NEW ENGLAND

The
JOURNAL of MEDICINE
ESTABLISHED IN 1812 AUGUST 20, 2009 VOL. 361 NO. 8

Denosumab in Men Receiving Androgen-Deprivation

Therapy for Prostate Cancer
Matthew R. Smith, M.D., Ph.D., Blair Egerdie, M.D., Narciso Hernndez Toriz, M.D., Robert Feldman,
M.D., Teuvo L.J. Tammela, M.D., Fred Saad, M.D., Jiri Heracek, M.D., Ph.D., Maciej Szwedowski, M.D.,
Chunlei Ke, Ph.D., Amy Kupic, M.A., Benjamin Z. Leder, M.D., and Carsten Goessl, M.D.,
for the Denosumab HALT Prostate Cancer Study Group*

ABSTR ACT
CONCLUSIONS
BACKGROUND From the
Androgen-deprivation therapy is well-established for Massachusetts
General Hospi tal
treating prostate cancer but is associated with bone loss Cancer Center
and an increased risk of fracture. We investigated the (M.R.S.) and the
effects of denosumab, a fully human monoclonal antibody Endo crine Unit
(B.Z.L.), Boston;
against receptor activa-tor of nuclear factor-B ligand, on Urology As sociates
bone mineral density and fractures in men re-ceiving Urologic Medical
androgen-deprivation therapy for nonmetastatic prostate Research, Kitchener,
ON, Canada (B.E.);
cancer. Centro Medico
Nacional Siglo XXI,
METHODS Mexico City (N.H.T.);
Connecticut Clinical
In this double-blind, multicenter study, we randomly assigned
Research Center
patients to receive de-nosumab at a dose of 60 mg Urology Specialists,
subcutaneously every 6 months or placebo (734 patients in Middlebury (R.F.);
Tampere University
each group). The primary end point was percent change in Hospital, Tam pere,
bone mineral density at the lumbar spine at 24 months. Key Finland (T.L.J.T.);
secondary end points included percent change in bone Centre Hospita lier
de lUniversit de
mineral densities at the femoral neck and total hip at 24 Montral, Montreal
months and at all three sites at 36 months, as well as (F.S.); Androgeos,
incidence of new vertebral fractures. Prague, Czech
Repub lic (J.H.);
Wojewdzkie
RESULTS Centrum Medy czne,
At 24 months, bone mineral density of the lumbar spine Opole, Poland
(M.S.); and Amgen,
had increased by 5.6% in the denosumab group as Thousand Oaks, CA
compared with a loss of 1.0% in the placebo group (C.K., A.K., C.G.).
(P<0.001); significant differences between the two groups Address reprint
requests to Dr. Smith
were seen at as early as 1 month and sustained through 36 at the Massachusetts
months. Denosumab therapy was also associated with sig- General Hospital
nificant increases in bone mineral density at the total hip, Can cer Center,
Yawkey 7038, 55
femoral neck, and distal third of the radius at all time Fruit St., Bos ton, MA
points. Patients who received denosumab had a de-creased 02114, or at
incidence of new vertebral fractures at 36 months (1.5%, smith.matthew@
mgh.harvard.edu.
vs. 3.9% with placebo) (relative risk, 0.38; 95%
confidence interval, 0.19 to 0.78; P=0.006). Rates of
adverse events were similar between the two groups. *Members of the
Denosumab
Hormone
 Ablation Bone Loss Trial (HALT) Pros tate Cancer Study Group areThis article (10.1056/NEJMoa0809003) was Copyright 2009
listed in the Appendix. published on August 11, 2009, at NEJM.org. Massachusetts Medical
Society.

N Engl J Med 2009;361:745-55.

Den n s CT0
osu - t 008
mab d a 967
was e t 4.)
asso p e
ciate r
d i c N ENGL J MED 361;8 N

with v a T
incr a n h
t c e
ease
d i e N
bon o r e
e n . w

min E
eral t ( n
dens h C g
ity e l l
r i a
at n
all a n d
sites p i
and y c J
a o
a u
redu f l r
ctio o T n
n in r r a
i l
the o
inci n a f
denc o l
e of n s M
m . e
new d
vert e g i
ebra t o c
l a v i
s n
fract e
ures t n Downloadedfrom
amo a u nejm.orgonDecember
ng t m 17,2013.Forpersonal
i b useonly.Nootheruses
men
withoutpermission.
rece c e
Copyright
ivin r 2009
g p , Massachusetts
andr r Medical
Society.All
oge o N
rightsreserved.
T h e NE W ENGL A ND JOUR NA L o f MEDICINE
prostate cancer lack-
treated with
P THE MOSTand
radical
CANCER ISprostatectomy
ROSTATE
pelvic
ing.10,14-18

is
Denosumab

human
a fully
lymphadenecto monoclonal
COMMON my.8
newly anti-body that
diagnosed Androgen-
cancer in specifically
men deprivation
worldwide. binds to the
In thethera-py is also
1
United receptor acti-
States, commonly vator of
prostate used in
cancer ac- nuclear factor-
counts forpatients with B ligand, a
approximately an increasing key mediator
25% of all newprostate- of osteoclast
cancer specific
formation,
diagnoses andantigen (PSA) function, and
10% of alllevel after
19
deaths from primary survival.
2 therapy. Denosumab
cancer. Androgen-
Androgen- use was
deprivation associated
deprivation
therapy, therapy with increased
through increases bone bone mineral
bilateral resorption, density at
orchiectomy orreduces bone multiple
treatment withmineral density, skeletal sites in
gonadotropin- and in-creases women
releasing the risk of receiving
hormone fracture in men aromatase-
(GnRH) with prostate inhibitor
agonists, is the 9-13 therapy for
stan-dard first-cancer. The
breast
line therapy forrisk of fracture 20
metastatic increases with cancer.
prostate in-creasing Similarly, in
3,4 postmenopaus
cancer. duration of
GnRH agonistsandrogen- al women with
are alsodeprivation low bone
frequently usedthera-py and is mass,
to treat menan important denosumab
with contributor to therapy was
nonmetastatic associated
the mor-bidity
prostate with increased
5 associated with
cancer. bone mineral
this
Androgen- 11,12 den-sity at all
deprivation therapy. measured
therapy Although skeletal sites
improves several drugs, and with de-
disease-free including creased levels
and overallbisphosphonate of markers of
survival ins and se-lective bone
various clinicalestrogen- 21,22
settings, such turnover.
as when usedreceptor In this
as adjuvantmodulators, randomized,
treat-ment inhave been phase 3 trial,
men with shown to we evaluated
locally prevent bone the effects of
advanced loss associated denosumab on
prostate can-with andro-gen- bone mineral
cer who aredeprivation den-sity and
undergoing therapy, fractures in
radiation published trial men receiving
6,7
therapy or inresults showing androgen-
men withan effect on deprivation
lymph nodefracture therapy for
positive prevention are prostate
cancer. instructed to
M take daily
ETsupplements of
H calcium, 1 g or
O more, and
DSvitamin D, 400
IU or more.
STUDY Data were
DESIGN collected from
This was a April 2004 to
multicenter, June 2008.
randomized, The primary
double-blind, end point was
placebo- the percent
controlled change in the
study of men baseline bone
undergoing an- mineral density
drogen- of the lum-bar
deprivation spine at 24
therapy for months; the
nonmetastatic, percent change
hor-mone- at 36 months
sensitive was a
prostate cancer. secondary end
Patients were point, as were
en-rolled in 156 per-cent
study centers in changes in the
North America baseline bone
and Europe and mineral density
randomly of the total hip
and femoral
assigned (by
neck at 24 and
means of an
36 months, the
interactive
incidence of
voice-response
newly
system) to
diagnosed
receive den verte-bral
osumab, 60 mg fractures at 36
subcutaneously months,
through a 1-ml fracture at any
in-jection, or site
placebo every 6 (morphometric
months. In July or clinical
2006, the study vertebral or
protocol was nonverte-bral
amended to fracture), time
extend the pe- to first clinical
riod for safety fracture, and
and fracture safety events.
evaluation from For the end
2 to 3 years. point of
Patients were fracture at any
stratified site, we
according to excluded
age (<70 vs. fractures
70 years) and associated with
duration of severe trauma,
pathologic
androgen-depri-
fractures, and
vation therapy
fractures of the
(6 months vs.
skull, face,
>6 months). All
mandible,
pa-tients were metacarpals,
fingers, anddensities of the participating.
toes. This endwhole body and
23 An exter-nal
distal third of data monitoring
point was based
the radius and committee
on published
changes over monitored pa-
data that
time in levels tients safety
showed a
of PSA and and efficacy
correlation
markers of
between andro- throughout the
bone turnover.
gen-deprivation 36-month study
therapy and the Institutional period. Early
risk of fracturereview boards stopping rules
across multipleat each center are described in
skeletal ap-proved the
the
11,12 protocol. All
sites. Supplementary
patients
Exploratory end Appendix
points includedprovided (available with
the percentwritten the full text of
changes in boneinformed this article at
min-eral consent before
NEJM.org).
2009 without
permission.
TheNewEnglandJournalofMedicine
Copyright
Downloadedfromnejm.orgon 2009
746
December Massachusett
N ENGL J
17,2013.ForsMedical
MED 361;8 personaluse Society.All
NEJM.ORG only.No rights
AUGUST 20,
otheruses reserved.
 DENOSUMAB FOR MEN WITH PROSTATE CANCER

1468 Patients were enrolled and

underwent randomization
ed
to
rec
eiv
734 Were e
as de
734 Were assigned to receive placebo nos
si
g um
n ab

289 Discontinued study

143
43
23
21 Figure 1. Enrollment,
21 Randomization, and
14 Follow-up of the Study
Patients.
o either a lowafter for
u bone mineralreceivi more
The P density (T scoreng an- than 3
study A at the lumbardrogen months
was T spine, total hip,- to less
codesig h or femoral neckdepriva than 3
ned by of less thantion years
the 1.0) at base-therapy were
princip line or a historyfor eligible
al (aca- of anmore if they
demic) osteoporotic than 1 had
investi fracture. Bonemonth, been
gator mineral densitycurrent free of
and the T scores wereuse of oral
sponsor calculated basedoral bispho
. The on the thirdbispho sphona
spon- National Healthsphona tes for
sor and Nutritiontes or 1 year
gathere Exami-nation previo before
d the Survey us en-
data (NHANES III)exposu rollme
and normative re to nt),
conduc database. oral and
ted the Patients had anbispho any
statisti- Eastern sphona exposu
cal Cooperative tes for re to
analyse Oncology 3 or intrave
s. The Group more nous
investi performance years bispho
gators status score of 2(althou s
had full or less. Keygh
access exclusion patient
to the criteria includeds who
study concurrent had
data receipt of an-used
and tineoplastic oral
were therapy orbis-
permitt radiotherapy, phosph
ed to PSA level ofonates
publish more than 5 ngprevio
with- per milliliterusly
 N ENGL J MED 361;8 NEJM.ORG AUGUST 20, 2009 747
of December other perm yright Medical
TheNew
Medic17,2013. uses issio 2009 Society.
Downloadedfromnejm.org
England
ine Forpersonal with n. Massachus Allrights
Journal
useonly.No out Cop etts reserved.
T h e NE W ENGL A ND JOUR NA L o f MEDICINE
osteoporosis STUDY
were also PROCEDURE
phonates excluded. S
within 5 years Bone mineral
before study densities of the
entry. Pa-tients lumbar spine,
with a bone fem-oral neck,
mineral density and total hip
T score of less were measured
than 4.0 at the by means of
lumbar spine, dual x-ray
total hip, or absorptiometry
femo-ral neck at baseline and
or who were at months 1, 3,
currently 6, 12, 24, and
receiving 36. In a
treatment for substudy of
on
ly.
No
ot
he
r
us
es
wi
th
ou
t
pe
748 rm
iss
io
n.
TheNewEnglandJournalofMedicine
Copyright
Downloaded
2009
from
Massachusetts
nejm.orgon
MedicalSociety.
December17,
Allrights
2013.For
reserved.
personaluse
 DENOSUMAB FOR MEN WITH PROSTATE CANCER

Table 1. (Continued.)

Characteristic Denosumab (N=734) Placebo (N=734)

Total hip BMD, according to densitometer type absolute
2
value in g/cm
Hologic
Median 0.9 0.9
Range 0.6 to 1.5 0.6 to 1.4
Lunar
Median 1.0 1.0
Range 0.6 to 1.4 0.6 to 1.6
Total hip BMD T score
Median (range) 0.9 (3.6 to 3.3) 1.0 (3.6 to 3.1)
Mean SD 0.91.0 0.91.0
Femoral neck BMD, according to densitometer type absolute
2
value in g/cm
Hologic
Median 0.8 0.8
Range 0.4 to 1.3 0.5 to 1.2
Lunar
Median 0.9 0.9
Range 0.5 to 1.3 0.6 to 1.4
Femoral neck BMD T score
Median (range) 1.5 (3.8 to 3.0) 1.5 (3.5 to 1.9)
Mean SD 1.40.9 1.40.9
Duration of previous androgen-deprivation therapy mo
Calculated median (range) 20.8 (0.0 to 195.3) 20.4 (0.0 to 354.6)
06 mo no. (%) 175 (23.8) 175 (23.8)
>6 mo no. (%) 559 (76.2) 559 (76.2)
Previous bisphosphonate therapy no. (%) 10 (1.4) 9 (1.2)
Vertebral fracture at baseline no. (%) 155 (21.1) 174 (23.7)
History of osteoporotic fracture no. (%) 163 (22.2) 196 (26.7)

* BMD denotes bone mineral density, ECOG Eastern Cooperative Oncology Group, and PSA prostate-specific antigen.
Race was self-reported.
The body-mass index (BMI) is the weight in kilograms divided by the square of the height in
meters. Any site refers to the lumbar spine, total hip, or femoral neck.
gen type I N-terminal screening methods
peptide, and tartrate- described previously.
21
309 patients, bone mineral densities of the whole resis-tant acid
body and distal third of the radius were measured phosphatase) All bone mineral
were
every 12 months. Investigators were unaware ofmeasured at baseline density and fracture
the bone mineral density results but were alertedand at 1, 6, 12, 24, and results were assessed in
about, and had the discretion of stopping the 36 months. Routine a blinded fashion by a
study drug in, patients who lost more than 7% of labo-ratory values, PSA reader at a central
the bone mineral density at the lumbar spine or levels, and testosterone facility (Synarc).
total hip within any 12-month period or who had levels were measured at Assessments of verte-
a T score of less than 4.0 at the total hip or lum- baseline and every 6
bar spine at any point during the study. Markers months during the
of bone turnover (serum C-telopeptide, procolla- study. Antidenosumab
antibody levels were
assessed with the use of
N ENGL J MED 361;8 NEJM.ORG AUGUST 20, 2009 749
Downloadedfromnejm.orgon personaluse permission.Copyright
TheNewEngland only.Noother 2009MassachusettsMedical
December17,
Journalof
2013.For useswithout Society.Allrightsreserved.
Medicine
T h e NE W ENGL A ND JOUR NA L o f MEDICINE
MedDRA terms dropout rate of
possibly related 10%. The study
bral fracturesto had a statistical
were based oncardiovascular power of 80%
readings ofevents. All cases to detect a 45%
lateral spineof osteonecrosis reduction in the
radiographs (ofof the jaw were risk of new ver-
T4 to L4) atadjudicated by tebral fracture
baseline and atan independent and a 45%
12, 24, and 36 reduction in the
external risk of fracture
months;
committee of at any site at 36
nonvertebral
experts in dental months with
fractures were
disease, in a denosumab as
also confirmed
blinded manner. compared with
by the reader.
placebo,
To avoidSTATISTICAL assuming a
uninten-tional ANALYSIS 12% inci-dence
unblinding ofThe primary of new
study-group analysis was vertebral
assignments, the comparison fractures at 36
se-rum calciumof per-cent months24,25
levels (unlesschange in bone and fracture
grade 3 ormineral density rates similar to
above, asat the lum-bar those reported
assessed spine between in a population-
according tobaseline and 24 based study of
the Nationalmonths in the men with
Cancer Insti-denosumab prostate
tutes Commongroup and the cancer.11
Terminology placebo group. Full
The planned
Criteria for
sample size was statistical
Adverse 1226 patients methods are
Events) and(613 pa-tients
described in the
results of bone-per group), Supplementary
marker testswhich was Appendix.
were notcalculated to Analysis of the
reported to theprovide a percent changes
sites. statistical
in bone mineral
All adversepower of 95%
density
events wereto detect an
included data
coded using theabsolute
Medical difference of 2 for all patients
who had been
Dictionary for percentage
Regulatory points between randomly
Activities
the two study assigned to a
groups in the study group and
(MedDRA)
percent change had a bone
system. An
in bone min- mineral density
independent, eral density at measurement at
external the lumbar baseline, and
committee ofspine between
one or more
cardiolo-gists baseline and 24
post baseline
who weremonths,
(the modified
unaware of theassuming an
intention-to-
study-group as-alpha value of
0.05, a standard treat popula-
signments
deviation of the tion). This
adjudicated all
mean change analysis
deaths and
from baseline consisted of an
serious ad-verse
10,15 analysis of
events that met a of 6.4%,
predefined set ofand an annual
covariance, withrandomized to a was extended
adjustment forstudy group. from 24 to 36
stratification All exploratory months.
fac-tors (ageanalyses were Baseline
and duration ofconducted us- characteristics
previous ing all data of the patients
androgen-depri- available at the who
vation therapy),time of participated
baseline boneanalysis. All throughout the
mineral density,statistical 36-month
densitometer testing was study period
type (Lunar ortwo-sided, with were similar to
Hologic), andan alpha value those of the
inter-action of 0.05. overall
between Analysis of population
baseline bonesafety included (see the
mineral densitydata for all Supplementary
and patients who Ap-pendix).
densitometer had received at Baseline
type. Missingleast one dose characteristics
values wereof a study drug. were generally
imputed No formal well bal-anced
according to thestatistical between the
last- testing was two groups
observation- performed for (Table 1). The
carried-forward safety analysis. mean age was
method. The 75 years;
numbers of RE83.0% of
patients whose SUpatients were
data were LT70 years of age
included in S or older. Most
analyses of the patients were
bone mineralSTUDY white and had
density arePOPULATION received
listed in theThe study androgen-
Supplementary included a deprivation
Appendix. total of 1468 therapy for
Analy sis of thepatients (734 more than 6
incidence ofin the months. Mean
new vertebraldenosumab bone mineral
fracture group and 734 density T
included datain the placebo scores were
for all patientsgroup) (Fig. 0.4 at the
who had been 1). In all, 912 lumbar spine,
ran-domly patients 0.9 at the total
assigned to a(62.1%) com- hip, and 1.4 at
study group andpleted the 36- the femoral
had a base-linemonth study. neck. Approxi-
evaluation andThe primary mately 77.9%
one or morereason for of patients had
postbaseline study a T score of
evaluations ofdiscontinuatio less than 1.0
vertebral n was at the spine or
fracture. withdrawal of hip at baseline;
Analysis of in- con-sent 63.1% had a T
cidence of(18.4%), the score from 1.0
fracture at anymajority of to 2.5, and
site included cases of which 14.7% had a T
data for alloc-curred score of less
patients whowhen the than 2.5. The
had beenblinded period median serum
25-hydroxy
TheNewEnglandJournalofMedicine
permission.
Downloadedfromnejm.orgon Copyright
750 December 2009
17,2013.ForMassachusett
N ENGL J personaluse sMedical
MED 361;8 Society.All
only.No
NEJM.ORG
AUGUST 20, otheruses rights
2009 without reserved.
 DENOSUMAB FOR MEN WITH PROSTATE CANCER

A Lumbar Spine B Total Hip

10 10
Percent Change in BMD from Baseline

Percent Change in BMD from Baseline

8 8

6 Denosumab 6

4 4 Denosumab
Difference at 24 mo,
2 6.7 percentage points 2
Difference at 24 mo,
0 0 4.8 percentage points

2 2
Placebo
4 4 Placebo

6 6
01 3 6 12 24 36 01 3 6 12 24 36
Month Month

C Femoral Neck D Distal Third of Radius

10 10
PercentChange in BMD from Baseline

PercentChange in BMD from Baseline

8 8

6 6

4 Denosumab 4
Denosumab
2 2
Difference at 24 mo,
0 3.9 percentage points 0
Difference at 24 mo,
2 2 5.5 percentage points
Placebo Placebo
4 4

6 6
01 3 6 12 24 36 0 12 24 36
Month Month

Figure 2. Mean Percent Changes from Baseline Bone Mineral Density (BMD) Values during the Study Period, According
to Skeletal Site and Study Group.
Results are presented as least-squares means of the BMDs of the lumbar spine (Panel A), the total hip (Panel B), the femoral neck (Pan el
C), and the distal third of the radius (Panel D). All values shown were significantly higher in the denosumab group than in the placebo
group (P0.001). The means were estimated with the use of analysis-of-covariance models adjusting for study group, stratification vari
ables, baseline BMD value, densitometer type, and the interaction between baseline BMD value and densitometer type. The means are
based on data for 734 patients in each of the two groups except for the distal third of the radius, for which data were available for 161
patients in the denosumab group and 148 patients in the placebo group. I bars indicate 95% confidence intervals.
through 36 months, as
at the lumbar spine was com-pared with placebo
vitamin D level was similar in the two groups at baseline increased by 6.7 percent- (P<0.001 at all measured
(24.4 ng per milliliter with denosumab and 24.9 ng per age points over that in time points).
milliliter with placebo) and re-mained so at 36 months (31.4 the placebo group at 24 At 24 months,
and 31.0 ng per milliliter, respectively). months (5.6% vs. 1.0%, denosumab therapy was
P<0.001) (Fig. 2A). Bone asso-ciated with
EFFICACY mineral density at the significantly increased
Bone Mineral Density lumbar spine was signifi- bone mineral density of
Denosumab was associated with increased bone mineralcantly increased with the total hip, femoral
density at all measured sites (Fig. 2). In the denosumab denosumab at 1 month, neck, distal third
group, the bone mineral density and continued to increase
N ENGL J MED 361;8 NEJM.ORG AUGUST 20, 2009 751
Downloadedfromnejm.orgon personaluse permission.Copyright2009
TheNewEnglandJournal December17, only.Noother MassachusettsMedicalSociety.
ofMedicine
2013.For useswithout Allrightsreserved.
 T h e NE W ENGL A ND JOUR NA L o f MEDICINE
( k, 0.72;
r 95% CI,
e 0.48 to
Placebo
Denosumab l 1.07; P=
a 0.10). More
ti than one
v fracture at
e any site
ri developed
s in sig-

New VertebralFracture (%)

P 0n h were
= .
0 if e found
0 ic betwe
6
a en the
n groups
Figure 3. Cumulative Incidence of New Vertebral Fracture at
12, 24, and 36 Months, According to Study Group. tl in the
y time
The relative risk for vertebral fracture among 679 patients in the denosu
mab group as compared with 673 patients in the placebo group was 0.15 f to first
at 12 months, 0.31 at 24 months, and 0.38 at 36 months. e clinica
No. of Patients
w l
e fractur
of the radius, and whole body (absolute difference Month
r e (any
vs. value for placebo, 4.8, 3.9, 5.5, and 4.0 percent- 22
p nonver
age points, respectively) (P<0.001 for all compari-
at tebral
sons) (Fig. 2B, 2C, and 2D and data not shown,
ie or
respectively). The between-group differences were
n clinica
significant at all measured time points (P0.001 for
ts lly
all comparisons). Denosumab use was also
i eviden
associated with significant increases in bone min-
n t
eral density at all measured skeletal sites for every
t verteb
subgroup of patients, including older men and those
h ral
with lower baseline values of bone mineral density,
e fractur
higher levels of serum C-telopeptide and tartrate-
d e).
resistant acid phosphatase, and a history of vertebral
e
fracture at baseline (data not shown).
n Marke
o rs of
s Bone
u Turno
m ver
a At 36
b month
g s (6
r month
o s after
u the
p last
( dose
5 of the
[ study
0. drug),
7 levels
% of
]) bioche
t mical
h marke
a rs of
n bone
i turnov
n er
t decrea
sed
significa
ntly with
denosum
ab
treatmen
t as
compare
d with
placebo
(P<0.001
for each
comparis
on).
Serum
levels of
serum C-
telo-
peptide,
procolla
gen type
I N-
terminal
peptide,
and
TRAP-
5b were
decrease
d from
the
baseline
values
by a
median
of 45%,
61%,
and
33%,
respec-
tively, in
the
denosum
ab group
as
compare
d with
13%,
18%,
and 8%,
respectiv
ely, in
the
placebo
group.
 E UST per
N 20,
miss
200
9 ion.
Copyright2009
MassachusettsMedical
TheNewEnglandJournalofMedicine
Downloadedfrom Society.Allrights
7 nejm.orgon reserved.
5 December17,
2 2013.Forpersonal
useonly.Noother
N useswithout
DENOSUMAB FOR MEN WITH PROSTATE CANCER
osteonecrosis cancer.
of the jaw Bisphosphonates
values were (e.g., pamidronate,
(including reported. zole-dronic acid,
serum and alendronate)
creatinine) or and selective
DI
hematologic estro-gen-receptor
SCmodulators (e.g.,
values in
USraloxifene and
association
SI tore-mifene) have
with
O been associated
denosumab
therapy, other
N with increases in
than theIn this study bone mineral
expected density of the hip
of men and spine and
transient receiving decreases in bone
decreases inandrogen-
turnover in men
se-rum depriva-tion receiving
calcium, therapy for androgen-
phosphorus, prostate deprivation
and totalcancer, a therapy for
alkaline phos-significant in- prostate can-
phatase levels.crease in bone 10,14-18,26
cer. In
The incidencemineral
of Commondensity was the present study,
the beneficial
Termi-nology seen with effects in the
Criteria gradeden osumab
denosumab group
2 at all appeared robust,
hypocalcemia measured as they were found
(changes inskeletal sites, as early as 1
laboratory including the month after
values oflumbar spine, therapy was begun
albumin- hip, and and were sustained
adjusted radius. for 3 years.
serum cal-Denosumab Denosumab was
cium) was lesswas associated with
than 1% inassociated significant in-
each of thewith creases in bone
two groups.significant mineral density of
PSA levelsdecreases, as the distal third of
over timecompared the radius, a site of
were predominantly
with placebo, 27
unaffected byin the cortical bone,
either studycumulative for which neither
drug (data notincidence of bisphosphonates
shown). new vertebral nor selective
There estrogen-receptor
fractures at
were no12, 24, and 36 modulators have
delays inmonths. been reported to
healing of Several have a positive
nonverte-bral randomized, effect. In a
randomized,
fractures incontrolled
controlled trial of
either group.trials have men receiving
No eval-uated the androgen-depri-
neutralizing effects of vation therapy for
an- other drugs prostate cancer, for
tidenosumab on bone example, bone
antibodies mineral mineral density of
were density and the distal radius
detected. Nobone turnover de-creased, despite
cases ofin men with treatment with
prostate
 16 Se
alendronate.
ve
There are Table 2.
limited data Summary of ral
Adverse s
about fracture Events.* m
preven-tion in all
men with st
osteoporosis, ud
Event ie
and more
s
specifi-cally, ha
Adverse event
in men ve
receiving Most common: su5% in either group
androgen- Arthralgiagg
deprivation Back paines
ther-
te
Constipation
d
Pain in extremity
th
at
Hypertension
bo
Peripheral edema
th
Nasopharyngitis
or
Fatigue al
Dizzinessbi
sp
Musculoskeletal pain
ho
Diarrhea sp
Hot flush ho
na infection
Urinary tract
te
Possibly treatment-related
s
CTC grade 3,an 4, or 5
d
Serious adverse event
ter
Adjudicated cardiovascular
ip
Cardiovascular
ar death
ati syndrome
Acute coronary
Stroke or de
transient ischemic attack
m
Congestive heart failure
ay
re
Other vascular
Arrhythmiadu
ce
Most common other serious adverse
event:th1% in either group
e
Pneumonia
ris
Syncope k
Dyspnea of
fr
Metastasis to bone
ac
Possibly treatment-related
tu
Death re
in
1* CTC m
denotes en
Common wi
Terminology th
Criteria of the
National os
Cancer te
Institute o-
(version 3). po
ro
a sis
p ,
y un
. rel
at
e r re
d - po
a rt
t p of
o y a
. 2-
a 2 ye
n 8 ar,
d pl
r - a-
o 3 ce
g 1
bo
e -
n co
- I nt
d n ro
e lle
p a d
r tri
i p al
v r in
a e vo
t l lvi
i i ng
o m m
n i en
n re
t a ce
h r ivi
e y ng
 N ENGL J MED 361;8 NEJM.ORG AUGUST 20, 2009 753
of December Nootheruses Massachuset
The Medicin17,2013. without tsMedical
New e
For permission. Society.All
Englan
Downloadedfrom personal Copyright rights
d
nejm.or useonly. 2009 reserved.
Journal
gon
T h e NE W ENGL A ND JOUR NA L o f MEDICINE
to evaluate the denosumab
risk of fracture was associated
androgen- associated with with increases
deprivation
therapy fordenosumab in in bone
prostate cancer,compari-son mineral
toremifene usewith an active density at all
decreased thedrug would
risk of newhave skeletal sites
been and reduction
verte-bral
fractures by imprac-tical in vertebral
approximately because of the fractures in
32 large sample
50%. men receiving
We used arequired.33-36 androgen-
placebo-control deprivation
In
design in our therapy for
conclusion,
study for several
twice- prostate
reasons. First,
yearly cancer.
there are limited administrati
data about on of Supported by
grants from Amgen,
fracture the National
prevention in Institutes of Health
men in any (K24 Midcareer
Investigator Award
context, 5K24CA121990
including in -02, to Dr. Smith),
men receiving and the Prostate
androgen- Cancer Foundation
(to Dr. Smith).
deprivation
therapy for Dr. Smith reports
prostate cancer. receiving consulting
fees from Amgen,
Second, no GTx, and Novartis
approved and advisory and
therapy is lecture fees from
Amgen and GTx;
indicated for Dr. Egerdie,
reduction of the consulting,
risk of fracture advisory, and
lecture fees from
in men Amgen, Bayer, and
receiving Pfizer; Dr. Feldman,
androgen- advisory fees from
Amgen, GTx, and
deprivation Eli Lilly and lecture
therapy for fees from Eli Lilly;
prostate cancer. Dr. Tammela,
consult-ing and
Third, the
advisory fees from
natural history Orion Pharma and
of bone loss and AstraZeneca and
fractures has not lecture fees from
AstraZeneca and
been Astellas; Dr. Saad,
prospectively grant sup-port from
described in Sanofi-Aventis,
Novartis, and
such men. Amgen and
Fourth, there are advisory,
no evidence- consulting, and
lecture fees from
based guidelines Novartis, Amgen,
or established Merck, and Sanofi-
standards of Aventis; and Drs.
Heracek and
care for fracture Szwedowski,
prevention in advisory fees from
men receiving Amgen. Dr. Ke, Ms.
Kupic, and Dr.
androgen- Goessl report being
deprivation em-ployees of
therapy for Amgen and
receiving stocks and
pros-tate cancer.
stock options from
Lastly, a study Amgen. Dr. Leder
reports receivingNovartis. No other Chang, Ph.D., of
consulting fees frompotential conflict of Amgen, and Linda
Amgen and the Newinterest rele-vant to Melvin, B.A., for
England Researchthis article was providing writing
Institutes and lecturereported. assistance in a draft
fees from Merck and We thank Ting
of the manuscript.
G. Go- Moseley, DiConstanzo, B. Donnelly,
palakrishna M. S. Flax, M. Gleave, B.
APPENDIX
n, R. Murdock, Goldfarb, R. Hewitt, E.
In addition toGreengold, D. Penson,Hirshberg, K. Jansz, A.
the authors, G. D. Reed, B.Kapoor, T. Kinahan, L.
members of
Grossfeld, Roberts, D.Klotz, L. Lacombe, W.
the
Denosumab N. Hahn, B. Saltzstein, Leung, M. Liquornik, W.
HALT Hale, D. J. Sharkey,Love, A. Mathur, C. Mo-
Prostate Hassman, D. rash, B. Okafo, B. Palmer,
Cancer S. Hopkins, Shepherd, P. Pommerville, D.R.
Study Group A. A. Sidhom,Siemens, G. Steinhoff, S.
were as Iranmanesh, P. Sieber, J.Tanguay, J. Trachtenberg,
follows: R. Israeli, Sipio, R.E. Woods, J. Zadra; Mexico
United B. Jepson, Smith, Jr., M. Cruz-Rodriguez, R.
States D.
W. Jones, F. Smith, C.Galicia-Samano, O.
Agus,
R. Kagan, Steidle, S.Hernandez-Ordonez, C.
4. Aronoff, G. Karlin, J. Tchekmedyi Martinez-Martinez, J.
M. Axler, K.Katz, J. an, C.Robles-Avina, C. Octavio-
Baker, S.Kaufman, Teigland, J.Rovelo-Diaz, T. Suarez-
Brosman, S.D. Keiller, Thrasher, Sahui, H. Vargas-Zamora;
Chang, V.D. Kim, I. K. Tomera,Poland K. Bar, B.
Charu, G.Klimberg, J. Darewicz, T. Demkow, Z.
Chodak, F.E. Updegrove, Jablonska, P. Jarzemski, P.
Chu, J.Kramolows B. Wachs,Kania, J. Niezabitowski, W.
Cochran, G.ky, H. W.G. Wells,Pypno, R. Szwedowski;
Colombo, G.Lanctin, J. N. Czech Republic M.
Dhillon, M.Lilly, J. Whitlock, Hanus, P. Hesoun, J. Jansa,
Dineen, E.Lugg, J. R. D. Pacik, J. Pernicka, J.
Dula, M.Lumerman, Williams, Richter, M. Urban, P.
Efros, S.M. R. Wurzel,Zmeskal; the Nether-lands
Ekbal, R.G.Madorsky, L. Yee; E. Barten, P.J. van den
Feldman, H.J. Canada Broeke, J.L. Bruins, G.
Fisher, W.McMurray, L. Aaron,Khoe, P.J.M. Kil, A.H.P.
Friedel, M.B. C. Andreou,Meier, J. van Berkel;
Gittelman, Mehlhaff, J. Barkin,Hungary G. Body, J.
D. Gleason,B. B. Bora, R.Kondas, L. Koranyi, P.
K. Goldberg,Mellinger, Buckley, R.Tenke, F. Torzsok, T. Toth;
E. M. Casey, M.Switzerland O. Lamy,
Goldfischer, Modiano, Chetner, J.K. Lippuner, R. Theiler;
W. Chin, G.Finland M. Leppilahti.
enreich tic, Dahut WL. An- 1:S gen
A, Aus recurre drogen 23- sup
REFER G,
ENCES Bolla
nt, ordeprivation
pro- therapy
6. B S2
6.
pres
sion
forolla
M, et gressiv prostate and
1. Park
al. e JAMA
cancer.M. 7. exte
in DM, Adj Bo
EAU prostat 2005;294:238-44. rnal
Bray F, uva lla
guideli e irra
Ferlay J, nt M,
nes on cancer: diati
Pisani P. hor Co
prostat 2006 on
Global mon llet
e update in
cancer al te
cancer. of an pati
statistics treat L,
Eur Americ ents
, 2002. men Bl
Urol an with
CA t an
2008;5 Society loca
Cancer J with k
3:68- of lly
Clin radi L,
80. Clinica adva
2005;55: othe et
l nced
74-108. 4. Lo
Oncolo
rapy al. pros
blaw for Lo
2. Jem
DA,
gy
loca ng-
tate
al A, practic canc
Virgo lly ter
Siegel e er
KS, adv m
R, Ward guideli (an
Nam R, ance res
E, et al. ne. J EO
et al. d ult
Can-cer Clin RTC
Initial pros s
statistics Oncol stud
hormon -tate wit
, 2008. 2007;2 y): a
al canc h
CA 5: phas
manage er. im
Cancer J 1596- e III
ment of Eur me
Clin 605. ran-
androg Urol dia dom
2008;
en- 5. Sha 199 te ised
58:71- 9;35
sensitiv rifi N, an trial.
96. :Sup
e Gulley dro Lan
3. Heid metasta JL, pl - cet
2002;36 y in n AL, et al.clai iga
0:103-8. men Pamidronate toms- no
with tion prevent bone lossbase CS
8. Mes
node- therapy during androgen-d .
sing positiv to deprivation coh An
EM, e elevate therapy forort dro
Manola prostat d prostate cancer. Nstud ge
J, e osteocl Engl J Medy of n-
Sarosdy cancer. ast 2001;345: 948-55. men de
M, N Engl activity with pri
Wilding J Med in men 11. Shahi
non vat
G, 1999;3 with nian VB, Kuo YF,met ion
Crawfor 41:178 metasta Freeman JL, astat -
d ED,1-8. tic Goodwin JS. Riskic
Trump prostat of fracture afterpros
D. Im- 9. Mi e andro-gen tate
mediate chaelso cancer. deprivation forcan-
hormona n MD, Clin prostate cancer. N cer.
l therapyMarujo Cancer Engl J MedJ
compare RM, Res 2005;352:154-64. Clin
d withSmith
observat MR.
2004;1 12. Smith Onc
0:2705-MR, Lee WC,ol
ion afterContrib 8.
radical ution Brandman J,200
prostate 10. Wang Q,5;23
ctomy
of
Smith Botteman M,:789
and
androg MR, Pashos CL.7-
en 903.
pelvic McGov Gonad-otropin-
lymphad depriva ern FJ, releasing hormone 13
enectom - Zietma agonists and
fracture risk: a . H
361; 2009 useonly. chusetts
8 Noother Medical
NEJM
.ORG
TheNewEnglandJournalofMedicine
uses Society.
754
Downloadedfromnejm.orgon
N
AUG without Allrights
UST
ENGL December17,permission reserved.
20,
J MED 2013.Forpersonal
DENOSUMAB FOR MEN WITH PROSTATE CANCER
prostate III,
cancer: hibitors for Alothman
therapy-induced interim nonmetasta KI, Khosla
fractures in menanalysis of a tic breast S,
with nonmetastaticmulticenter cancer. J Achenbach
prostate cancer:phase 3 Clin Oncol SJ, Oberg
what do we really clinical 2008;26:48 AL, Zincke
know? Nat Clinstudy. J Urol 75-82. H. Frac-ture
Pract Urol 2008;5:2008;179:15 21.
risk
24-34. 2-5. following
McClung bilateral
14. Michael 19. L MR, orchiectomy
son MD, Kaufmanacey DL, Lewiecki . J Urol
DS, Lee H, et al.Timms E, EM, Cohen 2003;169:17
Randomized Tan HL, et SB, et al. 47-50.
controlled trial ofal. Os- Denosuma
an-nual zoledronicteoprotegeri b in 25. K
acid to preventn ligand is a postmenop rupski TL,
gonado-tropin- cytokine ausal Smith MR,
releasing hormonethat women Lee WC, et
agonist-induced regulates with low al. Natural
bone loss in menosteoclast bone history of
with prostate cancer.differentiati mineral bone
J Clin Oncolon and density. N complicatio
2007;25:1038-42. activation. Engl J Med ns in men
Cell 2006;354:8 with
15. Smith 1998;93:165 21-31. prostate
MR, Eastham J,-76. carcinoma
Gleason DM, 22. initiating an-
Shasha D,
20. E Miller PD, drogen
Tchekmedyian S,llis GK, Bolognese deprivation
Zinner N.Bone HG, MA, therapy.
Randomized Chlebowski Lewiecki Cancer
controlled trial ofR, et al. EM, et al. 2004;
zoledron-ic acid toRandomized Effect of 101:541-9.
prevent bone loss intrial of denosumab [Erratum,
men receiv-ingdenosumab on bone Cancer
androgen in pa-tients density and 2004;101:
deprivation therapyreceiving turnover in 2370.]
for non-metastaticadjuvant postmenopa
prostate cancer. Jaromatase usal women 26. S
Urol 2003;in- with low teiner MS,
169:2008-12. bone mass Patterson A,
after long- Israeli R,
16. Greensp term Barnette
an SL, Nelson JB, continued, KG, Boger
Trump DL, Resnick discontinue R, Price D.
NM. Effect of once- d, and Toremifene
weekly oral restarting of citrate
alendronate on bone therapy: a versus
loss in men randomized placebo for
receiving androgen blinded treatment of
deprivation therapy phase 2 bone loss
for prostate cancer: clinical trial. and other
a randomized trial. Bone complicatio
Ann Intern Med 2008;43:222 ns of an-
2007;146:416-24. -9. drogen
17. Smith 23.
deprivation
therapy in
MR, Fallon MA, Stone KL, patients with
Lee H, Finkel-stein Seeley DG, prostate
JS. Raloxifene to Lui LY, et cancer. J
prevent gonadotro- al. BMD at Clin Oncol
pin-releasing multiple 2004;22:
hormone agonist- sites and Suppl:406s.
induced bone loss in risk of abstract.
men with prostate fracture of
cancer: a multiple
27. D
randomized types: empster DW.
controlled trial. J long-term Anatomy and
Clin Endo-crinol results func-tions of
Metab from the the adult
2004;89:3841-6. Study of skeleton. In:
18. Smith Osteoporoti Favus MJ,
ed. Primer on
MR, Malkowicz SB, c Fractures.
J Bone the metabolic
Chu F, et al.
Miner Res bone disease
Toremifene
2003;18:19 and disorders
increases bone
47-54. of mineral
mineral density in
metabolism.
men receiving 24. 6th ed.
androgen depri- Melton LJ Washington,
vation therapy for
DC: American et al. The Zoledronic
Society for Bone andAlendronate effect of acid and
Mineral Research,for the teriparatide secondary
2006:7-11. treatment of [human prevention
para- of fractures.
28. Orwoll osteopo-
thyroid N Engl J
E, Ettinger M,rosis in men.
N Engl J hormone Med
Weiss S, et al.
Med (1-34)] 2007;357:18
2000;343:60 therapy on 61-2.
bone
4-10.
density in
34. R
29. R men with agi-Eis S,
inge JD, osteoporosi Zerbini CA,
Faber H, s. J Bone Provenza JR,
Farahmand et al. Is it
Miner Res
P, Dorst A. 2003;18:9- ethical to use
Efficacy of 17. placebos in
risedronate osteo-porosis
in men with 32. trials? J Clin
primary and Smith M, Densitom
secondary Morton RA 2006;9:274-
osteoporo- Jr, Wallace 80.
sis: results H, et al. A 35. R
of a 1-year phase III osenblatt M.
study. randomized
controlled Is it ethical
Rheumatol to conduct
Int trial of
placebo-
2006;26:427 toremifene controlled
-31. to prevent
fractures clinical
30. K and other trials in the
aufman JM, adverse developmen
Orwoll E, effects of t of new
Goemaere androgen agents for
S, et al. therapy in osteoporo-
Teriparatide men with sis? An
effects on prostate industry
vertebral cancer. perspective.
fractures Presented J Bone
and bone at the Miner Res
mineral American 2003;18:114
density in Association 2-5.
men with for Cancer 36. T
osteoporosis Re-search
emple RJ.
: treatment 100th
Study
and discon- Annual
designs in
tinuation of Meeting,
therapy. osteopo-
San Diego,
Osteoporos rosis. J Bone
CA, April
Int 2005; 1216, Miner Res
16:510-6. 2008. 2003;18:112
9-32.
31. O 33. Copyright
rwoll ES, Calis KA, 2009
Massachusetts
Scheele Pucino F. Medical
WH, Paul S, Society.
a n to
C l g b
o e
m E t re
m d w pr
i
ICMJE i o
SEEKING es
t
TWO t
NEW e
t o n nt
MEMBER
e r e e
JOURNALS
e s w d
T b
h o ( m y
e f I e th
C m ei
I M M b r
n e J e e
t d E r di
e i ) to
r c j rs
n a i o -
a l s u in
t r -
i J s n c
o o e a hi
n u e l ef
a r k s .
l n i In
f e o c r who is
o c w a knowledgeable
r t i ) about publication
m i n o ethics
r
a
t
o
n
g
p
4 editor who
u expects to be in the
i c
b position for at least
o o r
li 3 years
n f i
t c
a n e aT
b e r to
o w i ia
u a op
t m : npl
y,
e
t m
1 me
pe odi
h b
e dto
e e
r ers
r
r l-
I s sin
e
C
vi -
M b e (c
J y w ohi
E e pef
N d eof
i o , nin
s v g te
e e are
a m n cst
v b e ce
a e r ed
i r al sjo
l m sur
a 1 e )
n
b , di n
al
l c o
s
e 2 al t
sh
0 jo w
o
a 0 u e
t 9 r ll ul
. n rd
w al ese
pn
w C 2 rd
w a rep
. n eel
r sec
i d e
c i etr
s no
m d e
j a t ni
n ec
e t t dc
. e g o
o e bpi
r j o yes
g o g of
. u r cth
r a ue
T n p r fo
h a hi r ll
e l c eo
s a nw
I r t in
C s e Ig
M h a Cto
J o s Mth
E u ( Je
l L EI
a d a
ti C
n mM
t m n e
A J
i e m
m E
c e b
e se
i t e
ri cr
p r
a t
c s et
a ar
t h
, 3 ia
e e
s
A
si
et
(
f d
a C
s o i
, hr
e l t
A
l l ois
fri
t a s l
i i y i i
n n s o c
e c , n a
l s t
L u o i
a d p p o
i i e e n
n n n r ,
e g
a y a
a a c e c
t g c a c
e e r e
c , s , p
l s t
a s , d a
i p e n
n o e s c
e n t c e
@ s c r
a o . i r
c r ) p a
p / , t t
o p i e
n u t o ,
l b a n
i l r b
n i g o i
e s e f b
. h t l
o e p i
r r a e o
g , u e g
) d r r
p i a
b u e r p
y b n e h
l c v i
S i e i c
e s , e a
p h w l
t i c
e n i p d
m g r r a
b c o t
e m u c a
r o l e b
d a s a
1 e t s s
: l i e
u s
1 o
n s
brief (
s , e w
curric
u d h
ulum
b n e
vitae
s u t r
2 c m o e
b
d r
e s i
e i
p r e n
s l d
c t
i o e e
r f c x
i o
n t e
p m d
t a m ,
i m
o n a
o u t W
n d
e s e e
l c r b
o r i
f ,
i a s
a p l i
j t t
o u
f e
u t
s o
r h
u r a
n o
b d
a r
m p d
l i u r
, p
s b e
s co
s n
t
i a
f c
t
a i
p n
p f
l o
i r
c m
a a
b ti
l o
e n
,

a
n
d

c
o
p
y

o
f

g
u
i
d
e
l
i
n
e
s

f
o
r

a
u
t
h
o
r
s

3
statem
ent
on
why
the
journ
al/edi
tor-
in-
chief
want
s to
be an
ICMJ
E
mem
ber
(shou
ld not
exce
ed
1000
word
s in
lengt
h)
4
 N ENGL J MED 361;8 NEJM.ORG AUGUST 20, 2009
Journalof
m. cem Forpersonaluse Medical
TheMedicine
or ber only.Nootheruses Society.All
New
Downloadedfrom g 17, withoutpermission. rights
Englan
nej on 201 Copyright2009 reserved.
d
De 3. Massachusetts