New Agents for the Management of Castration-Resistant Prostate Cancer

Robert J Cersosimo PharmD BCOP

Disclosures

The Annals of Pharmacotherapy. 2012;46(11):1518-1528. 

In This Article

Cabazitaxel

Mechanism of Action

Cabazitaxel is indicated for use in combination with prednisone for treatment of patients with metastatic CRPC previously treated with a docetaxel-containing regimen.[22] Cabazitaxel is a member of the taxane family, which includes paclitaxel and docetaxel. Cabazitaxel binds to tubulin and promotes assembly into microtubules and inhibits disassembly, resulting in stabilization of microtubules, which interferes with mitotic and cellular interphase activity.[22]

Pharmacokinetics

The pharmacokinetics of cabazitaxel were evaluated in a Phase 1 trial of 25 patients with advanced cancer.[9] Patients received a total of 102 courses of therapy at doses of 10–25 mg/m2. A triphasic model with mean half-lives of 2.6 minutes, 1.3 hours, and 77.3 hours described elimination of cabazitaxel from the plasma. The volume of distribution at steady-state was 2034 L/m2, suggesting extensive extravascular distribution, and the mean clearance was 53.5 L/h, representing 61% of hepatic blood flow. There were no significant changes in the pharmacokinetic parameters among patients who received multiple doses, implying no accumulation or autoinduction. Cabazitaxel is metabolized in the liver primarily by the CYP3A4/5 isoenzymes and to a lesser extent by the CYP2C8 enzymes.[22] Although no formal drug interaction studies have been performed, the manufacturer recommends that coadministration of cabazitaxel and strong inhibitors or strong inducers of CYP3A enzymes should be avoided.[22]

Administration

Cabazitaxel is supplied in vials containing 60 mg/1.5 mL. It is administered intravenously as a 60-minute infusion. It should be administered through an in-line filter of 0.22-μm nominal pore size. The recommended dose is 25 mg/m2 administered every 3 weeks along with prednisone 10 mg daily. Patients should be premedicated at least 30 minutes before treatment with the following intravenous medications: an antihistamine such as diphenhydramine 25 mg or equivalent, an H2 antagonist such as ranitidine 50 mg or equivalent, and a corticosteroid such as dexamethasone 8 mg or equivalent to reduce the risk and/or severity of a hypersensitivity reaction. Subsequent doses should be reduced to 20 mg/m2 if the patient experiences grade 3 or greater neutropenia that persists for more than 1 week despite administration of G-CSF, febrile neutropenia, or grade 3 or greater persistent diarrhea despite administration of appropriate medication, fluid, and electrolyte replacement.[22]

The NCCN states that patients receiving cabazitaxel should follow guidelines for white blood cell growth factor use, especially if the patient has been heavily pretreated.[6] Supportive care should include antiemetics and symptom-directed antidiarrheal agents.

Clinical Activity

Cabazitaxel and prednisone were compared to mitoxantrone plus prednisone in the TROPIC (Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resitant prostate cancer progressing after docetaxel treatment: a randomised open-label trial) study, a randomized open-label trial of 755 men with metastatic CRPC.[23] All patients had progressed during or after docetaxel treatment. Eligible patients had to have an ECOG performance status of 0–2; 91% of patients randomized to receive mitoxantrone and 93% of patients randomized to receive cabazitaxel had a performance status of 0–1. Visceral disease, a negative prognostic factor, was present in 25% of the patients. The median ages of patients who received mitoxantrone and cabazitaxel were 67 and 68 years, respectively. All patients received prednisone 10 mg daily and were randomized to receive intravenous mitoxantrone 12 mg/m2 over 15–30 minutes (n = 377) or intravenous cabazitaxel 25 mg/m2 over 60 minutes (n = 378) every 3 weeks. The primary end point was overall survival calculated from randomization to death. Secondary end points were progression-free survival (from randomization to progression), PSA response (≥50% reduction in serum PSA concentration in patients with a baseline value ≥20 μg/L), PSA progression (increase of ≥25% over nadir PSA concentrations provided that the increase in the absolute value of PSA was ≥5 μg/L for men with no PSA response or ≥50 μg/L over nadir for PSA responders), tumor response, pain response, pain progression, and time to tumor progression (from randomization to progression).

Median overall survival was 12.7 months in the mitoxantrone group and 15.1 months in the cabazitaxel group, a gain of 2.4 months. The hazard ratio for death in men treated with cabazitaxel versus those treated with mitoxantrone was 0.70 (95% CI 0.59 to 0.83; p < 0.0001), which corresponded to a 30% reduction in the relative risk of death. Among patients with measurable disease, the tumor response rates with mitoxantrone and cabazitaxel regimens were 4.4% and 14.4%, respectively (p = 0.0005). The respective PSA response rates for mitoxantrone and cabazitaxel regimens were 17.8% and 39.2% (p = 0.0002) and the respective pain response rates were 7.7% and 9.2% (p = 0.63). Median progression-free survival was 1.4 months with mitoxantrone and 2.8 months with cabazitaxel (p < 0.0001). In the intention-to-treat analysis there was a significantly longer median time to tumor progression (8.8 vs 5.4 months; p < 0.0001) and median time to PSA progression (6.4 vs 3.1 months; p = 0.001) in favor of cabazitaxel. This was the first study to demonstrate a significant improvement in overall survival in patients with metastatic CRPC after prior docetaxel treatment.[23]

Adverse Effects

The following grade 3–4 adverse effects were reported in greater than or equal to 5% of patients who received cabazitaxel versus mitoxantrone, respectively, in the TROPIC trial: neutropenia (82% vs 58%), febrile neutropenia (8% vs 1%), anemia (11% vs 5%), leukopenia (68% vs 42%), diarrhea (6% vs <1%), fatigue (5% vs 3%), and asthenia (5% vs 2%).[22] Diarrhea was more common in patients aged 75 years or older (55.7% vs 44.5%; p < 0.1) and in patients who had undergone prior radiation therapy (50.0% vs 41.4%; p < 0.1).[24] There were no differences in diarrhea or neutropenia in subgroups identified by race, baseline liver or renal function, performance status, or prior chemotherapy. Neutropenia was more common in patients aged 65 years or older (24.2% vs 17.6%). The incidence of neutropenia reported with cabazitaxel necessitates careful monitoring of blood counts and use of G-CSF, if needed. Primary prophylaxis with G-CSF has been suggested for patients at high risk for neutropenia (age >65 years, poor performance status, prior febrile neutropenia, extensive prior radiation therapy, poor nutritional status, and other serious comorbidities).[22,24] Cabazitaxel is contraindicated in patients with a neutrophil count of less than or equal to 1500/mm3.[22] A Phase 3 clinical trial comparing the efficacy and toxicity of cabazitaxel 20 mg/m2 plus prednisone versus cabazitaxel 25 mg/m2 plus prednisone (PROSELICA) is underway.[25]

Peripheral neuropathy was reported in 14% of patients who received cabazitaxel and 3% who received mitoxantrone; however, grade 3 peripheral neuropathy was reported in only 1% of patients who received each drug.[26] There were 18 deaths in the cabazitaxel group (5%) and 9 (2%) in the mitoxantrone group within 30 days of the last dose. Neutropenia and its clinical consequences was the most common cause of death among cabazitaxel patients (n = 7 [2%]) compared with mitoxantrone patients (n = 1 [<1%]), followed by cardiac events (n = 5 [1%] vs n = 0). The fatal cardiac events were cardiac arrest (n = 3), sudden death (1), and ventricular fibrillation (1), none of which were considered to be drug related by the investigators.

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