised
phase
1/2
ial,
he e
was
no
con ol
g oup
and
a
ela i ely
small
numbe
o
pa ien s
was
included
(n
=
41).
The e o e,
al hough
mul iple
doses
we e
es ed,
no
de ini-
i e
conclusion
may
be
d awn
ega ding
he
op imal
e i-
cacy
o
each
ODM-201
dose.
Ne e heless,
he
p omising
an i umou
ac i i y
and
a ou able
sa e y
p o ile
o
ODM-
201
p o ide
a
basis
o
u u e
con i ma o y
phase
3
ials
[29].
In
his
ega d,
he
e icacy
and
sa e y
o
ODM-201
a e
cu en ly
being
e alua ed
in
la ge
placebo-con olled
phase
3
ials
among
men
wi h
high- isk
nonme as a ic
CRPC
(ARAMIS,
NCT02200614)
and
men
wi h
me as a ic
cas a-
ion-sensi i e
p os a e
cance
(ARASENS,
NCT02799602).
Ano he
limi a ion
is
ha
QoL
measu emen s
we e
no
included
du ing
his
ollow-up
analysis.
As
a
spec um
o
neu ocogni i e
psychological
e ec s
ha e
been
associa ed
wi h
ADT
and
AR
inhibi o s,
u he
s udies
a e
wa an ed
o
assess
he
e ec
o
ex ended
ODM-201
ea men
on
pa ien - epo ed
QoL
[30].
5.
Conclusions
Ex ended
ea men
wi h
ODM-201
a
doses
o
1200–
1800
mg/d
con inued
o
show
encou aging
an i umou
ac i i y
in
pa ien s
wi h
mCRPC
who
had
no
ecei ed
p io
chemo he apy
and
CYP17i.
No
addi ional
o
unexpec ed
sa e y
signals
we e
obse ed
beyond
hose
epo ed
a
he
ini ial
analysis
poin s
o
he
ARADES
and
ARAFOR
ials.
ODM-201
may
ep esen
a
well- ole a ed
and
e ec i e
ea men
op ion
o
pa ien s
wi h
mCRPC.
Au ho
con ibu ions:
Neal
D.
Sho e
had
ull
access
o
all
he
da a
in
he
s udy
and
akes
esponsibili y
o
he
in eg i y
o
he
da a
and
he
accu acy
o
he
da a
analysis.
S udy
concep
and
design:
Sho e,
Aspeg en,
Mus onen,
Fizazi.
Acquisi ion
o
da a:
Sho e,
Tammela,
Massa d,
Bono,
Fizazi.
Analysis
and
in e p e a ion
o
da a:
Sho e,
Tammela,
Massa d,
Bono,
Aspeg en,
Mus onen,
Fizazi.
D a ing
o
he
manusc ip :
Sho e,
Fizazi,
Mus onen.
Fig.
2
–
(A)
P os a e-speci ic
an igen
(PSA)
pe cen age
change
om
baseline,
by
subjec ,
unca ed
a
+50%.
(B)
Maximum
PSA
pe cen age
change
om
baseline
du ing
s udy,
by
subjec .
(C)
Time
o
PSA
p og ession.
CI
=
con idence
in e al.
E
U
R
O
P
E
A
N
U
R
O
L
O
G
Y
F
O
C
U
S
4
(
2
0
1
8
)
5
4
7
–
5
5
3
552
C i ical
e ision
o
he
manusc ip
o
impo an
in ellec ual
con en :
Sho e,
Tammela,
Massa d,
Bono,
Aspeg en,
Mus onen,
Fizazi.
S a is ical
analysis:
Aspeg en.
Ob aining
unding:
Mus onen,
Aspeg en.
Adminis a i e,
echnical,
o
ma e ial
suppo :
None.
Supe ision:
Sho e,
Fizazi,
Mus onen.
O he :
None.
Financial
disclosu es:
Neal
D.
Sho e
ce ifies
ha
all
conflic s
o
in e es ,
including
specific
financial
in e es s
and
ela ionships
and
a filia ions
ele an
o
he
subjec
ma e
o
ma e ials
discussed
in
he
manusc ip
(eg,
employmen /a filia ion,
g an s
o
unding,
consul ancies,
hono a ia,
s ock
owne ship
o
op ions,
expe
es imony,
oyal ies,
o
pa en s
filed,
ecei ed,
o
pending),
a e
he
ollowing:
Neal
D.
Sho e
has
pa icipa ed
in
ad iso y
boa ds
o
Baye ,
O ion
Co po a ion,
O ion
Pha ma,
Abb ie,
Amgen,
As ellas,
Dend eon,
Fe ing,
Janssen,
Medi a ion,
Pfize ,
Roi an ,
Sanofi,
and
Tolma .
Teu o
L.
Tammela
has
ecei ed
g an s
om
O ion
Co po a ion,
O ion
Pha ma,
Baye ,
As ellas,
Fe ing,
and
Medi a ion.
Ch is ophe
Massa d
has
ecei ed
pe sonal
ees
and
nonfinancial
suppo
om
O ion
Co po a ion,
O ion
Pha ma,
and
pe sonal
ees
om
Sanofi,
Genen ech,
Ipsen,
As ellas,
and
Jansen.
Pe i
Bono
has
ecei ed
pe sonal
ees
om
O ion
Co po a ion,
O ion
Pha ma,
BMS,
No a is,
MSD,
and
Pfize .
John
Aspeg en
and
Mika
Mus onen
a e
employees
o
O ion
Co po a ion,
O ion
Pha ma.
Ka im
Fizazi
has
pa icipa ed
in
ad iso y
boa ds
o
O ion
Co po a ion,
O ion
Pha ma.
Funding/Suppo
and
ole
o
he
sponso :
The
ials
we e
suppo ed
by
O ion
Co po a ion,
O ion
Pha ma.
Medical
w i ing
assis ance
was
p o-
ided
by
D .
Laila
Cancian
o
Biosc ip
Medical
(Macclesfield,
UK)
and
unded
by
O ion
Co po a ion,
O ion
Pha ma
(Espoo,
Finland).
The
spon-
so
played
a
ole
in
da a
managemen
and
analysis
and
in
manusc ip
p epa a ion
and
e iew.
Acknowledgemen s:
The
au ho s
hank
all
he
pa ien s
and
hei
amilies,
o
pa icipa ing
in
he
ARADES
and
ARAFOR
ials,
as
well
as
he
in es iga o s
and
si e
pe sonnel.
Re e ences
[1]
Fe lay
J,
S elia o a-Fouche
E,
Lo e -Tieulen
J,
e
al.
Cance
inci-
dence
and
mo ali y
pa e ns
in
Eu ope:
es ima es
o
40
coun ies
in
2012.
Eu
J
Cance
49201313741403.
[2]
Ho wich
A,
Hugosson
J,
de
Reijke
T,
e
al.
P os a e
cance :
ESMO
Consensus
Con e ence
Guidelines
2012.
Ann
Oncol
2013;24:1141–62.
[3]
Wya
AW,
Glea e
ME.
Ta ge ing
he
adap i e
molecula
landscape
o
cas a ion- esis an
p os a e
cance .
EMBO
Mol
Med
2015;7:878–94.
[4]
Hu wi z
M,
Pe ylak
DP.
Sequencing
o
agen s
o
cas a ion-
esis an
p os a e
cance .
Oncology
2013;27:1144–9,
1154–8.
[5]
Tho eson
GR,
Gayed
BA,
Chung
PH,
Raj
GV.
Eme ging
he apies
in
cas a ion
esis an
p os a e
cance .
Can
J
U ol
2014;21:98–105.
[6]
Fi zpa ick
JM,
Bellmun
J,
Fizazi
K,
e
al.
Op imal
managemen
o
me as a ic
cas a ion- esis an
p os a e
cance :
highligh s
om
a
Eu opean
Expe
Consensus
Panel.
Eu
J
Cance
2014;50:1617–27.
[7]
Gillessen
S,
Omlin
A,
A a d
G,
e
al.
Managemen
o
pa ien s
wi h
ad anced
p os a e
cance :
ecommenda ions
o
he
S
Gallen
Ad anced
P os a e
Cance
Consensus
Con e ence
(APCCC)
2015.
Ann
Oncol
2015;26:1589–604.
[8]
Maughan
BL,
An ona akis
ES.
And ogen
pa hway
esis ance
in
p os a e
cance
and
he apeu ic
implica ions.
Expe
Opin
Pha -
maco he
2015;16:1521–37.
[9]
Rod iguez-Vida
A,
Galazi
M,
Rudman
S,
Chowdhu y
S,
S e nbe g
CN.
Enzalu amide
o
he
ea men
o
me as a ic
cas a ion- esis an
p os a e
cance .
D ug
Des
De
The
2015;9:3325–39.
[10]
Visako pi
T,
Hyy inen
E,
Koi is o
P,
e
al.
In
i o
amplifica ion
o
he
and ogen
ecep o
gene
and
p og ession
o
human
p os a e
cance .
Na
Gene
1995;9:401–6.
[11]
A agon-Ching
JB.
The
e olu ion
o
p os a e
cance
he apy:
a ge -
ing
he
and ogen
ecep o .
F on
Oncol
2014;4:295.
[12]
Massa d
C,
Fizazi
K.
Ta ge ing
con inued
and ogen
ecep o
signal-
ing
in
p os a e
cance .
Clin
Cance
Res
2011;17:3876–83.
[13]
Sche
HI,
Fizazi
K,
Saad
F,
e
al.
Inc eased
su i al
wi h
enzalu amide
in
p os a e
cance
a e
chemo he apy.
N
Engl
J
Med
2012;367:
1187–97.
[14]
de
Bono
JS,
Logo he is
CJ,
Molina
A,
e
al.
Abi a e one
and
inc eased
su i al
in
me as a ic
p os a e
cance .
N
Engl
J
Med
2011;364:
1995–2005.
[15]
Fizazi
K,
Sche
HI,
Molina
A,
e
al.
Abi a e one
ace a e
o
ea men
o
me as a ic
cas a ion- esis an
p os a e
cance :
final
o e all
su i al
analysis
o
he
COU-AA-301
andomised,
double-blind,
placebo-con olled
phase
3
s udy.
Lance
Oncol
2012;13:983–92.
[16]
Bee
TM,
A ms ong
AJ,
Ra hkop
DE,
e
al.
Enzalu amide
in
me a-
s a ic
p os a e
cance
be o e
chemo he apy.
N
Engl
J
Med
2014;371:
424–33.
[17]
Ryan
CJ,
Smi h
MR,
de
Bono
JS,
e
al.
Abi a e one
in
me as a ic
p os a e
cance
wi hou
p e ious
chemo he apy.
N
Engl
J
Med
2013;368:138–48.
[18]
Moilanen
AM,
Riikonen
R,
Oksala
R,
e
al.
Disco e y
o
ODM-201,
a
new-gene a ion
and ogen
ecep o
inhibi o
a ge ing
esis ance
mechanisms
o
and ogen
signaling-di ec ed
p os a e
cance
he a-
pies.
Sci
Rep
2015;5:12007.
[19]
Fizazi
K,
Massa d
C,
Bono
P,
e
al.
Ac i i y
and
sa e y
o
ODM-201
in
pa ien s
wi h
p og essi e
me as a ic
cas a ion- esis an
p os a e
cance
(ARADES):
an
open-label
phase
1
dose-escala ion
and
an-
domised
phase
2
dose
expansion
ial.
Lance
Oncol
2014;15:975–85.
[20]
Massa d
C,
Pen inen
HM,
Vja e s
E,
e
al.
Pha macokine ics,
an i umo
ac i i y,
and
sa e y
o
ODM-201
in
pa ien s
wi h
chemo-
he apy-naï e
me as a ic
cas a ion- esis an
p os a e
cance :
an
open-label
phase
1
s udy.
Eu
U ol
2015;69:834–40.
[21]
Sche
HI,
Halabi
S,
Tannock
I,
e
al.
Design
and
end
poin s
o
clinical
ials
o
pa ien s
wi h
p og essi e
p os a e
cance
and
cas a e
le els
o
es os e one:
ecommenda ions
o
he
P os a e
Cance
Clinical
T ials
Wo king
G oup.
J
Clin
Oncol
2008;26:1148–59.
[22]
Ga ell
BA,
Saad
F.
Abi a e one
in
he
managemen
o
cas a ion-
esis an
p os a e
cance
p io
o
chemo he apy.
The
Ad
U ol
2015;7:194–202.
[23]
Higano
CS,
Bee
TM,
Taplin
ME,
e
al.
Long- e m
sa e y
and
an i u-
mo
ac i i y
in
he
phase
1-2
s udy
o
enzalu amide
in
p e-
and
pos -doce axel
cas a ion- esis an
p os a e
cance .
Eu
U ol
2015;
68:795–801.
[24]
Sche
HI,
Bee
TM,
Higano
CS,
e
al.
An i umou
ac i i y
o
MDV3100
in
cas a ion- esis an
p os a e
cance :
a
phase
1–2
s udy.
Lance
2010;375:1437–46.
[25]
Ra hkop
DE,
Mo is
MJ,
Fox
JJ,
e
al.
Phase
I
s udy
o
ARN-509,
a
no el
an iand ogen,
in
he
ea men
o
cas a ion- esis an
p os-
a e
cance .
J
Clin
Oncol
2013;31:3525–30.
[26]
Fizazi
K.
Nonho mone
he apy
o
me as a ic
cas a ion- esis an
p os a e
cance :
chemo he apy,
bone- a ge ed
ea men s,
and
o he s.
Ame ican
Socie y
o
Clinical
Oncology
Educa ional
Book/
ASCO.
e161-5:
Ame ican
Socie y
o
Clinical
Oncology
Mee ing
2013;
2013.
[27]
Fos e
WR,
Ca
BD,
Shi
H,
e
al.
D ug
sa e y
is
a
ba ie
o
he
disco e y
and
de elopmen
o
new
and ogen
ecep o
an agonis s.
P os a e
2011;71:480–8.
[28]
Clegg
NJ,
Wong ipa
J,
Joseph
JD,
e
al.
ARN-509:
a
no el
an iand o-
gen
o
p os a e
cance
ea men .
Cance
Res
2012;72:1494–503.
[29]
Hackshaw
A.
Small
s udies:
s eng hs
and
limi a ions.
Eu
Respi
J
2008;32:1141–3.
[30]
Dono an
KA,
Walke
LM,
Wasse sug
RJ,
Thompson
LM,
Robinson
JW.
Psychological
e ec s
o
and ogen-dep i a ion
he apy
on
men
wi h
p os a e
cance
and
hei
pa ne s.
Cance
2015;121:4286–99.
E
U
R
O
P
E
A
N
U
R
O
L
O
G
Y
F
O
C
U
S
4
(
2
0
1
8
)
5
4
7
–
5
5
3
553