The year 2010 was an encouraging time for prostate cancer patients, as
significant strides in research led to the FDA approval of two new agents,
sipuleucel-T and cabazitaxel.
Until recently, only docetaxel-based regimens had demonstrated an
improvement on OS in patients with metastatic castration-resistant prostate
cancer (mCRPC), making docetaxel plus prednisone the standard first-line
regimen for this disease. No standard treatment alternatives have been
available for patients who progress on docetaxel therapy. Recognizing this
unmet need, researchers have focused their efforts on developing new drugs that
may extend survival in these individuals.
Cabazitaxel (Jevtana, Sanofi-Aventis) was approved by the FDA on June
17, in combination with prednisone for patients with mCRPC who were previously
treated with a docetaxel-containing regimen. Cabazitaxel is a semisynthetic
taxane. Similar to docetaxel and paclitaxel, it functions as a microtubule
inhibitor and binds to tubulin, leading to microtubule stabilization,
inhibition of mitosis and cell death.
Unlike the other taxanes, cabazitaxel exhibits poor affinity for
P-glycoprotein-mediated efflux pumps. Docetaxel and paclitaxel are particularly
susceptible to these efflux pumps, and this accounts for the development of
taxane resistance in tumors with P-glycoprotein overexpression; therefore,
cabazitaxel may benefit patients with demonstrated taxane resistance. Because
P-glycoprotein pumps are also prevalent in the blood brain barrier, cabazitaxel
penetrates the blood brain barrier to a greater extent than docetaxel and
paclitaxel, thus potentially augmenting its ability to target metastatic brain
After phase 1 trials demonstrated cabazitaxel dose-limiting neutropenia
at a dose of 25 mg/mg2, phase 2 trials were conducted at 20
mg/m2 administered every 3 weeks. In one phase 2 trial with
metastatic breast cancer patients, nearly one-third (28%) of patients were able
to safely escalate their dose to 25 mg/m2 after one cycle.
Therefore, subsequent phase 3 trials in patients with mCRPC were designed
utilizing a dose of 25 mg/m 2 with a rigorous dose-reduction
Only one phase 3 trial (TROPIC trial) has been reported to date and was
the basis for the FDAs expedited approval in 2010. In this trial,
patients with mCRPC who had previously received docetaxel were randomly
assigned prednisone daily with IV cabazitaxel 25 mg/m2 or IV
mitoxantrone 12 mg/m2 every 3 weeks. Cabazitaxel significantly
improved OS by 2.4 months compared with mitoxantrone (15.1 months vs. 12.7
months; P<.0001). Patients in the cabazitaxel arm also had
significantly greater PFS, tumor response rates and PSA response rates.
Other trials investigating cabazitaxels role in mCRPC are required
by the FDA for sustained approval, including a dosing trial comparing
cabazitaxel 20 mg/m2 to 25 mg/m2 (both in combination
with prednisone), and a head-to-head phase 3 trial comparing docetaxel plus
prednisone with cabazitaxel plus prednisone as first-line therapy for mCRPC.
Ongoing clinical trials are also evaluating the efficacy of cabazitaxel
combined with other cytotoxic agents and for other cancer types (eg, breast and
Myelosuppression appears to be dose-limiting with cabazitaxel and is
more pronounced in patients who have received several prior chemotherapy
regimens. Neutropenia is common and occurred in nearly all patients who
received cabazitaxel combined with prednisone in the TROPIC trial (94%, all
grades; 82%, grade 3 or 4). However, similar to other taxanes, neutrophils
recover rapidly, and only 8% of patients experience febrile neutropenia.
Nonetheless, clinicians may want to consider the use of prophylactic growth
factors in patients who are elderly, have extensive prior chemotherapy, have
poor performance or nutritional status, or possess other known risk factors for
In the TROPIC trial, anemia also occurred in nearly all patients (97%).
However, only 11% of patients had grade 3 or 4 anemia. Thrombocytopenia was
also frequently encountered (47%) but was seldom severe (4%, grade 3 or 4).
Caution should be used when adding myeloid growth factors because this may
exacerbate anemia and thrombocytopenia in patients whose blood cell lineages
are already compromised.
Compared with the other taxanes, cabazitaxel appears to be less
neurotoxic, with only 14% of patients experiencing peripheral neuropathy (1%,
grade 3). Fluid retention also appears to be less frequently encountered with
cabazitaxel (9%, all grades). However, the maximum number of cycles allowed in
the TROPIC trial was 10, limiting detection of a cumulative neuropathy that may
be seen with additional cycles. At the very least, neuropathy associated with
cabazitaxel appears to be more delayed compared with docetaxel. Other adverse
effects that are similar to the other taxanes include diarrhea (47%), fatigue
(37%), nausea (34%), vomiting (23%) and asthenia (20%). See Table 1 for a
detailed list of adverse effects.
The recommended cabazitaxel dose is 25 mg/m2 administered
intravenously for 60 minutes every 3 weeks with prednisone 10 mg orally daily.
Although there have been no dedicated studies analyzing cabazitaxels
safety in organ impairment, cabazitaxel is minimally excreted via the kidney
and should be safe to use in patients with mild to moderate renal impairment.
Cabazitaxel undergoes extensive metabolism in the liver, so patients with
hepatic impairment may have increased serum drug concentrations.
The manufacturer recommends avoiding cabazitaxel in patients with serum
total bilirubin of at least the upper limit of normal or an aspartate
aminotransferase or alanine aminotranferease level of at least 1.5 times the
upper limit of normal. Ongoing trials are examining the use of cabazitaxel in
patients with liver dysfunction. Liberal dose reduction should be undertaken if
the patient experiences grade 3 or 4 myelosuppression, diarrhea or other severe
Cabazitaxel is primarily metabolized via cytochrome P450 3A4 (CYP3A4)
and may be affected by strong inducers or inhibitors of this enzymatic pathway.
No formal studies have been conducted evaluating drug-drug interactions with
cabazitaxel and their clinical implications. Strong CYP3A4 inhibitors may
increase cabazitaxel concentration and worsen toxicities, whereas strong CYP3A4
inducers may decrease cabazitaxel concentration and efficacy. There are
currently no recommendations from the FDA regarding empiric cabazitaxel dose
adjustments; however, concomitant administration of cabazitaxel with these
agents should be approached with caution.
Similar to docetaxel, cabazitaxel is relatively insoluble in water and
is therefore formulated in polysorbate-80. This vehicle may lead to
hypersensitivity reactions during chemotherapy infusion.
To minimize the incidence and severity of hypersensitivity reactions,
studies with cabazitaxel included premedications with an antihistamine, steroid
and an H2 antagonist. A popular regimen used in the US is IV
diphenhydramine 25 mg, dexamethasone 8 mg and famotidine 20 mg, given 30
minutes before administration of cabazitaxel. As with other taxanes,
cabazitaxel administration requires non-polyvinyl chloride bags, tubing, and
connectors and a 0.22-mcm inline filter. Unfortunately, there is no real
advantage to cabazitaxel over the other taxanes in this regard.
Cabazitaxel fills a gap in the prostate cancer treatment algorithm by
offering an FDA-approved regimen for patients who have progressed on first-line
docetaxel. Patients who have received multiple chemotherapy regimens after
progressing on docetaxel may also be candidates for cabazitaxel therapy.
However, these patients may be at greater risk for myelosuppression.
Cabazitaxel may also limit the selection of successive chemotherapy regimens.
It is imperative that clinicians exercise clinical judgment and consider
patient characteristics when deciding whether cabazitaxel is a suitable
treatment option. Studies have yet to determine if cabazitaxel may have greater
benefit when used first-line before docetaxel.
The increased survival benefit demonstrated with cabazitaxel use is not
without costs, including adversely affecting patients quality of life and
creating a possible financial burden. Compared with other chemotherapy regimens
for mCRPC, cabazitaxel is significantly more costly (see Table 2). Fortunately,
Sanofi-Aventis offers a patient assistance program (PACT+) through which
qualified patients may receive financial assistance.
Cabazitaxel is a recently FDA-approved chemotherapy agent for the
second-line treatment of mCRPC after docetaxel therapy. Although it offers the
hope of prolonged survival, cabazitaxel also carries significant hematological
toxicities that may outweigh its benefits. Additional studies will better
elucidate the role of cabazitaxel in combination therapy and other clinical
Adrienne H. Tam, PharmD, BCPS, is a clinical pharmacist at MD
Anderson Cancer Center.
Laura Boehnke Michaud, PharmD, BCOP, FASHP, is manager of Clinical
Pharmacy Services at MD Anderson Cancer Center.
Disclosures: The authors report no relevant financial
For more information:
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- Galsky MD. Nat Rev Drug Discov. 2010;9:677-678.
- Mita AC. Clin Cancer Res. 2009;15:723-730.
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- Pivot X. Ann Oncol. 2008;19:1547-1552.
- Tannock IF. N Engl J Med. 2004;351:1502-1512.