©TheCanadian Journal ofUrology™: International Supplement, April 2014
surrogate end points, and the Food and Drug
Administration (FDA) requirement of a survival end
point fordrugapproval, rapidly led toaparadigmof
testingnewagents in thepostdocetaxel settinggiven
the shorter time lines for readouts.
The initial approval of abiraterone in the post-
docetaxelsetting ledtoabroaddiscussionoftheoptimal
timingof initiatingnext generationandrogen receptor
(AR) targeting therapies,given thesomewhatarbitrary
natureofthetimingofdocetaxeladministrationandthe
criticalnatureof theandrogenreceptorasa therapeutic
target.
8
Subsequent level 1 evidence of abiraterone’s
clinical utility in the “pre-docetaxel setting, led to
regulatory approval of this agent for use inmCRPC
irrespectiveofprior therapies.
9
Data from thephase III
pre-chemotherapy trial of enzalutamide is anticipated
within the year. The phase III trial for the recently
approved alpha emitter radium 223 included men
withmCRPCbothdocetaxelpre-treatedanddocetaxel
naïve.
6
Of interest, theFDAapproved label forradium
223makesnomentionofdocetaxel.
Theelephant in the room for anydiscussionof the
role of sequencing therapy inmCRPC is the issue of
cost. The role of pharmacoeconomics will without
questionultimately influencemanagement decisions
in many clinical settings, however for the purposes
of this review, the clinical utility not the costs of the
agentswill be theprimary consideration.
Theconceptofmoving themanagementofmCRPC
towards a chronic diseaseparadigmhas increasingly
becomeagoalofcliniciansheavily involved inboth the
managementand investigationof therapies inpatients
with mCRPC. Goals of managing chronic disease
typically requiresclinicians tooptimize the timing for
therapies taking into consideration issues of risk and
benefit from level1evidenceor insomecasesevolving
clinical experience/expert opinion.
The extraordinary speed of the introduction of
novel therapies into the clinical armamentarium
(sipuleucel-T and cabazitaxel in 2010, abiraterone
in 2011, enzalutamide in 2012, radium 223 in 2013)
has provided important new therapeutic options for
patients,butwithoutanyopportunity toprospectively
address sequencingquestions.
Initialtherapyoptions: asymptomaticmCRPC
The role of subsequent therapeutic intervention for
patients with castration resistant prostate cancer,
biochemically defined is undefined, and beyond the
scopeof the currentdiscussion. Although theoptimal
therapeuticparadigmforpatientswithmCRPCremains
undefined, anumberof clinicalparametershelpguide
the decision making process. Immunomodulatory
therapyappearsbestutilized inasymptomaticpatients
witha lessaggressivediseasephenotype. Symptomatic
patients, thosewith progressive fatigue, appetite loss
or pain require intervention with agents with overt
anti-tumoractivitysuchasdocetaxelornextgeneration
androgenreceptor targetedagents, suchasabiraterone
or enzalutamide. Selected patients with bone only
metastatic disease with progressive symptoms may
beappropriate candidates for earlyuseof radium223.
Sipuleucel-T remains the only FDA approved
therapeutic vaccine in oncology. Utilization of this
agent in the United States has remainedmodest for
a variety of reason, including the poorly understood
mechanism of action, and its lack over objective anti-
tumor activity in most patients.
10
Although in the
phase III trial that led to its regulatoryapproval, 18.2%
of patients received sipuleucel-T post chemotherapy,
recent evidence provides evidence that the optimal
timing is much earlier in the disease process.
5,11
In a
post hoc analysis of the phase III IMPACT study of
sipuleucel-T, Schellhammer and colleagues evaluated
arangeofclinical factorsandassessed theirassociation
withoverallsurvival. Inthisanalysis,baselineprostate-
specific antigen (PSA) was divided in quartiles, with
patients in the lowest PSA quartile (< 22.1 ng/mL)
having amedian survival of 13months compared to
2.8months in thehighestPSAquartile (>134ng/mL).
11
Among the controversies surrounding the potential
timing of administration of sipuleucel-T is the
theoretical concern that even the low doses (5mg-10
mg)ofprednisone thatareusedalongwithabiraterone
acetate, may impair an immune response to this
dendritic cell vaccine. Recently Small and colleagues
presentedapreliminaryanalysisof randomizedphase
II trial of sipuleucel-T with concurrent or sequential
administration of abiraterone acetate andprednisone.
In thissmall trial (63patients)nosignificantdifferences
wereseenbetweenarms inmediancumulativeantigen
presenting cell activation or total counts. Increased
CD54 up-regulation with the 2
nd
and 3
rd
treatments
were indicative of a prime boost effect in both arms.
12
This dataprovides some evidence that 5mg-10mgof
prednisonehasno “significant” effect on the ability to
mount an immune response to sipuleucel-T.
Given the lack of overt anti-tumor activity
and compelling evidence that patients with lower
volume disease may derive greater benefit, if
sipuleucel-T is to be part of an individual patient
managementparadigm, it shouldbeusedearly in the
management of patients with mCRPC, optimally in
essentially asymptomatic patients with biochemical,
not symptomaticprogression.
94
How to approach sequencing therapy inpatientswithmetastatic castration resistant prostate cancer
