©TheCanadian Journal ofUrology™: International Supplement, April 2014
80
Practical guide to theuseof chemotherapy in castration resistant prostate cancer
deathbymicrotubule stabilization through inhibition
of disassembly. Cabazitaxel binds the N-terminal
aminoacidsof thebeta-tubulinsubunit,andpromotes
stabilizationofmicrotubules and themitotic spindle.
Inaddition toactivityagainstpaclitaxelanddocetaxel
sensitive human cervical, breast, and leukemia and
prostate cancer cell lines, cabazitaxel demonstrates
activity in taxaneresistantcell lines.
25
Theexplanation
for this pattern of activity stems from cabazitaxel’s
effecton theeffluxpumpofp-glycoprotein, known to
beresponsible for themultidrugresistancephenotype.
Expressed in a variety of human tumors including
prostate cancer, p-glycoprotein is responsible for
the adenosine-5
′
-triphosphate (ATP) dependent
extrusion of natural product chemotherapeutic
agents such as doxorubicin, vinca alkaloids, as well
aspaclitaxel anddocetaxel. The extramethyl groups
found on cabazitaxel are more effective against the
ATP dependent efflux pump of p-glycoprotein than
similarly placed hydrol groups on docetaxel and
paclitaxel. Thisphenomenonmayalsoberesponsible
for thedisproportional increaseCNSaccumulationof
cabazitaxel with increasing plasma concentrations,
demonstrated in rodent models; p-glycoprotein is
known tobeexpressed in thecapillaryendotheliumof
the brain andmaybe responsible for the blood-brain
barrier.
26
Phase I studyof cabazitaxel
Mitaetalconductedaphase1study in25patientswith
chemotherapy refractory solid tumors. Cabazitaxel
was administered at four dose levels (10, 15, 20, and
25 mg/m
2
) as an intravenous (IV) infusion every 3
weeks. Of the eight CRPC patients entered on the
trial, two, previously treated with mitoxantrone
and docetaxel, demonstrated partial responses in
soft tissue lesions to 15 mg/m
2
and 25 mg/m
2
, of
cabazitaxel, respectively. Both also manifested
>50%declines inPSA. Athirdprostatecancerpatient
demonstrated a minor response. Neutropenia was
the major dose limiting toxicity observed, with two
patientsdemonstratingprolongedgrade4neutropenia
at 25 mg/m
2
, and another demonstrating febrile
neutropenia at the same dose level.
27
In contrast to
patients treatedwithdocetaxel,fluidretentionwasnot
observedwithcabazitaxel treatment. Thecommonest
non-hematologic toxicities observed were diarrhea
(52%),nausea (40%),andvomiting (16%). Theauthors
concluded that20mg/m
2
of cabazitaxel administered
every 3weeks as the recommendedphase II dose. It
is to be noted that prophylactic granulocyte colony
stimulating factor (GCSF)wasnot administered.
Phase III studies of cabazitaxel in docetaxel
pretreatedCRPCpatients
The activity of cabazitaxel demonstrated against
taxane resistant cell lines, as well as the responses
observed in phase I lead investigators to study
cabazitaxel inmenwith castration resistant prostate
cancerpreviouslytreatedwithdocetaxel. TheTROPIC
trial randomized 755 men to either cabazitaxel
25mg/m
2
Q3weeks ormitoxantrone 12mg/m
2
Q3
weeks. Prednisone 5mg POBIDwas administered
in both arms.
28
All patients were required to have
progressivedisease as evidencedbyRECIST criteria
or two consecutive rising PSAs at least 1 week
apart inpatientswithnon-measurable disease. The
median age of patients entered in the metastatic
study was 68. Amedian dosage of 529.2 mg/m
2
and 576.6 mg/m
2
of docetaxel were administered
in the cabazitaxel and mitoxantrone/prednisone
arms, respectively. Two ormore cytotoxic regimens
werepreviouslyadministered to29%and31%of the
patientsenteredon themitoxantroneandcabazitaxel
arms, respectively. Nearlyhalfof thepatientsentered
in the trial had symptomatic bonepain,with 25%of
patients demonstratingvisceralmetastases.
After a median follow up of 12.5 months, a 3.1
month improvement inmediansurvivalwasnoted in
favor of cabazitaxel treatment, with a hazard ratio of
0.7. At amedian followup of 25.5months, 15.9% of
thecabazitaxelpatientssurvived>2yearscompared to
8.2%ofpatientstreatedwithmitoxantrone. Asubgroup
analysis demonstrated that the survival benefit of
cabazitaxel over mitoxantrone was maintained in
patients who discontinued docetaxel for disease
progressioncompared to thosewhostoppeddocetaxel
due to toxicity, completion of 10 cycles of treatment,
or forotherreasons.
19
Althoughpatient selectionmay
play a role, themedian survival from the time of the
first docetaxel dose in the cabazitaxel groupwas 29
months (95%CI 27-31) versus 25months (95%CI 23-
28) in themitoxantronegroup. PSAdeclinesof>50%
andobjectiveresponseratesweresuperior (39.2%and
14.4%) in the cabazitaxel armwhen compared to the
mitoxantrone arm (17.8% and 4.4%). The palliation
ratesusing thePPI,were similar inboth arms.
Neutropeniawas themostcommonlyencountered
toxicity, with grade 3 or higher events occurring in
82% of patients treated with cabazitaxel. Febrile
neutropenia was observed in 8% of patients. The
prevalence of cabazitaxel induced neutropenia
increaseswithage, andwasobservedata6.6%higher
rate in patients over the age of 65. Grade 3 diarrhea
wasobserved in6%ofpatientson thecabazitaxelarm
