Background
Phase III, open-label RCT. 255 patients with mCRPC who had previously received docetaxel AND progressed within 12 months of receiving either abiraterone or enzalutamide (the other ARPI was allowed prior to study entry). Cabazitaxel compared to the alternative ARPI switch (abi→enza or enza→abi) to test whether chemotherapy outperforms sequential ARPI use after prior ARPI + docetaxel failure.
Interventions and follow up
Arm A: Cabazitaxel 25mg/m² IV q3wk + prednisone 10mg/day (max 10 cycles)
Arm B: Abiraterone 1000mg/day + prednisone OR enzalutamide 160mg/day (investigator choice: switch to the other ARPI not previously received)
Primary endpoint: Radiographic PFS (rPFS)
mFollow up: 9.2 mo
Arm B: Abiraterone 1000mg/day + prednisone OR enzalutamide 160mg/day (investigator choice: switch to the other ARPI not previously received)
Primary endpoint: Radiographic PFS (rPFS)
mFollow up: 9.2 mo
Results
rPFS: 8.0 vs 3.7 mo, HR 0.54, P<.001
OS: 13.6 vs 11.0 mo, HR 0.64, P=.008
PSA response (≥50% decline): 35.7% vs 13.5%
ORR (soft tissue): 36.5% vs 11.5%
OS: 13.6 vs 11.0 mo, HR 0.64, P=.008
PSA response (≥50% decline): 35.7% vs 13.5%
ORR (soft tissue): 36.5% vs 11.5%
Adverse events
Overall: Grade ≥3 AEs 56.3% (cabazitaxel) vs 52.4% (ARPI); discontinuation 19% vs 18%
Hematologic: Febrile neutropenia 3.2% vs 0; G-CSF use recommended per protocol
Neurologic: Peripheral neuropathy grade ≥3 3.2% vs 0
GI/constitutional: Diarrhea grade ≥3 4.0% vs 1.8%; fatigue grade ≥3 4.0% vs 5.0%
Hematologic: Febrile neutropenia 3.2% vs 0; G-CSF use recommended per protocol
Neurologic: Peripheral neuropathy grade ≥3 3.2% vs 0
GI/constitutional: Diarrhea grade ≥3 4.0% vs 1.8%; fatigue grade ≥3 4.0% vs 5.0%
Conclusions
Cabazitaxel significantly improved rPFS and OS compared to sequential ARPI switch in patients with mCRPC who had progressed on prior docetaxel AND abiraterone or enzalutamide, demonstrating that cross-resistance between ARPIs limits efficacy of sequential ARPI use and that chemotherapy should be preferred in this setting.
Key Limitations
Key Limitations: Relatively small trial (n=255) with a short median follow-up. Open-label design may introduce bias in soft tissue response assessment. Sequential ARPI arm represents what many clinicians were doing prior to CARD, but not necessarily current standard practice, as Lu-PSMA-617 (VISION) and PARP inhibitors (for HRR-mutated) have since emerged as alternatives. The benefit of cabazitaxel over sequential ARPI in the era of PSMA-targeted therapies and PARP inhibitors warrants ongoing contextualization.
Clinical Context
CARD definitively established that sequential ARPI switching (abi→enza or enza→abi) after docetaxel provides minimal benefit due to cross-resistance, and cabazitaxel is clinically superior in this setting. FDA approved cabazitaxel as a result. Current practice also considers Lu-PSMA-617 (PSMAfore) in taxane-naïve post-ARPI mCRPC and olaparib/rucaparib in HRR-mutated disease as alternatives to cabazitaxel in heavily pretreated mCRPC.
References
References: de Wit R et al, NEJM 2019