©TheCanadian Journal ofUrology™: International Supplement, April 2014
82
Practical guide to theuseof chemotherapy in castration resistant prostate cancer
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Sequencingof treatments
With therecentapprovalsofabiraterone,
30
radium223,
31
sipuleucel T
32
in the pre-docetaxel space, given the
relativelackoftoxicityoftheaforementionedtreatments,
chemotherapy potentially could be administered
later in the course of disease. It is unclear whether
administration of any of these agents before either
docetaxel or cabazitaxel affects efficacy and toxicity of
thesecytotoxicagents. Retrospectivestudieshavebeen
performed in small, select groups of patients and are
difficult toapply to individual treatmentdecisions. For
example, thepreclinicalobservation thatdocetaxelmay
actuallyhavecrossresistancewithhormonalagentsdue
todocetaxelinhibitionof androgenreceptortranslocation
theoretically could make taxanes less effective after
administration of abiraterone or enzalutamide.
33,34
Pond et al found that patients previously treatedwith
ketoconazole/hydrocortisone in a randomized trial of
docetaxel+/- AT-101, a novel bcl-2 inhibitor, trended
towards bursting overall survival, objective response
rates,andPSAdeclinescompared to thosepatientswho
had not received prior ketoconazole/hydrocortisone.
35
Inaretrospectiveevaluationof35patientswhoreceived
docetaxel after abiraterone treatment, the median
survival was 12.5 months, significantly lower than
what was observed in TAX 327. Patients refractory
to abiraterone were also refractory to docetaxel. In a
small subgroup of patients treated with cabazitaxel
after abiraterone alone, abiraterone followed by
enzalutamide, or in enzalutamide alone, 16/41(39%)
of patients demonstrated a > 50% PSAdecline, with a
median survival of 15.8months.
36
Clearly, prospective
randomized trials are needed, utilizing biomarkers, to
determine theoptimal sequenceof theseagents forboth
survival and toxicity.
Conclusions
Bothdocetaxel and cabazitaxel have antitumor activity
in chemotherapy naïve and chemotherapy pre-treated
patients, respectively. Combination therapy with
docetaxelhasnotresultedinincreasedsurvival.Although
randomized trials are currently underway to define
which of these two agents should be administered as
front linetherapy, theoptionalsequencesoftheseagents
withneweragentssuchasabiraterone,enzalutamideand
radium223haveyet tobedefined.
Disclosure
Dr.DanielP.Petrylak hasconsultedforBayer,Bellicum,
Dendreon, Sanofi Aventis, Johnson and Johnson,
Exelixis, Ferring, Millineum, Medivation and Pfizer.
He has also received grant support fromOncogenix,
Progenies, Johnsonand Johnson,Millineum,Celgene
andDendreon.
