©TheCanadian Journal ofUrology™: International Supplement, April 2014
96
How to approach sequencing therapy inpatientswithmetastatic castration resistant prostate cancer
providingsurvivalbenefit,docetaxelandcabazitaxel.
7,16
As abirateronemoves into thepre-docetaxel space in
a number of countries around the world, docetaxel
and subsequently cabazitaxel’s usemoves further to
the right in the disease course. Although there are
some reports questioning whether prior abiraterone
impactson theresponserate todocetaxel, thisremains
a preliminary observation, worthy of prospective
evaluation.
17
Thequestionof taxanesequencing isalso
under investigation, with an ongoing phase III trial
randomizing patients withmCRPC to receive either
docetaxel or cabazitaxel (NCT01308567).
Radium223
Among the most intriguing questions of drug
sequencing involves the novel alpha emitter, radium
223,whichrecentlygainedFDAapproval for treatment
of patients with mCRPC with symptomatic bone
metastases and without known visceral disease. In
the phase III trial patients treated with radium 223
had a median survival of 14.9 months compared to
11.3 months in patients receiving a placebo (hazard
ratio, 0.70; 95%CI, 0.58 to0.83;p<0.001).
6
Of interest,
patientswereeligible for this trial if theyhad received
docetaxel, were not healthy enough or declined to
receive it, or itwas not available. Of the 614patients
randomized to radium 223, 262 (43%) didnot receive
prior docetaxel. The authors noted that this trial
incorporated patients that represent a substantial
number of similar patients who for one reason or
anotherdonot receivedocetaxel.
6,18
In addition to the impact on survival, patients
receiving radium 223 had a significantly prolonged
time to the first symptomatic skeletal event (defined
as first use of external-beam radiation therapy
to relieve skeletal symptoms, new symptomatic
pathologic vertebral or non-vertebral bone fractures,
spinal cordcompression,or tumor-relatedorthopedic
surgical intervention)median, 15.6monthsversus9.8
months.
6
Radium 223 was relatively well tolerated
with relativelymodestmyleosuppression, presenting
intriguingopportunities for combination therapy.
Conclusions
With the rapid introduction of multiple new agents,
the lack of clarity regarding the optimal integration
of these drugs into the management paradigm of
patientswithadvancedprostatecancer isunsurprising.
Prospective studies designed to inform clinicians
regarding the optimal sequence of new drugs are
uncommon inoncologyand in thenear termclinicians
will use best evidence and clinical experience along
with pragmatism i.e. is the drug approved in the
clinical settingand“canmypatient afford it” tomake
management decisions.
The emerging evidence of clinically meaningful
cross resistance in some patients between lyase
inhibitors such as abiraterone and next generation
androgen receptor antagonists such as enzalutamide
requiresprospectiveassessment tobetterunderstand
fromaclinicalperspectiveoptimal sequencingand to
improve the understanding of themolecular biology
of resistance to these agents.
The optimal timing of radium 223 administration
remainsundefined, although it seems clear that some
patientswith bone predominant diseasemay benefit
from itsuseprior todocetaxel administration.
Otherdrugssuchascabozantonib, ipilimumaband
custirsen are in late stage evaluation andmay in the
near termadd to thearmamentariumandquandaryof
managingpatientswithadvancedprostate cancer.
19-21
Disclosure
Dr.RobertDreicerreceivedhonoraria fromMillenium,
Bayer andMedivation.
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