Cabazitaxel: Just another taxane for prostate cancer?

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 lesions.

Clinical efficacy

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 strategy.

Only one phase 3 trial (TROPIC trial) has been reported to date and was the basis for the FDA’s 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 cabazitaxel’s 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 lung cancers).

Tolerability

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 febrile neutropenia.

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.

Dosing and administration

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 cabazitaxel’s 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 adverse effects.

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.

Place in therapy

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.

Conclusion

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 settings.

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 disclosures.

For more information:

• De Bono JS. Lancet. 2010;376:1147-1154.
• Galsky MD. Nat Rev Drug Discov. 2010;9:677-678.
• Mita AC. Clin Cancer Res. 2009;15:723-730.
• Pazdur R. NDA 201023 approval letter. FDA website.
• Pivot X. Ann Oncol. 2008;19:1547-1552.
• Tannock IF. N Engl J Med. 2004;351:1502-1512.