©TheCanadian Journal ofUrology™: International Supplement, April 2014
established the rationale formoreeffective therapeutic
agents targeting the androgen receptor. In addition,
despite castrate levelsof circulating serumandrogens,
the local tumor milieu was noted to be replete with
androgen.
14,15
These studies led to the development
of therapeutic agents targeting both systemic and
intratumoral synthesis of androgens. Since the
androgen receptor signaling isactive inCRPC, several
newagents recentlyFDAapprovedor indevelopment
target theandrogen receptoractivationbyoneof three
mechanisms:
1. Directandrogenreceptorantagonists:Enzalutamide
(FDAapproved) andARN-509 (in clinical trials)
2. Androgen biosynthesis inhibitors: Abiraterone
(FDAapproved), TAK-700 (in clinical trials)
3. Androgen receptors coactivators: OGX-111 and
OGX-427 (in clinical trials)
Direct androgen receptor antagonists
Enzalutamide
Enzalutamide is an oral androgen-receptor–signaling
inhibitor that inhibits nuclear translocation of the
androgen receptor hormone complex, DNA binding,
andcoactivator recruitment, and inducescell apoptosis.
Enzalutamide has a higher affinity for the androgen
receptor than bicalutamide.
16
Phase II clinical studies
showed antitumor effects at all doses, but maximum
tolerateddosewas set to240mgperday,withahigher
frequency of seizures and grade 3 fatigue noted at
the 320mg per day dose.
17
In theAFFIRM phase III
clinical trial (NCT00974311), enzalutamide showed an
improvement in overall survival by 4.8 months over
placebo (18.4 months versus 13.6 months, p < 0.001)
in patients withmetastatic prostate cancer previously
TABLE 2.
Clinical trialsevaluatingnew therapeutics inpatientswithmetastaticprostate cancer
Phase I Phase II
Phase III
FDA
approval
Androgen receptor
MDV3100
NCT00974311 (AFFIRM)
8/31/12 Completed, has results
ARN-509
NCT01171898
Active, not recruiting
Androgenproduction
Abiraterone
NCT00638690 (COU-301)
4/28/11 Completed, has results
TAK-700
NCT01193257 (ELM-PC5
Completed, has results
(C21005))
TOK-001
NCT01709734
Active, recruiting
(ARMOR2)
Targeted therapy
OGX-111
NCT01578655 (AFFINITY)
Active, recruiting
OGX-111
NCT01188187 (SYNERGY)
Active, not recruiting
OGX-111
NCT01083615
Active, not recruiting
OGX-427
NCT01681433
Active, recruiting
(Pacific)
Immunologic
Sipuleucel-T
NCT00065442 (IMPACT)
4/29/10 Completed, has results
Prostvac
NCT01322490 (BNIT-PRV-301)
Active, recruiting
Ipilimumab
NCT01057810
Active, not recruiting
Ipilimumab
NCT00861614
Active, not recruiting
Radiopharmaceuticals
Radium 223
NCT00699751
5/15/13 Completed, has results
Tyrosinekinase inhibitors
Cabozantinib
NCT01605227 (COMET-1)
Active, recruiting
Cabozantinib
NCT01522443 (COMET-2)
Active, recruiting
100
Emerging therapies in castration resistant prostate cancer
