Cabazitaxel improves radiographic progression-free survival compared to abiraterone or enzalutamide in metastatic castration-resistant prostate cancer
In the CARD study, cabazitaxel was compared with abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer, who were previously treated with docetaxel and the alternative androgen receptor-targeted therapy. After a median follow-up time of 9.2 months, cabazitaxel significantly improved clinically important patient outcomes, including radiographic progression-free survival and overall survival, compared to abiraterone or enzalutamide. Cabazitaxel reduced the risk of death by 36% compared to the androgen receptor-targeted therapies, regardless of the abiraterone-enzalutamide sequence. Other secondary endpoints, like progression-free survival, tumor and pain responses, and time to symptomatic skeletal events, also improved with cabazitaxel. Therefore, these results support the use of cabazitaxel over abiraterone or enzalutamide in this setting.
Background
Taxanes, like docetaxel and cabazitaxel (CBZ), and androgen receptor-targeted therapies (ARTs) with abiraterone or enzalutamide are standard of care in metastatic castration-resistant prostate cancer (mCRPC). Although these treatments have shown survival benefits in mCRPC patients, the optimal treatment sequence is unknown. For example, patients may not respond to abiraterone after progressing on prior enzalutamide and vice versa. However, CBZ retains activity in patients progressing on prior docetaxel, abiraterone or enzalutamide. In the CARD study CBZ was compared with abiraterone or enzalutamide in patients with mCRPC, who were previously treated with docetaxel and the alternative ART. During ESMO 2019, De Wit presented safety and efficacy data of the CARD study.
Methods
The CARD study is a multicenter randomized open-label study. The median follow-up time was 9.2 months. Patients with mCRPC previously treated with ≥3 cycles of docetaxel and progressing within 1 year on an alternative ART, in any order, were randomized 1:1 to CBZ (25 mg/m2 IV Q3W + prednisone + G-CSF; n=129) versus ART (abiraterone 1000 mg QD + prednisone or enzalutamide 160 mg QD; n=126). Randomization was stratified by ECOG performance status, time to progression on prior alternative ART, and timing of ART. Primary endpoint was radiographic progression-free survival (rPFS), with 196 rPFS events needed to detect a HR of 0.67 for CBZ versus ART (80% power, 2-sided alpha 0.05). Secondary efficacy endpoints and safety were also assessed.
Results
Overall, 255 patients with a median age of 70 years were randomized. The median number of cycles was higher for CBZ (7 cycles) compared to ART (4 cycles). The median rPFS was significantly higher with CBZ (8.0 months) versus ART (3.7 months; HR 0.54 [95% CI: 0.40–0.73]; p<0.0001). This rPFS benefit of CBZ over ART did not depend on the abiraterone-enzalutamide sequence and occurred in all preplanned subgroups. Median overall survival was also improved with CBZ (13.6 months) compared to ART (11.0 months; HR 0.64 [95% CI: 0.46–0.89]; p=0.0078) despite crossover. Additionally, CBZ improved median progression-free survival (4.4 versus 2.7 months; p<0.0001), confirmed PSA50 response (35.7% versus 13.5%; p=0.0002), and objective tumor response (36.5% versus 11.5%; p=0.004) compared to ART, as well as pain response (45.0% versus 11.5%, p=0.004) and time to symptomatic skeletal events (HR 0.59 [95% CI: 0.35-1.01], p=0.05).
The rate of adverse events (AEs) was similar in both treatment groups: any AE occurred in 98.4% of CBZ patients and in 94.4% of ART patients. Grade ≥3 AEs occurred in 71 patients (56.3%) in the CBZ group and in 65 patients (52.4%) in the ART group. For CBZ versus ART, the main grade ≥3 AEs were: renal disorders (3.2% versus 8.1%); infections (7.9% versus 7.3%); musculoskeletal pain/discomfort (1.6% versus 5.6%); cardiac disorders (0.8% versus 4.8%); spinal cord and nerve root disorders (2.4% versus 4.0%); asthenia/fatigue (4.0% versus 2.4%); diarrhea, peripheral neuropathy and febrile neutropenia (3.2% versus 0% for each). With CBZ 19.8% of patients discontinued treatment due to AEs compared to 8.9% of ART. However, AEs leading to death occurred more often with ART (14 patients, 11.3%) compared to CBZ (7 patients, 5.6%), mainly due to disease progression.
Conclusions
In conclusion, CBZ significantly improved clinically important patient outcomes, including rPFS and overall survival, compared to the ARTs abiraterone and enzalutamide in patients with mCRPC previously treated with docetaxel and the alternative ART. CBZ reduced the risk of death by 36% compared to abiraterone or enzalutamide, regardless of the abiraterone-enzalutamide sequence. Other secondary endpoints, like progression-free survival, tumor and pain responses, and time to symptomatic skeletal events, also improved with CBZ. Hence, the results of the CARD study support the use of CBZ over abiraterone or enzalutamide in this setting.
Reference
De Wit R, Kramer G, Eymard J, et al. CARD: Randomized, open-label study of cabazitaxel (CBZ) vs abiraterone (ABI) or enzalutamide (ENZ) in metastatic castration-resistant prostate cancer (mCRPC). Presented at ESMO 2019; abstract LBA13.
