The FDA approval of Jevtana is based primarily on the results of a randomized, open-label, international trial of 755 patients from 146 sites in 26 countries in Europe, USA, South America, and Asia Pacific regions. The study spanned January 2, 2007 to September 25, 2009. This study included patients over 18 years of age (range 49-62) with hormone-refractory metastatic prostate cancer either measurable by RECIST (Response Evaluation Criteria In Solid Tumors) criteria or non-measurable disease with rising PSA levels or appearance of new lesions, and ECOG (Eastern Cooperative Oncology Group) performance status 0-2. Patients had to have neutrophils >1,500 cells/mm3, platelets > 100,000 cells/mm3, hemoglobin > 10 g/dL, creatinine < 1.5 x upper limit of normal (ULN), total bilirubin < 1 x ULN, AST < 1.5 x ULN, and ALT < 1.5 x ULN. Patients with a history of congestive heart failure, or myocardial infarction within the last six months, or patients with uncontrolled cardiac arrhythmias, angina pectoris, and/or hypertension were not included in the study. Patients were randomized to receive either cabazitaxel 25 mg/m2 intravenously every three weeks in combination with prednisone 10 mg/day, or mitoxantrone 12 mg/m2 intravenously every three weeks in combination with prednisone 10 mg/day. Patients were treated until disease progression, death, unacceptable toxicity, or completion of 10 cycles of therapy.
Median survivals were 15.1 and 12.7 months for cabazitaxel-treated and mitoxantrone-treated patients, respectively [HR 0.70 (95% CI 0.59-0.83), p<0.0001.] Investigator-assessed response rates using RECIST criteria was 14.4 and 4.4% for cabazitaxel-treated and mitoxantrone-treated patients, respectively, p=0.0005. No complete responses were observed on either arm.
The most common (≥10%) grade 1-4 adverse reactions included neutropenia, anemia, leukopenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea, dysgeusia, cough, arthralgia and alopecia. The most common (≥5%) grade 3-4 adverse reactions were neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, fatigue and asthenia.
Deaths due to causes other than disease progression within 30 days of the last dose were reported in 18 (5%) cabazitaxel-treated patients and three (<1%) mitoxantrone-treated patients. The most common fatal adverse reactions in cabazitaxel-treated patients were infections (n=5), and renal failure (n=4). One death was due to diarrhea-induced dehydration and electrolyte imbalance.
Because of the risk of severe hypersensitivity, patients should be premedicated with an antihistamine, a corticosteroid and an H2 antagonist. In addition, antiemetic prophylaxis is recommended.
The National Comprehensive Cancer Network (NCCN) panel recommendations include cabazitaxel as an option for second-line therapy after docetaxel failure for men with mHRPC. The NCCN advises physicians to follow current guidelines for prophylactic white blood cell growth factor use; to provide supportive care, including antiemetics and symptom-directed anti-diarrheal agents; and to stop cabazitaxel upon clinical disease progression or intolerance. In addition, cabazitaxel has not been tested in patients with hepatic dysfunction and should not be used on these patients.