©TheCanadian Journal ofUrology™: International Supplement, April 2014
79
Petrylak
objective response rates were observed in the three
treatment arms. Docetaxel therapy was associated
withsuperiorpalliationofbonepain (33%and31% in
the docetaxel every 3weeks andweekly regimens as
compared to21% in themitoxantronegroup). Quality-
of-life, ingeneral,whenusing theFACT-P instrument
was significantly better in the docetaxel groups as
compared to themitoxantronegroup.
Neutropenia was more frequent in the Q3 week
docetaxel group (32% compared to 21.7% in the
mitoxantrone group). Grade 3 and 4 neutropenia
occurred in 3% of patients in the docetaxel Q3week
group, with 2.7% experiencing febrile neutropenia.
Neuropathy and alopeciawere alsomore frequent in
the docetaxel arms; however the patterns of toxicity
werenot significantlydifferentbetween thedocetaxel
andmitoxantronegroups.
SWOG lead an intergroup study comparing
docetaxel/estramustinetomitoxantrone/prednisone.
18
Men randomized to the experimental arm received
estramustine at 280mgPO tidondays 1-5, docetaxel
at 60 mg/m
2
IV on day 2 every 21 days, and
dexamethasone 60 mg PO in 3 divided doses prior
to docetaxel. In contrast to TAX 327, patients did
not receive prednisone. Men randomized to the
control mitoxantrone arm received mitoxantrone at
the same dosage and schedule as in TAX 327. Dose
escalation to docetaxel 70 mg/m
2
or mitoxantrone
14mg/m
2
was permitted for those patientswho did
not experience grade 3 or 4 toxicity in the first cycle
of therapy. Docetaxel combined with estramustine
improved median survival (17.5 months compared
to 15.6 months, p = 0.01), progression-free survival
(6.3 months compared to 3.2 months, p < 0.001). A
greater percentage of patients demonstrated a > 50%
PSAdecline (50% as comparedwith 27%, p< 0.0001)
with docetaxel/estramustine than mitoxantrone/
prednisone. A trend towards an improved rate of
objective responses inmeasurable soft tissue disease
wasnoted in favorofQ3weekdocetaxel (17%versus
11%, p = 0.030). In addition, palliation of bone pain
was not found to be statistically different in the two
arms. Overall, the relative riskof deathwas reduced
by20%withdocetaxel andestramustineascompared
tomitoxantrone andprednisone (HR for death, 0.80;
95%CI: 0.67-0.97).
Grade 3 and 4 toxicities was reported at higher
rates in the docetaxel prednisone arm compared to
mitoxantrone/prednisone. The incidence of grade
3 or 4 cardiovascular (15% versus 7%, p = 0.001),
neurological (7% versus 2%, p = 0.001), neutropenic
fever (5%versus 2%, p<0.001), gastrointestinal (20%
versus 5%, p < 0.001), and metabolic disturbances
(6% versus 1%, p < 0.001) were increased in the
experimental arm. However, therewas not a higher
rate of discontinuation from the study and there
was no increase in toxic deaths in the docetaxel/
estramustinearm. Prophylacticanticoagulationwith
Coumadinandaspirinwasadded to theexperimental
armapproximatelyhalfway through the trial. Apost-
hoc analysis of toxicity revealed that anticoagulation
decreased the rateof cardiac ischemiabutnot the rate
of thrombosis. However, the evaluationof theuseof
anticoagulation is limitedas the trialwasnotdesigned
to detect a difference in vascular events for patients
using anticoagulation as compared to thosewhodid
not receiveCoumadin and aspirin.
Docetaxel based investigational therapies
Anumber of novel agents havebeen investigated for
combinationwithdocetaxel inanattempt to improve
survival and response in patients with CRPC. The
resultswithdocetaxel-basedcombinationtherapyhave
been disappointing. Although serum VEGF levels
correlate inversely with survival, antiangiogenesis
agents (bevacizumab,
19
aflibercept,
20
lenalidomide,)
combinedwith docetaxel/prednisone have not been
a therapeuticadvance. Combinationsofbone targeted
agent such as atrasentan,
21
dasatinib,
22
andZD4054
23
with docetaxel have also had disappointing results.
VitaminD (calcitriol, DN-101 combinedwithweekly
docetaxel also demonstrates no survival advantage
over docetaxel/prednisone.
24
Reasons for the failure
of combination therapy include marginal activity of
theagents thatwerecombinedwithdocetaxel, aswell
as dose reduction of docetaxel due to overlapping
toxicities.
Cabazitaxel
Granted fast trackdesignation inNovember of 2009,
cabazitaxel combinedwithprednisonewasapproved
by theFDA in June2010 for the treatmentofmenwho
hadpreviouslyreceivedadocetaxel-basedregimen for
CRPC. Cabazitaxel is the third cytotoxic agent to be
approvedby theFDA for castration resistant disease,
and thesecond todemonstrateasurvivalbenefitover
mitoxantrone combinedwithprednisone.
Mechanismof action
Similar in structure and antitumor mechanism to
paclitaxelanddocetaxel, cabazitaxel isanovelsecond-
generation, semisynthetic taxane that induces cell
