©TheCanadian Journal ofUrology™: International Supplement, April 2014
wild type and mutant androgen receptor protein
expression.
28-30
Phase Iclinical studies [NCT00959959]
resulted in>50%PSAdecline in11/49patients (22%)
andanadditional 13/49 (26%)had30%-50%declines.
Thirty-six of 49 (74%) patients completed 12 weeks
of the studybut earlydiscontinuationwas seen in 13
of 49 (26%) patients for toxicity (6/13), progression
(5/13),orwithdrawalofconsent (2/13). Themaximal
tolerateddosewasnot reached in thisstudy. TOK-001
iscurrentlybeingreformulatedwithpotentialphase II
clinical trialsplanned in thenear future.
31
Additional
modifications to exploit the chemical framework of
TOK-001to create novel potent/efficacious androgen
receptordegrading agents (ARDAs) areunderway.
32
Targeted therapy against androgen receptor
coactivators
OGX-111
Clusterin (CLU) isa stress-inducedandrogen-receptor
regulatedcytoprotectivechaperone that isupregulated
incelldeath. Increasedconcentrationsconfertreatment
resistance in experimental and clinical studies.
33,34
Custirsen,asecond-generationantisenseoligonucleotide
(ASO), has high affinity for CLURNA, and has been
shown to suppress CLU levels.
35,36
Treatment with
custirsen increased tumor cell death and improved
chemosensitivitytomultipledrugs, includingdocetaxel
andmitoxantrone, inpreclinicalCRPCprostatecancer
models. In a phase II clinical study [NCT00258388],
men withmetastatic CRPCwith disease progression
after two or more cycles of first line docetaxel-based
therapy showed improvements in overall survival,
although not statistically significant, when custirsen
was combined with docetaxel and prednisone,
compared to docetaxel and prednisone alone (23.8
months versus 16.9 months).
37
Currently, there are
three randomized phase III clinical trials underway
evaluating theutilityofOGX-111 in combinationwith
chemotherapy.
OGX-427
Heat ShockProtein27 (Hsp27) is a chaperoneprotein
that regulates cell signaling and survival pathways
involved in cancer progression and is uniformly
expressedinmetastaticCRPC.
38
Itsexpressionisinduced
byhormonalwithdrawal and/or chemotherapy, and
inhibits treatment inducedapoptosis throughmultiple
mechanisms.
39,40
Inprostatecancer,Hsp27complexes
withandrogen receptor andenhances transactivation
of androgen receptor-regulatedgenes.
41
OGX-427 isa
2
nd
generation antisense oligonucleotide that inhibits
Hsp27 expression. Phase I clinical studies showed
that the drugwas well tolerated [NCT00487786]. In
a phase II clinical study investigating the utility of
OGX-427 in chemotherapy-naïve patients, patients
withminimal symptomswere randomized to receive
OGX-427weeklywithprednisoneorprednisoneonly
[NCT01120470]. In theOGX-427plusprednisonearm,
71% of patients were progression-free at 12 weeks,
compared to 33% in the prednisone only arm. 41%
of patients who received OGX-427 plus prednisone
experienced a > 50% decline in PSA, versus 20% of
patientswho receivedprednisonealone.
42
Aseparate
phase IIclinical trial is investigating theutilityofOGX-
427 incombinationwithabirateroneversusabiraterone
alone, and is in active recruitment with estimated
completiondate listed as June 2015 [NCT01681433].
Immunologic therapies
Immunologic therapies offer an alternative approach
for patients with CRPC. Indeed, sipuleucel-T was
the first of the new generation of FDA-approved
agents againstmetastaticCRPC inApril 2010. These
immunomodulatoryagentsoffer thepotential for long
term therapeutic responses againstCRPC.
Sipuleucel-T
Sipuleucel-T is apersonalized antigenpresenting cell-
basedimmunotherapyproductthatshoweda4.1month
improvement in overall survival (25.8months versus
21.7months, hazard ratio fordeath in the sipuleucel-T
group, 0.78; 95% confidence interval [CI], 0.61 to 0.98;
p = 0.03) in a phase III clinical trial [NCT00065442].
43
Sipuleucel-T is FDA approved formetastatic prostate
canceracrossallstages. Howeverpatients treatedwith
sipuleucel-Tshowanabsence insignificantdifferenceof
objective tumor diseaseprogression,
44,45
Despite early
approvalofsipuleucel-T, ithasfailedtogainwidespread
tractionandmarketshare.
46
Prostvac-VF
Prostvac-VF is a prostate cancer vaccine approach
consistingofarecombinantvacciniavectorasaprimary
vaccination, followedbymultiplerecombinantfowlpox
booster vaccinations.
47
Phase II studies showed an
increase in OS (25.1 months versus 16.6 months,
p = 0.0061), but no statistically significant difference
in the median progression-free survival (3.8 months
versus 3.7 months, p = 0.60). These results mirror
those seen with sipuleucel-T and follow a trend
of improved overall survival without a change in
measurable tumor response.
48
Aphase III trialwithan
estimatedprimary completiondate at the endof 2015
is investigating the use of Prostvac-VF in 1200 men
102
Emerging therapies in castration resistant prostate cancer
