What is Cabazitaxel
Cabazitaxel is a semisynthetic taxane chemotherapy agent that improves survival in metastatic castration-resistant prostate cancer (mCRPC) after docetaxel failure, providing a median 2.4-month survival benefit but serving as palliative rather than curative therapy. 1
Drug Classification and Mechanism
Cabazitaxel is an antineoplastic agent belonging to the taxane class, prepared by semi-synthesis with a precursor extracted from yew needles. 2 It functions as a microtubule inhibitor that binds to tubulin and promotes its assembly into microtubules while simultaneously inhibiting disassembly, leading to stabilization of microtubules and inhibition of mitotic and interphase cellular functions. 2
A key distinguishing feature is cabazitaxel's poor affinity for P-glycoprotein (P-gp), an ATP-dependent drug efflux pump. 3 This characteristic allows cabazitaxel to retain activity in docetaxel-resistant tumors, as cancer cells expressing P-gp become resistant to taxanes with high P-gp substrate affinity like docetaxel. 3
Clinical Indications and Positioning
Cabazitaxel is FDA-approved and designated as a Category 1 preferred option specifically after progression on both docetaxel and a novel hormone therapy in patients with mCRPC. 1 The NCCN guidelines position it as a later-line palliative treatment following docetaxel failure, not as curative therapy. 4
The FIRSTANA study demonstrated that cabazitaxel has clinical activity in chemotherapy-naïve mCRPC patients, with median overall survival similar between cabazitaxel doses and docetaxel (24.5-25.2 months vs 24.3 months). 1 However, the NCCN panel does not currently recommend cabazitaxel in docetaxel-naïve patients. 1
Survival Benefits and Realistic Expectations
The pivotal TROPIC trial demonstrated that cabazitaxel 25 mg/m² improved median overall survival to 15.1 months compared to 12.7 months with mitoxantrone (HR 0.72, P<0.0001), representing a 2.4-month improvement and 30% reduction in mortality risk. 1, 5
In heavily pretreated patients, the CARD study showed cabazitaxel improved median overall survival to 13.6 months versus 11.0 months with abiraterone/enzalutamide (HR 0.64, P=0.008) in patients who had previously received docetaxel and either abiraterone or enzalutamide. 1, 4
The PROSELICA trial found that even with optimal dosing, median survival was only 13.4-14.5 months, with 83% of patients dying during follow-up, confirming that cabazitaxel is not curative. 4 Treatment provides palliative benefits including improved pain response and delayed time to skeletal-related events, but these are temporary measures. 4
Dosing Recommendations
Cabazitaxel at 20 mg/m² every 3 weeks, with or without growth factor support, is the recommended dose for fit patients. 1 The PROSELICA study demonstrated this lower dose was noninferior to 25 mg/m² for median overall survival (13.4 vs 14.5 months), while grade 3-4 adverse events were significantly decreased (39.7% vs 54.5%). 1
Cabazitaxel at 25 mg/m² may be considered for healthy patients who wish to be more aggressive. 1 The drug is administered as a 1-hour intravenous infusion every 3 weeks. 5
Required Supportive Care
Cabazitaxel must be given with concurrent steroids (daily prednisone or dexamethasone on the day of chemotherapy). 1 Physicians should follow current guidelines for prophylactic white blood cell growth factor use, particularly in this heavily pretreated, high-risk population. 1
Primary prophylaxis with G-CSF is essential to manage the high risk of neutropenic complications. 4 Additional supportive care should include antiemetics (prophylactic antihistamines, H2 antagonists, and corticosteroids prophylaxis) and symptom-directed antidiarrheal agents. 1
Toxicity Profile and Safety Considerations
Grade 3-4 adverse events occur in 39.7-54.5% of patients, with the toxic death rate at 4.9%. 1, 4 The most common grade 3-5 adverse events include fatigue, anemia, neutropenia, and thrombocytopenia. 1
Grade ≥3 neutropenia rates were 41.8% with 20 mg/m² and 73.3% with 25 mg/m² dosing. 1 Febrile neutropenia was observed in 7.5% of cabazitaxel-treated patients in the TROPIC trial. 1 The incidences of severe diarrhea (6%), fatigue (5%), nausea/vomiting (2%), anemia (11%), and thrombocytopenia (4%) were higher with cabazitaxel compared to mitoxantrone. 1
Cabazitaxel was associated with lower rates of peripheral sensory neuropathy than docetaxel, particularly at 20 mg/m² (12% vs 25%). 1
Special Populations and Contraindications
Patients with mild hepatic impairment (total bilirubin >1 to ≤1.5 × ULN or AST >1.5 × ULN) should receive a reduced cabazitaxel dose of 20 mg/m². 2 The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 to ≤3.0 × ULN) was 15 mg/m², though efficacy at this dose is unknown. 2
Cabazitaxel is contraindicated in patients with severe hepatic impairment (total bilirubin >3 × ULN). 2 No dose adjustment is necessary in patients with renal impairment not requiring hemodialysis, though patients with end-stage renal disease should be monitored carefully. 2
Combination Therapy Option
Cabazitaxel 20 mg/m² plus carboplatin AUC 4 mg/mL per minute with growth factor support can be considered for fit patients with aggressive variant mCRPC (visceral metastases, low PSA with bulky disease, high lactate dehydrogenase, high carcinoembryonic antigen, lytic bone metastases, neuroendocrine histology) or unfavorable genomics (defects in at least 2 of PTEN, TP53, and RB1). 1 In these patients, median progression-free survival was 7.3 months with combination therapy versus 4.5 months with cabazitaxel alone (HR 0.69, P=0.018). 1
Treatment Discontinuation
Treatment should be stopped upon clinical disease progression or intolerance, acknowledging that progression is inevitable. 1, 4