P os a e Cance
In e mi en Ve sus Con inuous And ogen Dep i a ion The apy in
Pa ien s wi h Relapsing o Locally Ad anced P os a e Cance :
A Phase 3b Randomised S udy (ICELAND)
Claude Schulman
a,
*, E ik Co nel
b
, Vse olod Ma ee
c
, Teu o L. Tammela
d
, Jan Sch aml
e
,
Hen i Bensadoun
, Wol gang Wa nack
g
, Raj Pe sad
h
, Ma ek Salagie ski
i
,
F ancisco Go
´mez Veiga
j
, Edwina Baskin-Bey
k
, Bea iz Lo
´pez
k
, Be and Tombal
l
a
Clinic E Ca ell and Uni e si y o B ussels, B ussels, Belgium;
b
Depa men o U ology, Ziekenhuis G oep Twen e, Hengelo, The Ne he lands;
c
Depa men o
Onco-U ology, Cance Resea ch Cen e, Moscow, Russia;
d
Depa men o U ology, Tampe e Uni e si y Hospi al and Medical School, Uni e si y o Tampe e,
Tampe e, Finland;
e
Clinic o U ology and Robo ic Su ge y, Masa yk’s Hospi al, Us i nad Labem, Czech Republic;
Depa men o U ology and T ansplan a ion,
Caen Uni e si y Hospi al, Caen, F ance;
g
Wa nack P i a e P ac ice, Hagenow, Ge many;
h
Depa men o U ology, Uni e si y Hospi als B is ol NHS
Founda ion T us , B is ol, UK;
i
Second U ology Depa men , Medical Uni e si y o Lodz, Lodz, Poland;
j
A Co un
˜a Uni e si y Hospi al, U ology, A Co un
˜a,
Spain, and U ology Depa men and Kidney T ansplan Uni , Salamanca Uni e si y Hospi al, Salamanca, Spain;
k
As ellas Pha ma Global De elopmen ,
Leiden, The Ne he lands;
l
Ins i u de Reche che Clinique, Uni e si e
´ca holique de Lou ain, B ussels, Belgium
EUROPEAN UROLOGY 69 (2016) 720–727
a ailable a www.sciencedi ec .com
jou nal homepage: www.eu opeanu ology.com
A icle in o
A icle his o y:
Accep ed Oc obe 3, 2015
Associa e Edi o :
James Ca o
Keywo ds:
And ogen dep i a ion
Con inuous and ogen
dep i a ion
In e mi en and ogen
dep i a ion
P os a e cance
Nonme as a ic
P os a e-speci ic an igen
p og ession
Tes os e one
Abs ac
Backg ound: In e mi en and ogen dep i a ion (IAD) has ecei ed inc easing a en ion; howe e , he
cu en li e a u e is s ill limi ed, especially in nonme as a ic p os a e cance (PCa), and he ela i e
e icacy and sa e y bene i s o IAD e sus con inuous and ogen dep i a ion (CAD) emain unclea .
Objec i e: To add o he knowledge base ega ding e ficacy and po en ial benefi s, including educed
side e ec s and imp o ed quali y o li e (QoL), o IAD e sus CAD in pa ien s wi h nonme as a ic
elapsing o locally ad anced PCa.
Design, se ing, and pa icipan s: A 42-mo phase 3b open-label andomised s udy in 933 pa ien s
om 20 Eu opean coun ies.
In e en ion: Following a 6-mo induc ion wi h leup o elin ace a e (Eliga d) 22.5 mg 3-mo depo ,
pa ien s we e andomised o CAD o IAD wi h leup o elin o 36 mo.
Ou come measu emen s and s a is ical analysis: The p ima y end poin was ime o p os a e-specific
an igen (PSA) p og ession while ecei ing lu einising ho mone- eleasing ho mone agonis , defined as
h ee consecu i e inc easing PSA alues 4 ng/ml 2 wk apa . Seconda y end poin s included PSA
p og ession- ee su i al (PFS), o e all su i al (OS), es os e one le els, pe o mance s a us, and QoL.
Resul s and limi a ions: A o al o 933 pa ien s en e ed he induc ion phase; 701 we e andomised.
The median numbe o injec ions adminis e ed a e andomisa ion was 12 ( ange: 112) o he
CAD g oup and 3 ( ange: 1–10) o he IAD g oup. The e we e no s a is ically significan o clinically
ele an di e ences be ween he g oups o ime o PSA p og ession, PSA PFS, OS, mean PSA le els
o e ime, o QoL. A simila numbe o ad e se e en s was obse ed in each g oup; he mos common
we e ho flushes and hype ension. S udy limi a ions include he open-label design and absence o
o mal es os e one eco e y assessmen .
Conclusions: IAD and CAD demons a ed simila e ficacy, ole abili y, and QoL in men wi h non-
me as a ic PCa. The p incipal benefi o IAD compa ed wi h CAD is a po en ial cos educ ion wi h
compa able OS a es. The e a e no appa en QoL benefi s.
Pa ien summa y: This andomised ial showed ha bo h in e mi en and con inuous ho mone
he apy had simila e ficacy, ole abili y, and quali y-o -li e p ofiles in pa ien s wi h elapsing M0 o
locally ad anced p os a e cance . In e mi en he apy may be a alid op ion o selec ed pa ien s.
T ial egis a ion: ClinicalT ials.go iden ifie NCT00378690.
#2015 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 . Clinic E Ca ell and Uni e si y o B ussels, B ussels, Belgium.
Tel. +32 475 42 36 96.
E-mail add ess: [email p o ec ed] (C. Schulman).
h p://dx.doi.o g/10.1016/j.eu u o.2015.10.007
0302-2838/#2015 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
I has long been ecognised ha con inuous and ogen
dep i a ion (CAD) he apy in pa ien s wi h p os a e cance
(PCa) can induce side e ec s such as dec eased libido,
impo ence, dec eased lean body mass, inc eased a mass,
inc eased insulin esis ance, and os eopo osis [1]. These
e ec scansigni ican lyal e quali yo li e(QoL),especiallyin
younge men. One al e na i e app oach o CAD, ecom-
mended by he Eu opean Associa ion o U ology (EAU) [2]
and heNa ionalIns i u eo Heal handCa eExcellence [3],is
in e mi en and ogen dep i a ion (IAD) he apy, du ing
which and ogen dep i a ion he apy (ADT) is discon inued
once p os a e-speci ic an igen (PSA) le els all below a
ce ain le el and is es a ed when PSA le els begin o ise
[4]. The 2015 EAU guidelines sugges ha IAD can be o e ed
o a ange o pa ien s wi h PCa a e a s anda dised induc ion
pe iod o ADT [2], p o iding hey a e willing and able o
comply wi h he s ic ollow-up (and clinical examina ions)
necessi a ed by his ea men app oach.
Al hough he concep o IAD is no new [5], he li e a u e
s ill la gely ails o answe he ques ion o he ela i e
bene i s o IAD e sus CAD, especially in nonme as a ic
pa ien s. Recen s udies conclude ha IAD is nonin e io o
CAD in e ms o o e all su i al (OS), al hough one s udy in
pa ien s wi h me as a ic disease showed small OS bene i s
wi h IAD [6] and was equi alen o CAD o cance con ol.
Findings a e less clea ega ding p e en ion o long- e m
e ec s o ADT and QoL ou comes [4,7–9]; howe e , p e ious
s udies we e he e ogeneous in design, s udy popula ions,
and ea men schedules.
As such, he ICELAND s udy, conduc ed in 20 Eu opean
coun ies, aimed o add o he knowledge base ega ding
he e icacy and sa e y p o ile o IAD compa ed wi h CAD,
ocusing on a nonme as a ic popula ion ea ed wi h he
lu einising ho mone- eleasing ho mone (LHRH) analogue
leup o elin ace a e 3-mo depo , which has no been widely
e alua ed in he con ex o IAD.
2. Pa ien s and me hods
2.1. Design and p ocedu es
This was a 42-mo phase 3b open-label andomised mul icen e s udy,
ec ui ing pa ien s om 102 cen es in 20 Eu opean coun ies
(Supplemen a y Table 1). Men wi h locally ad anced PCa (T3T4)
o ele a ed o ising PSA le els (5 mg/ml) a e adical p os a ec omy
(RP) o adio he apy we e sc eened. Inclusion c i e ia we e age 18
and <80 y , Gleason sco e 6, Eas e n Coope a i e Oncology G oup
(ECOG) pe o mance s a us sco e 0–2, and 5-y li e expec ancy.
Pa ien s we e excluded i hey had any o he malignancy o me as a ic
disease, we e ecei ing chemo he apy o o he ho monal he apy, had
es os e one le els 1.7nmol/lo 50ng/dl,o hadanycondi ion ha
would p eclude sa e s udy comple ion. Pa ien s unde wen a igo ous
assessmen a sc eening, including TNM classifica ion and a biopsy-
based Gleason assessmen . Radionuclide bone scan ( echne ium 99m-
me hylene diphosphona e bone scin ig aphy) o a compu ed omog-
aphy scan o he abdomen and pel is was also pe o med o exclude
he p esence o me as ases. Pa ien s p o ided w i en in o med
consen p io o s udy en y. The p o ocol was e iewed by he
independen e hics commi ee/ins i u ional e iew boa d a each
s udy cen e.
2.1.1. T ea men
The induc ion ea men phase an om sc eening ( isi 1) o
andomisa ion ( isi 4). Pa ien s we e ea ed wi h leup o elin ace a e
(Eliga d; As ellas Pha ma Inc[1_TD$DIFF]., No hb ook, IL, USA) 22.5 mg 3-mo depo
o 6 mo and ecei ed bicalu amide (Casodex; As aZenica, London, UK)
50 mg once daily o 1 mo om he fi s injec ion. PSA de e mina ions
we e made up o 2 wk be o e each isi so he esul was a ailable o he
in es iga o a he isi . Two successi e PSA le els 1 ng/ml (2wk
apa ) a e 6 mo we e equi ed o pa ien s o p oceed o andomisa ion.
The andomised phase an om isi 4 (mon h 6) o isi 16
(mon h 42). Pa ien s we e andomly assigned o ei he CAD o IAD wi h
leup o elin ace a e 22.5 mg 3-mo depo . Pa ien s andomised o IAD had
ADT discon inued immedia ely a e andomisa ion and en e ed he fi s
o - ea men phase. I he pa ien ’s se um PSA le el ose o 2.5 ng/ml,
independen o es os e one le el, ea men was es a ed e e y 3 mo
(plus bicalu amide 50 mg o 1 mo) un il PSA declined o 1 ng/ml (on
wo successi e occasions 2 wk apa ). Bo h CAD and IAD we e s opped
36 mo a e andomisa ion, and pa ien ollow-up was a 6-mo in e als
o 18 mo. S udy isi iming is ou lined in Supplemen a y Figu e 1. The
fi s pa ien ’s fi s isi was in Ma ch 2006; he final pa ien ’s las isi
was in Ap il 2013.
2.1.2. P ima y end poin
The p ima y end poin was ime o PSA p og ession, defined as h ee
consecu i e inc easing PSA alues 4 ng/ml a leas 2 wk apa while
ecei ing leup o elin.
2.1.3. Seconda y end poin s
Seconda y e ficacy end poin s included PSA p og ession- ee su i al
(PFS), defined as ime om andomisa ion o ei he PSA p og ession o
dea h; OS, defined as ime om andomisa ion o ei he he las a ailable
assessmen o dea h, occu ing no la e han 60 mo a e andomisa ion;
ime o se um es os e one >50 ng/dl o 1.7 nmol/l (CAD g oup only);
Wo ld Heal h O ganiza ion (WHO)/ECOG pe o mance s a us (5-poin
scale); and heal h- ela ed QoL, measu ed by EORTC QLQ-C30 and
PCa-specific module QLQ-PR25.
Tes os e one le els and es os e one b eak h ough (defined as
ime o se um es os e one >50 ng/dl o 1.7 nmol/l [con en ional] o
>20 ng/dl o 0.7 nmol/l [conse a i e]) we e assessed a each isi .
EORTC QLQ-C30 and QLQ-PR25 ques ionnai es [10,11] we e comple ed
a isi s 2–16 and a ea ly wi hd awal.
2.1.4. Sa e y
Repo ed ad e se e en s (AEs) we e g aded acco ding o he Na ional
Cance Ins i u e Common Te minology C i e ia o Ad e se E en s, .3.0.
2.1.5. Powe calcula ions and s a is ical analyses
Wi h 350 andomised pa ien s pe a m, i was calcula ed ha he s udy
would p o ide 90% powe o demons a e supe io i y on he p ima y
end poin a he final analysis (3 y a e andomisa ion) i he p opo ion
o pa ien s wi h PSA p og ession a 3 y was 38.9% in he CAD a m, based
on p e ious es ima es [12], and <27.3% o >51.2% in he IAD a m.
E ficacy, sa e y, and ole abili y da a we e analysed o all pa ien s
who we e andomised a isi 4 and ea ed. Time- o-e en da a we e
analysed using he Kaplan-Meie me hod.
3. Resul s
O 1131 sc eened pa ien s, 933 en e ed he induc ion phase
(Fig. 1). The e we e no ele an di e ences be ween
EUROPEAN UROLOGY 69 (2016) 720–727
721
ea men g oups o baseline disease cha ac e is ics o
como bidi ies (Table 1).
Du ing induc ion, median es os e one le els o all
pa ien s dec eased om 397ng/dl (13.8 nmol/l) o11.0 ng/dl
(0.4 nmol/l) a mon h 3, wi h a u he small decline a
mon h 6. Median PSA le els dec eased om 8.6 ng/ml o
0.20 ng/ml a mon h 3 and emained a his le el a mon h 6.
O e all, 701 pa ien s we e andomised (Fig. 1), o whom
58% had locally ad anced disease, 26.7% had elapsing PCa
ollowing RP, and 15.3% had elapsing PCa ollowing o he
he apies. A o al o 131 pa ien s (19.1%) wi hd ew a e
andomisa ion: 70 in he CAD g oup and 61 in he IAD
g oup. Supplemen a y Table 2 de ails he p ima y easons
o s udy wi hd awal.
[(Fig._1)TD$FIG]
Sc eened
n = 1131
Randomised, n = 701
CADb
Sa e y, n = 361
E icacy, n = 361
IADb
Sa e y, n = 340
E icacy, n = 340
CAD
Sa e y, n = 353
E icacy, n = 352
IAD
Sa e y, n = 337
E icacy, n = 334
Wi hd awals be o e
ollow-up (CAD)
Sa e y, n = 43
E icacy, n = 43
En e ing he ollow-up (CAD)
Sa e y, n = 310
E icacy, n = 309
En e ing he ollow-up (IAD)
Sa e y, n = 292
E icacy, n = 290
Comple ing he ollow-up (CAD)
Sa e y, n = 59
E icacy, n = 59
Comple ing he ollow-up (IAD)
Sa e y, n = 42
E icacy, n = 42
En e ed induc ion phase, n = 933
Analysed o sa e y, n = 932
Analysed o e icacy, n = 932
No eligible
n = 198
Discon inued/no andomised, n = 232a
No ul illing inclusion o exclusion
c i e ia, n = 176 (75.9%)
Ad e se e en , n = 5 (2.2%)
Dea h, n = 6 (2.6%)
Wi hd awal o consen , n = 13 (5.6%)
Subjec los o ollow-up, n = 3 (1.3%)
P o ocol iola ion, n = 5 (2.2%)
Wo sening o disease, n = 2 (0.9%)
O he , n = 22 (9.5%)
Wi hd awals be o e
ollow-up (IAD)
Sa e y, n = 45
E icacy, n = 44
Fig. 1 – Disposi ion o pa ien s.
a
The e is a disc epancy in he non andomised g oup due o a pa ien who was no documen ed as a sc eening ailu e, al hough he should ha e
been, based on he ac ha one o he inclusion c i e ia was no me (locally ad anced bu TNM classi ica ion was missing); no leup olide ace a e
was adminis e ed.
b
Popula ion addi ionally included pa ien s who we e no andomised.
CAD = con inuous and ogen dep i a ion; IAD = in e mi en and ogen dep i a ion.
EUROPEAN UROLOGY 69 (2016) 720–727
722
3.1. Desc ip ion o in e mi en and ogen dep i a ion cycles
The median numbe o IAD injec ions adminis e ed du ing
he andomised phase was 3 ( ange: 1–10) compa ed wi h
12 ( ange: 1–12) o he CAD g oup, wi h a mean du a ion o
327 d and 89 d be ween injec ions o he IAD and CAD
g oups, espec i ely. O pa ien s ecei ing IAD, 36%, 22%,
and 16% did no need o eini ia e ADT a mon hs 12, 24, and
36, espec i ely. In he IAD g oup, 184 pa ien s ecei ed
13 injec ions, 76 ecei ed 46 injec ions, 8 ecei ed
79 injec ions, and 5 ecei ed 1012 injec ions.
The mean es os e one le el a andomisa ion was
11.4 ng/dl (0.4 nmol/l) o he IAD g oup. Mean es os e one
le els subsequen ly inc eased ( ange: 61.0268.0 ng/dl
[2.19.3 nmol/l]), and a 36 mo ( isi 16) mean es os e one
was 174.3 ng/dl (6 nmol/l).
3.2. P ima y end poin
Time o PSA p og ession did no s a is ically di e be ween
ea men g oups (p= 0.718), wi h a simila numbe o
e en s eco ded in each g oup (34 o CAD and 30 o IAD)
(Fig. 2) a 36 mo. Median ime o PSA p og ession was no
eached. Es ima ed 3-y PSA p og ession a e pe cen age
was 10.6 (95% con idence in e al [CI], 7.714.6) and 10.1
(95% CI, 7.114.2) o CAD and IAD, espec i ely. Simila
esul s we e obse ed when he analysis was s a i ied by
p ima y diagnosis.
3.3. Seconda y end poin s
PSA PFS did no di e signi ican ly (p= 0.865) be ween he
CAD and IAD g oups (43 s 41 e en s) (Supplemen a y Fig.
2); es ima ed 3-y PSA PFS pe cen age was 13.2 (95% CI,
10.017.5) and 13.1 (95% CI, 9.717.5) o CAD and IAD,
espec i ely. The e was a s eep dec ease in mean PSA le els
by he end o he induc ion phase in bo h g oups ha was
main ained h ough o isi 16 (Fig. 3).
O e all, 86 men died wi hin 5 y o s udy en y (44 in he
CAD g oup and 42 in he IAD g oup) wi h no di e ence in OS
be ween g oups (p= 0.969) (Fig. 4). The es ima ed 5-y OS
pe cen age was 85.0 (95% CI, 80.088.8) and 81.8 (95% CI,
74.787.2) o CAD and IAD, espec i ely; his di e ence
was no s a is ically signi ican .
Mos CAD pa ien s main ained cas a e le els o
es os e one h oughou ea men ( alues emained
be ween 9.0 and 12.9 ng/dl [0.3 and 0.5 nmol/l]), wi h
b eak h ough e en s occu ing in 22 pa ien s (6.3%). Time
o con en ional es os e one b eak h ough du ing CAD is
shown in Supplemen a y Figu e 3.
3.4. Wo ld Heal h O ganiza ion/Eas e n Coope a i e Oncology
G oup pe o mance s a us
The pa ien s’ WHO/ECOG s a us ended o de e io a e
owa d he end o he ea men pe iod, wi h no no able
di e ences be ween ea men g oups.
Table 1 – Baseline disease cha ac e is ics and como bidi y p o ile
CAD
(n= 361)
IAD
(n= 340)
No andomised
(n= 231)
To al
(n= 932)
p alue
Indica ions o ADT, n(%) 0.534
a
Locally ad anced PCa 211 (59.9) 187 (56.0) NA NA
Relapsing PCa ollowing RP 88 (25.0) 95 (28.4) NA NA
Relapsing PCa ollowing o he he apies 53 (15.1) 52 (15.6) NA NA
Time since diagnosis, d, median ( ange) 74 (0–4401) 88 (0–4185) 43 (0–5470) 66 (0–5470) 0.544
b
P io he apy, n(%)
Any su ge y 120 (33.2) 115 (33.8) 35 (15.2) 270 (29.0) 0.870
a
Any adia ion 60 (16.6) 66 (19.4) 30 (13.0) 156 (16.7) 0.336
a
Any chemo he apy 0 3 (0.9) 1 (0.4) 4 (0.4) 0.114
c
Any o he he apy 56 (15.5) 55 (16.2) 24 (10.4) 135 (14.5) 0.810
a
Gleason sco e, n(%) 0.752
a
6 142 (39.7) 127 (37.7) 72 (31.2) 341 (36.8)
7 134 (37.4) 125 (37.1) 85 (36.8) 344 (37.1)
8 82 (22.9) 85 (25.2) 74 (32.0) 241 (26.0)
Missing
d
330 6
T, n(%) 0.082
c
T0–2 64 (9.1) 78 (11.7) 25 (5.5) 167 (9.2)
T3–4 284 (40.6) 254 (38.3) 204 (44.5) 742 (40.7)
TX 4 (0.6) 0 0 4 (0.2)
Missing
d
982 19
Como bidi ies o in e es , n(%)
Hype ension 194 (53.7) 173 (50.9) 118 (51.1) 485 (52.0) 0.449
a
Hype choles e olaemia 47 (13.0) 61 (17.9) 17 (7.4) 125 (13.4) 0.071
a
Diabe es melli us 33 (9.1) 39 (11.5) 17 (7.4) 89 (9.5) 0.310
a
Myoca dial ischaemia 35 (9.7) 45 (13.2) 36 (15.6) 116 (12.4) 0.141
a
ADT = and ogen dep i a ion he apy; CAD = con inuous and ogen dep i a ion; IAD = in e mi en and ogen dep i a ion; NA = no applicable; PCa = p os a e
cance ; RP = adical p os a ec omy.
a
Chi-squa e es .
b
Log ank es .
c
Fishe exac es .
d
Missing pa ien s no included in pe cen age calcula ions.
EUROPEAN UROLOGY 69 (2016) 720–727
723
3.5. Quali y o li e
QoL using EORTC QLQ-C30 was compa able o he IAD
and CAD g oups (Supplemen a y Table 3). Fo he
unc ional scales, he mean sco es we e all >80 wi h no
no able changes du ing he andomised phase. Mean
global heal h s a us sco es dec eased sligh ly du ing
he andomised phase, wi h no no able di e ences
be ween g oups. Nausea, omi ing, and appe i e loss
we e he mos dis essing symp oms epo ed. Addi ional
QoL da a a e epo ed in Supplemen 1 and Supplemen a y
Table 4.
[(Fig._3)TD$FIG]
1
0
5
10
15
20
25
A
B
2 3 45 678910
Visi
11 12 13 1514 16
Mean PSA le el, ng/ml
CAD
IAD
Mean se um es os e one
le el, ng/dl
Visi
16151413121110987654321
0
100
200
300
400
500
600
700 IAD
CAD
Fig. 3 – (A) Mean p os a e-speci ic an igen le els a each isi ; (B) mean (s anda d de ia ion) es os e one le els a each isi .
CAD = con inuous and ogen dep i a ion; IAD = in e mi en and ogen dep i a ion; PSA = p os a e-speci ic an igen.
[(Fig._2)TD$FIG]
0
0.5
0.6
0.7
0.8
0.9
1.0
6121824
Time, mo
30 36 42
P opo ion o pa ien s wi h
no PSA p og ession
CAD
IAD
Numbe o subjec s a isk
CAD
IAD
352
334
338
325
322
308
304
293
291
280
275
269
63
85
0
0
Fig. 2 – Kaplan-Meie plo o ime o p os a e-speci ic an igen p og ession.
CAD = con inuous and ogen dep i a ion; IAD = in e mi en and ogen dep i a ion; PSA = p os a e-speci ic an igen.
EUROPEAN UROLOGY 69 (2016) 720–727
724

3.6. Toxici y and ad e se e en s
Du ing he andomised phase, 510 pa ien s (73.9%) had one
AE o mo e, wi h no clinically ele an di e ence be ween
g oups (Table 2). O e all, 178 pa ien s (25.8%) had one o
mo e se ious AEs. The mos common AEs we e ho lushes,
hype ension, and cons ipa ion (Table 2); mos we e g ade 1
(mild) o g ade 2 (mode a e). Supplemen a y Table 5 shows
he AEs occu ing in 2% o pa ien s du ing he andomised
phase. Fo y- wo pa ien s (6.1%) discon inued andomised
[(Fig._4)TD$FIG]
0
0.0
0.2
0.3
0.4
0.5
0.6
0.7
0.9
0.8
1.0
6121824
Time, mo
30 36 42 48 54 60
P opo ion su i ing
CAD
IAD
Numbe o subjec s a isk
CAD
IAD
352
334
347
331
338
322
330
313
323
301
302
286
312
295
288
273
270
257
174
174
0
0
0.1
Fig. 4 – Kaplan-Meie plo s o ime o o e all su i al.
CAD = con inuous and ogen dep i a ion; IAD = in e mi en and ogen dep i a ion.
Table 2 – Summa y o ad e se e en s and ea men - ela ed ad e se e en s ( andomised phase)
a
CAD
(n= 352)
IAD
(n= 334)
To al
(n= 686)
p alue
Pa ien s wi h any TEAE, n(%) 256 (72.5) 254 (75.4) 510 (73.9) 0.394
b
Pa ien s wi h TEAE by se e i y, n(%) 0.966
b
G ade 1: mild 47 (13.3) 53 (15.7) 100 (14.5)
G ade 2: mode a e 109 (30.9) 107 (31.8) 216 (31.3)
G ade 3: se e e 73 (20.7) 63 (18.7) 136 (19.7)
G ade 4: li e h ea ening/disabling 17 (4.8) 16 (4.7) 33 (4.8)
G ade 5: dea h 9 (2.5) 14 (4.2)
c
23 (3.3)
Missing 1 (0.3) 1 (0.3) 2 (0.3)
Pa ien s wi h ea men - ela ed TEAEs
d
,n(%) 145 (41.1) 124 (36.8) 269 (39.0) 0.394
b
Pa ien s wi h se ious TEAEs, n(%) 88 (24.9) 90 (26.7) 178 (25.8) 0.594
b
Pa ien s wi h ea men - ela ed se ious TEAEs
d
,n(%) 4 (1.1) 4 (1.2) 8 (1.2) 1.000
e
Dea hs
,n(%) 9 (2.5) 15 (4.5) 24 (3.5) 0.173
b
Discon inued due o TEAE
g
,n(%) 17 (4.8) 25 (7.4) 42 (6.1) 0.153
b
Discon inued due o ea men - ela ed TEAE
d,g
,n(%) 4 (1.1) 0 4 (0.6) 0.124
e
AEs o in e es , n(%)
Ho flushes 68 (19.3) 72 (21.4) 140 (20.3) 0.493
b
Hype ension 45 (12.7) 37 (11.0) 82 (11.9) 0.473
b
Cons ipa ion 21 (5.9) 23 (6.8) 44 (6.4) 0.638
b
Back pain 18 (5.1) 19 (5.6) 37 (5.4) 0.753
b
Fa igue 17 (4.8) 15 (4.5) 32 (4.6) 0.820
b
AE = ad e se e en ; CAD = con inuous and ogen dep i a ion; IAD = in e mi en and ogen dep i a ion; TEAE = ea men -eme gen ad e se e en .
a
S udy popula ion includes pa ien s who we e andomised and o whom pos andomisa ion sa e y da a we e a ailable.
b
Chi-squa e es .
c
One pa ien died, bu he cause o dea h was no eco ded as a g ade 5 AE.
d
AEs ha a e possibly o p obably ea men ela ed o o which he ela ionship is missing.
e
Fishe exac es .
Only AEs wi h ou come ‘‘ a al’’ a e coun ed.
g
Only AEs ha we e he p ima y eason o discon inua ion a e aken in o accoun .
EUROPEAN UROLOGY 69 (2016) 720–727
725
ea men due o AEs. Analysis o AEs in pa ien s wi h locally
ad anced e sus elapsing PCa a baseline e ealed no
di e ences be ween CAD and IAD ega ding numbe o AEs,
se ious AEs, o AEs leading o d ug discon inua ion. Twen y-
ou pa ien s (3.5%) died du ing andomised ea men ; no
dea hs we e deemed ela ed o ea men .
4. Discussion
In his la ge mul icen e andomised s udy o IAD and CAD in
pa ien s wi h elapsing M0 a e RP o adio he apy o locally
ad anced PCa, he e we e no s a is ically signi ican o
clinically ele an di e ences be ween g oups o any ime-
o-e en end poin s ( ime o PSA p og ession, PSA PFS, o OS)
o mean PSA le els o e ime. Resul s we e seen in he
con ex o conside ably ewe injec ions in he IAD han CAD
g oup (median: 3 o IAD and 12 o CAD). Howe e , he e
we e no appa en di e ences in pe o mance s a us, QoL, o
ea men ole abili y be ween g oups; bo h ea men
s a egies we e simila ly well ole a ed, and mos d ug-
ela ed (and non–d ug- ela ed) AEs we e mild o mode a e.
A numbe o p e iously published s udies ha e com-
pa ed CAD and IAD, many in samples o <500 pa ien s
[4,6–9,12–20], bu only one phase 3 s udy has been
conduc ed in a pu ely nonme as a ic popula ion [13]. C ook
e al compa ed IAD wi h CAD in a la ge pa ien g oup ha
p e iously ecei ed p ima y o sal age adio he apy o
localised PCa [13]. IAD was ound o be nonin e io o CAD
wi h espec o OS (median: 8.8 s 9.1 y ). All o he s udies
compa ing IAD wi h CAD included ei he a mix o pa ien s
wi h me as a ic and nonme as a ic disease, o only pa ien s
wi h me as a ic disease. Some o hese ha e shown be e
QoL o imp o emen in indi idual side e ec s among hose
ea ed wi h IAD compa ed wi h CAD [14,17]. A ecen
open-label s udy assessing IAD wi h a LHRH an agonis in
213 pa ien s o a ying disease s age obse ed imp o ed
sexual unc ioning and ewe AEs du ing he o - ea men
pe iod [21].
Bene i s o IAD on sexual unc ioning and AEs we e also
con i med in a ecen me a-analysis o 13 ials composed o
6419 pa ien s wi h ho mone-sensi i e PCa [8]. Al hough
hese indings a e gene ally posi i e, i has been sugges ed
ha such bene i s a e a bes modes and may depend on o -
ea men pe iod leng h and ime o eco e y o es os e one
le els [7]. Taken oge he , hese s udies ail o p o ide
consis en suppo o he heo e ical IAD bene i s, al hough
heysugges he e is no disad an age o his app oach ei he .
In ou s udy, PSA p og ession in he CAD a m was
ma kedlylowe han epo edin hes udybydeLe ale alon
which ou powe assump ions we e based, al hough he
small sample size and di e en popula ion in ha s udy
(n= 33 in he CAD g oup) could a leas pa ly explain he
di e ence [12].
IAD equi es ewe d ug doses, po en ially leading o cos
sa ings [4,22]. Al hough d ug adminis a ion cos s a e likely
o be lowe o IAD, i should be no ed ha his app oach
equi es s ic ollow-up moni o ing, esul ing in cos s no
associa ed wi h CAD ha would need o be balanced agains
any absolu e cos educ ions om dec eased d ug use.
S eng hs o his s udy a e i s la ge sample size, mul iple
objec i e ou come measu es, and he exclusi ely nonme a-
s a ic disease popula ion. Ou s udy, which adds o he
small numbe o well-powe ed compa a i e s udies in his
pa ien popula ion, is he i s indus y-sponso ed s udy o
i s kind. We ecognise ha he ea men app oach o he
pa ien s in he ICELAND s udy may ha e been di e en i
conduc ed oday; howe e , a he ime o s udy ini ia ion
(2006), he op ions p esen ed o pa ien s we e in line wi h
ypical p ac ice and accep ed guidelines. The p ima y s udy
limi a ions a e he open-label design and absence o o mal
assessmen o es os e one eco e y. We also acknowledge
ha PSA p og ession, as used in ou s udy, is no a
ecognised su oga e end poin o e icacy. I is, howe e ,
a modes end poin o objec i e esponse and is s ongly
associa ed wi h OS [23]. Fu he mo e, he o he ou comes
used in he ICELAND s udy, namely PFS and OS, a e o majo
clinical in e es . Taken oge he , hese end poin s p o ide
app op ia e da a o con ibu e meaning ully o he knowl-
edge base on IAD e sus CAD.
5. Conclusions
In his open-label ial, IAD and CAD adminis e ed a e a
6-mo induc ion wi h leup o elin ace a e 22.5 mg 3-mo
depo demons a ed compa able e icacy, ole abili y, and
QoL in pa ien s wi h nonme as a ic locally ad anced o
elapsing PCa. The p incipal po en ial bene i s o IAD
compa ed wi h CAD include educed d ug acquisi ion cos s
wi h compa able OS a es. The e we e no appa en
di e ences in QoL bene i s be ween he ea men g oups.
Au ho con ibu ions: Claude Schulman 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: Tombal, Schulman, Co nel, Baskin-Bey.
Acquisi ion o da a: Schulman, Co nel, Ma ee , Tammela, Sch aml,
Bensadoun, Wa nack, Pe sad, Salagie ski, Go
´mez Veiga, Baskin-Bey,
Lo
´pez, Tombal.
Analysis and in e p e a ion o da a: Lo
´pez, Schulman, Co nel, Ma ee ,
Tammela, Sch aml, Bensadoun, Wa nack, Pe sad, Salagie ski, Go
´mez
Veiga, Baskin-Bey, Tombal.
D a ing o he manusc ip : Schulman, Co nel, Ma ee , Tammela, Sch aml,
Bensadoun,Wa nack,Pe sad,Salagie ski,Go
´mezVeiga,Baskin-Bey, Lo
´pez,
Tombal.
C i ical e ision o he manusc ip o impo an in ellec ual con en :
Schulman, Co nel, Ma ee , Tammela, Sch aml, Bensadoun, Wa nack,
Pe sad, Salagie ski, Go
´mez Veiga, Baskin-Bey, Lo
´pez, Tombal.
S a is ical analysis: Lo
´pez.
Ob aining unding: Baskin-Bey.
Adminis a i e, echnical, o ma e ial suppo : None.
Supe ision: Schulman, Co nel, Ma ee , Tammela, Sch aml, Bensadoun,
Wa nack, Pe sad, Salagie ski, Go
´mez Veiga, Lo
´pez, Tombal, Baskin-Bey.
O he (speci y): None.
Financial disclosu es: Claude Schulman 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: Claude Schulman
EUROPEAN UROLOGY 69 (2016) 720–727
726
had a consul ing ela ionship wi h As ellas be ween 2005 and 2008,
al hough i does no cons i u e a cu en conflic o in e es acco ding o
he In e na ional Commi ee o Medical Jou nal Edi o s guidelines. Teu o
L. Tammela is a s udy in es iga o o As ellas. Edwina Baskin-Bey was an
employee o As ellas a he ime o manusc ip ini ia ion. Bea iz Lo
´pez is
an employee o As ellas. Be and Tombal is a paid ad ise and s udy
in es iga o o As ellas. E ik Co nel, Vse olod Ma ee , Jan Sch aml,
Hen i Bensadoun, Wol gang Wa nack, Raj Pe sad, Ma ek Salagie ski, and
F ancisco Go
´mez Veiga ha e no hing o disclose.
Funding/Suppo and ole o he sponso : The s udy was unded by
As ellas Pha ma, Inc., which helped design and conduc he s udy;
collec , manage, analyze, and in e p e he da a; and p epa e, e iew,
and app o e he manusc ip . The au ho s had ull access o he da a and
pa icipa ed in e iewing and in e p e ing he da a and manusc ip .
Acknowledgemen s: The au ho s acknowledge Da id McMinn a
Comple e Heal hVizion o assis ance wi h w i ing and e ising he
d a manusc ip , based on de ailed discussion and eedback om all
au ho s. The au ho s also hank Lau en Smi h a Comple e Heal hVizion
o copyedi ing he final manusc ip . W i ing and copyedi ing assis ance
was unded by As ellas Pha ma, Inc. P ima y esponsibili y o opinions,
conclusions, and in e p e a ion o da a lies wi h he au ho s. All au ho s
ead and app o ed he final e sion o his manusc ip .
Appendix A. Supplemen a y da a
Supplemen a y da a associa ed wi h his a icle can be
ound, in he online e sion, a h p://dx.doi.o g/10.1016/j.
eu u o.2015.10.007.
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