New study below [1] (full text).
"The efficacy and safety of cabazitaxel, as compared with an androgen-signaling–targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who were previously treated with docetaxel and had progression within 12 months while receiving the alternative inhibitor (abiraterone or enzalutamide) are unclear."
"Cabazitaxel significantly improved a number of clinical outcomes, as compared with the androgen-signaling–targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who had been previously treated with docetaxel and the alternative androgen-signaling–targeted agent (abiraterone or enzalutamide). (Funded by Sanofi; CARD ClinicalTrials.gov number, NCT02485691. opens in new tab.)"
"Our trial results prospectively confirm that patients with metastatic castration-resistant prostate cancer who had previously been treated with docetaxel and had disease progression within 12 months while receiving an androgen-signaling–targeted inhibitor (abiraterone or enzalutamide) had longer imaging-based progression-free survival and overall survival when treated with cabazitaxel than when treated with the other androgen-signaling–targeted inhibitor (abiraterone in patients who had previously received enzalutamide, or enzalutamide in those who had previously received abiraterone). Cabazitaxel more than doubled the imaging-based progression-free survival (median, 8.0 months vs. 3.7 months with an androgen-signaling–targeted inhibitor), and this benefit was observed across all the prespecified subgroups, regardless of the timing of the previous alternative androgen-signaling–targeted inhibitor therapy (before or after docetaxel). Cabazitaxel resulted in a risk of death from any cause that was 36% lower than that with abiraterone or enzalutamide, despite 33% of the patients in the androgen-signaling–targeted inhibitor group crossing over to receive cabazitaxel at the time of progression. All key secondary end points (overall survival, progression-free survival, PSA response, and tumor response) also favored cabazitaxel.
The results of the CARD trial are in agreement with those of previous studies that have shown poor outcomes with a second androgen-signaling–targeted inhibitor.22-25 This is probably due to the fact that these agents target the same pathway and thus share common mechanisms of resistance. Conversely, taxanes, owing to their different mechanism of action, are able to overcome several mechanisms of resistance to androgen-signaling–targeted inhibitors, such as increased androgen-receptor signaling and PTEN (phosphatase and tensin homologue) loss.29-33 In addition, although some studies suggest that docetaxel loses some activity in tumors that are resistant to androgen-signaling–targeted inhibitors, prospective and retrospective data show that cabazitaxel retains its activity in this context.18,19,26,34,35 This may be attributed to greater intratumoral penetration with cabazitaxel than with docetaxel, especially in treatment-resistant tumors.36,37
The incidence of adverse events of grade 3 or higher was similar in the two treatment groups (56.3% with cabazitaxel and 52.4% with an androgen-signaling–targeted inhibitor). The incidence of adverse events leading to death during the trial was twice as high with an androgen-signaling–targeted inhibitor as with cabazitaxel; this finding was mainly related to disease progression. Neutropenic complications with cabazitaxel usually occur at cycle 1, especially when the baseline neutrophil count is below 4000 per cubic millimeter.38 Therefore, all patients in the cabazitaxel group received prophylactic granulocyte colony-stimulating factor during every cycle in the trial. With granulocyte colony-stimulating factor, the incidence of febrile neutropenia of grade 3 or higher that was observed in this trial (3.2%) was similar to that observed in the AFFINITY phase 3 trial (3%), which also allowed the use of prophylactic granulocyte colony-stimulating factor from cycle 1, with 59% of the patients having received both docetaxel and an androgen-signaling–targeted inhibitor.39
This was an open-label trial with no central review of the standard imaging, although a previous study has suggested little variance between local and central imaging review in this population.40 Moreover, results regarding multiple secondary end points, including overall survival, in this trial were significant in favor of cabazitaxel. Second, the cabazitaxel starting dose of 20 mg per square meter was not tested. In the prospective, noninferiority, phase 3 trial PROSELICA, a dose of 20 mg per square meter maintained at least 50% of the survival benefit of a dose of 25 mg per square meter (which had been compared with mitoxantrone in the TROPIC trial) and was associated with a lower incidence of adverse events of grade 3 or higher.4,20 For the CARD trial, we used a dose of 25 mg per square meter because the trial was conducted in Europe and the European label was used as a reference. The incidence of febrile neutropenia with the cabazitaxel dose of 25 mg per square meter was lower in the CARD trial (3.2%) than in TROPIC (8%) and PROSELICA (9.2%), probably owing to the use of prophylactic granulocyte colony-stimulating factor from cycle 1.4,20
No preplanned analysis of the influence of the sequence of abiraterone–enzalutamide (or vice versa) was undertaken. However, since retrospective studies suggest that the sequence of androgen-signaling–targeted inhibitors may influence progression-free survival, post hoc analyses were performed, which confirmed the superiority of cabazitaxel over the androgen-signaling–targeted inhibitor regardless of whether abiraterone or enzalutamide was received during the trial.41-44
In conclusion, cabazitaxel led to longer imaging-based progression-free survival than abiraterone or enzalutamide among patients with metastatic castration-resistant prostate cancer who had previously received docetaxel and the alternative androgen-signaling–targeted inhibitor (abiraterone or enzalutamide). Cabazitaxel also significantly improved overall survival and other secondary end points."
-Patrick
'Substandard' Control Arms in Clinical Trials– Practice found common in prostate cancer studies
Abiraterone/enzalutamide+PARP inhibitor better than abiraterone/enzalutamide alone for mCRPC, even without BRCA+
Dr says Enzalutimide... what about Cabazitaxel?
