©TheCanadian Journal ofUrology™: International Supplement, April 2014
beentestedinarandomizedcontrolledtrial(RCT)on209
symptomaticbonemetastaticCRPCpatientsscheduled
to receivemitoxantrone andprednisone.
35
Therewas
no difference in palliative response, symptomatic
progression free survival (PFS), overall survival (OS),
andhealth relatedquality-of-life (HRQoL).
Triweeklypamidronate (IV90mg)hasbeen tested
in two similarly designed RCTs on a total of 378
symptomaticCRPCpatients.
36
Thepooledanalysisdid
notdetect significantdifferences in self-reportedpain
score, analgesic use, incidence of SREs, andmobility
betweenpamidronate andplacebo.
Zoledronicacid (ZA)was thefirstbisphosphonate
to be approved for the prevention of SREs in bone
metastaticCRPC. The3arms randomizedcontrolled
registration trial compared triweeklyZAIV, atadose
of 4 mg or 8 mg or placebo for 15 months.
32
The
endpoints includedproportionofpatientswithSREs,
time to first SRE, skeletal morbidity rate, pain and
analgesic scores, anddiseaseprogression. Excessive
nephrotoxicity lead to a dose-reduction to 4 mg in
the 8 mg treatment arm and to an increase in the
infusion time from 5minutes to 15minutes. At the
dose of 4mg, ZA reduced the incidence of SREs by
11% compared to placebo (44.2% versus 33.2%; p =
0.021).
37
In the long term report, themedian time to
thefirst on-studySREwas 488days for theZA4mg
versus321days for theplacebo (p=0.009); theannual
incidenceof SREswas 0.77withZAversus 1.47with
placebo (p=0.005).
32
The study failed to showanOS
improvement, although therewas a trend toward a
longer survival in patients receiving ZA (546 days
versus 469days for placebo; p= 0.103).
38
Denosumabhasbeendeveloped for theprevention
of SRE in various cancer types at the monthly dose
of 120mg sc, 12 times higher than the dose used in
osteoporosis treatment. The dose was optimized
to achieve sustained suppression of bone markers;
patients on less frequent dosing schedules showing
evidence of escape.
39
Denosumab has been directly
compared to monthly ZA (4 mg IV) in 1904 bone
metastaticCRPCpatients.
31
Theprimaryendpointwas
time tofirst on-study SRE andwas assessed for non-
inferiority. Secondaryendpoints includedassessment
forsuperiority in time tofirstSREandOS. Denosumab
delayedby18% the time to thefirston-studySRE (20.7
monthsdenosumabversus17.1monthsZA,HR=0.82,
95% CI 0.71-0.95; p = 0.0002 for non-inferiority and
0.008 for superiority). Denosumab also significantly
delayed the time to first and subsequent SRE and
reduced the total number of SREobserved in the trial
(494withdenosumabversus584withZA). Therewas
nodifference inOS and time todiseaseprogression.
The impact of ZA and denosumab on pain and
HRQoL has been also documented. In the ZA
registration trial,mean least-squares in thebonepain
index (BPI) change from baseline value at 18months
was 0.58 forZAand0.95 forplacebo (p=0.075); at 24
months itwas0.58and1.07 (p=0.024), respectively.
32
The additional benefit of denosumab over ZA has
beenmeasuredonadenosumabpooledanalysisof the
three similar trials inbreast cancer,metastaticCRPC,
and other solid tumors, for a total of 5544 patients.
40
Onset ofmoderate/severe painwas 4.7monthswith
ZAand increased to6.5monthswithdenosumab (HR
= 0.83; 95%CI 0.76-0.92; p< 0.001). Strongopioiduse
andworsening of health related quality-of-life were
less commonwithdenosumab.
Timingof administrationof boneprotecting
agents
EAU and NCCN treatment guidelines recommend
that bone metastatic CRPC patients should receive
ZA or denosumab and recognize the superiority of
the latter indelayingSRE.
19,21
Noneof theguidelines
howeverprovidespractical recommendationonwhen
to start, when to stop, and the interest of switching
between agents. A supplementary analysis of the
ZA registration trial indicated that ZAwas more
efficaciouswhen initiatedbefore theonset of pain.
41
Noteworthy,EMAandFDAhavegrantedregulatory
approvals for ZA and denosumab in patients with
hormonenaïveprostate cancerwithbonemetastases,
althoughpublishedstudieshavebeenconductedonly
inCRPCpatients. Sincemetastatic prostate cancer is
unique in that it is so frequently responsive to first-
line disease-modifying therapy, we believe that ZA
and denosumab prescription should be restricted to
CRPCpatients.
Toxicityofbone targetedagents inmetastatic
CRPC
Themostcommonexpected toxicitiesaresummarized
in Table 4. In contrast to ZA, there is no need
for denosumab dose-adjustment in case of renal
impairment, a common problem in prostate cancer
patients. In the denosumab registration trial, a dose
adjustment for creatinine clearance at baseline and a
dosewithhold forserumcreatinine increasesoccurred
in22%and15%ofpatientsreceivingZA, respectively.
31
Hypocalcemia is a known adverse effect of anti-
remodelingagents,which ismore frequent inCRCP
than other cancer type and with denosumab than
withZA (all grades: 12.8%denosumabversus 5.8%
88
Practical guide tobonehealth in the spectrumof advancedprostate cancer
