©TheCanadian Journal ofUrology™: International Supplement, April 2014
with chemotherapy-naïve metastatic prostate cancer
allocated to one of three treatment arms; (ArmV+G)
PROSTVAC-V/FplusadjuvantdoseGM-CSF, (ArmV)
PROSTVAC-V/FplusGM-CSFplacebo,(ArmP)double
placebo [NCT01322490].
Ipilimumab
Ipilimumab is a monoclonal antibody blocking the
immune checkpoint molecule cytotoxic T-lymphocyte
antigen-4 (CTLA-4). Ipilimumabhas showna survival
advantage in melanoma,
49
but the utility in prostate
cancerhasyettobeestablished. SeveralphaseI/IIclinical
studieshaveevaluated ipilimumab incombinationwith
GVAX, PROSTVAC, docetaxel, and radiotherapy, with
promising results.
50-53
Currently, there are two phase
III clinical trials investigating theutilityof ipilimumab.
The first study [NCT00861614] evaluated ipilimumab
versusplacebofollowingradiotherapy inpostdocetaxel
metastatic CRPC patients. Preliminary results were
released by Bristol-Myers Squibb showing that the
primaryendpointofoverallsurvivalwasnotmet (HR=
0.85;95%CI=0.72-1.00;p=0.053).
54
Thefinalresultswere
releasedat the2014GenitourinaryCancersSymposium
which showed that an improvement in progression
free survival (HR = 0.70; 95% CI = 0.61-0.82) and a
reduction inthePSAlevelby50%ormore(13.1%versus
5.3%).
55
The second [NCT01057810] is comparing the
efficacyof ipilimumabversusplacebo inasymptomatic
or minimally symptomatic patients with metastatic
chemotherapy-naïvecastrationresistantprostatecancer.
Tyrosinekinase inhibitors
The utility of tyrosine kinase inhibitors (TKI) and
vascular endothelial growth factor (VEGF) inhibitors
havebeenshownto improvesurvival inmanydifferent
types of cancers.
56-58
The utility of this modality of
treatment iscurrentlybeing investigated in thefieldof
metastaticCRPC.
Cabozantinib
Cabozantinib is an oral tyrosine kinase inhibitor with
specific activity against MET and VEGF receptor 2
(VEGFR2). In a phase II randomized discontinuation
trial, progression free survival was improved in the
cabozantinibarmwhencomparedtoplacebo(23.9weeks
versus5.9weeks,p<0.001). Usingresponseevaluation
criteria insolid tumors (RECIST) criteria, 5%ofpatients
showed apartial response, 75% showed stabledisease,
and11%showeddiseaseprogression to treatment. One
hundred forty-nine patients showed evidence of bone
metastasesatbaselineandofthesepatients,12%showed
complete resolution, 56% showed partial resolution,
28%showedstabledisease,and3%showedprogressive
disease in response to treatment with cabozantinib.
59
Currently, there are two phase III studies evaluating
the utility of cabozantinib in metastatic CRPC. The
first trial [COMET-1; NCT01605227] is a randomized
double-blind trial of patients with metastatic CRPC
who progressed on docetaxel and either abiraterone
orMDV3100 independently. The studywill compare
cabozantinib toprednisonewith theprimary endpoint
being overall survival and secondary endpoints being
bone scan response. This studyhas completed accrual
and iscurrentlyawaitingplannedanalyses. Thesecond
trial [COMET-2;NCT01522443] is another randomized
double-blind trial of patients with metastatic CRPC
who progressed on docetaxel and either abiraterone
orMDV3100. The studywill compare cabozantinib to
mitoxantroneplusprednisonewiththeprimaryendpoint
of pain response. Secondary endpoints include bone
scan response and overall survival. The study has an
estimatedprimarycompletiondate in June2014.
Radiopharmaceuticals
Radiopharmaceuticals such as strontium-89 (89Sr) and
samarium-153(153Sm)ethylenediaminetetramethylene
phosphonate (EDTMP), arebeta-emittingradioisotopes
and have long been used for palliation of bone
pain in metastatic prostate cancer.
60
This mode of
treatment is governed by the dose-limiting toxicity of
myelosuppression. In comparison to a beta-emitting
radioisotope,analpha-emittingradioisotopehasamuch
higherlinearenergytransfer(LET)andsubsequentlyhas
asmallerinfluenceonthesurroundingbonemarrowand
anincreasedanti-tumoreffect. Thesephenomenaexplain
the decreased bone marrow toxicity and improved
overall survival recently exhibited in alpha-emitting
radioisotopes.
61
Radium 223
Radium 223 is a novel alpha-particle–emitting
radiopharmaceutical targeting bone metastases. In a
phase III clinical study of patients with progressive,
symptomaticmetastaticCRPCwith≥2bonemetastasis,
radium 223 showed improvement in overall survival
when compared to placebo by 3.7 months (14.9
months versus 11.2months, p< 0.001)[NCT00699751].
Additionally, time to first skeletal related event was
significantly delayed in the radium 223 treatment arm
when compared to placebo (15.6 months versus 9.8
months, p< 0.001).
62
Radium 223 represents a unique
therapeuticoptionformetastaticprostatecancerandwill
likelyfind a role in themanagement inCRPCpatients
withmetastaticbone lesions.
103
ThoresonETAL.
