©TheCanadian Journal ofUrology™: International Supplement, April 2014
95
Dreicer
Nextgenerationandrogenreceptorsignaling
agents
As remains the case even for docetaxel, the optimal
timing for the initiation of therapy with abiraterone
remainsundefined. In thepre-docetaxel phase III trial,
patientsreceivingabiraterone+prednisonehadamedian
PSAof42.0,withnearly two-thirdsofpatientsreporting
essentiallynopainandonly2%ofpatientswithmoderate
orgreaterpain,presumed tobedisease related.
9
While thepre-chemotherapyphase III trial failed to
meetpre-specifiedendpointstodemonstrateasurvival
advantage, therewasahighlystatisticallyandclinically
significant improvement in time to radiographic
progression free survival: 16.5 months for patients
receiving abiraterone + prednisone in contrast to 8.3
months in patients receiving prednisone alone (0.53;
95% confidence interval [CI], 0.45 to0.62; p<0.001).
9
Concerns among some clinicians regarding the
tolerabilityof 10mgof prednisonewhich is typically
prescribed to minimize the mineralocorticoid side
effects of abiraterone acetate have not been realized
withbroaduse of this agent in theUnited States and
around the world. Studies are ongoing to evaluate
lower doses of steroids to further mitigate steroid
related complications i.e. blood sugar control etc.
Settingaside issuesof availability/affordabilityof
abiraterone +prednisonewhichwill always to some
extent influence therapeutic decision making, with
theexceptionofpatientswhopresentwithsignificant
disease related symptoms, i.e. hydronephrosis from
nodal disease progression or moderate-significant
bone pain, where the high clinical response rate of
docetaxelmaybepreferred, abiraterone+prednisone
both mechanistically and from a patient preference
perspective appears to have become a front-line
therapyforpatientswithmCRPCandobjectivedisease
progression (PSAor radiographicprogression).
At the time this manuscript was being prepared,
a press release indicated that the phase III trial
comparing enzalutamide and placebo in patients
withchemotherapynaïvemCRPCwas stoppedearly.
Patients treatedwithenzalutamidedemonstratedboth
a statistically significant overall survival advantage
and reduction in risk of radiographic progression
or death compared with placebo. To what extent
the impact of enzalutamide’ s ability to improve
overall survival (in contrast to thepre-chemotherapy
abiraterone) in this setting alters the initial sequence
of these agents remains tobe seen.
In the early phase of the development of next
generation androgen receptor targeted therapies i.e.
lyase inhibitorsandsecondgenerationantiandrogens
therewas hope that given the divergent mechanism
of these two classes of agents that sequential use or
combinationsoftheseagentswouldprovidesignificant
therapeutic benefit.
Although we are still early in the experience
with these agents, there is increasing, albeit limited
observationsofsomedegreeofcrossresistance to these
classes of agents. Noonan and colleagues recently
reported on 30 patients from a number of centers
treatedwith enzalutamide on the phase III AFFIRM
study who were subsequently managed (off study)
with abiraterone+prednisone.
13
Of the 27 evaluable
patients, the median prior enzalutamide treatment
duration was 41 weeks (6-95 weeks). Subsequent
abiraterone + prednisone treatment durationwas 13
weeks (1-52). No objective radiographic responses
were observed, and the median abiraterone time to
progression (PSA, objectiveor symptomatic)was15.4
weekswith amedianoverall survival of 50.1weeks.
Schrader et al reportedon35patientswithmCRPC
treatedonanexpandedaccessprogramofenzalutamide.
All patients had previously received abiraterone and
docetaxel. In this group themediandurationof prior
abirateronetreatmentwas9months(2-19months)with
16 patients demonstrating greater than a 50%decline
in PSA as their best response. The median duration
of subsequent enzalutamide therapywas 4.9months.
Seven of 16 patients who were initially abiraterone-
sensitive (44%) and3of 19patientswhowere initially
abiraterone-insensitive (16%)experienceda>50%PSA
declinewhile takingenzalutamide.
14
Loriotandcolleaguesreportedtheutilityofabiraterone
in38mCRPCpatientspreviously treatedwithdocetaxel
andenzalutamide. Inthisexperienceonlythreepatients
(8%) attainedagreater than≥50%decline inPSA. The
medianprogression-freesurvival (PFS)was2.7months.
Of 12 patients assessable radio logically, only 1 (8%)
attainedaconfirmedpartial response.
15
In the near term, decisions regarding treatment
sequenceofnextgenerationandrogenreceptortargeted
agentswill remainempiric, informedby issuessuchas
drugavailabilitybothapproval statusand cost aswell
as physician experience with the individual agents.
Prospective studies are planned, including a United
States Intergroup study thatwill randomizedpatients
to thecombinationof enzalutamideplusabiraterone+
prednisoneversus enzalutamide.
Cyotoxics
Among thequestions regarding therapeuticsequence
in themanagement ofmCRPC is the evolving role of
the approved cytotoxic agents that have evidence of
