Regarding the safety of the agents, the incidence of adverse events was similar in each group (38.9% in the cabazitaxel group and 38.7% in the ASTI group). Treatment discontinuation occurred more frequently in the cabazitaxel group (19.8%) compared to the ASTI group (8.9%). Adverse events of grade 3 or higher occurred more frequently with cabazitaxel; these were asthenia (4% vs 2.4%), diarrhea (3.2% vs 0), peripheral neuropathy (3.2% vs 0 patients), and febrile neutropenia (3.2% vs 0 patients).
Conclusion. Patients who had disease progression within 12 months on an ASTI and had previously been treated for metastatic castration-resistant prostate cancer with docetaxel had longer imaging-based progression-free survival and overall survival when treated with cabazitaxel compared to those treated with an alternative ASTI. Other clinical outcomes, including overall survival and progression-free survival, were also improved in the cabazitaxel group.
Commentary
Four ASTIs are approved for therapy in men with advanced prostate cancer. The next line of therapy following progression on an ASTI, whether to consider second-line androgen targeted inhibitors or proceed to taxane-based chemotherapy, has been unclear. The current CARD trial sought to answer this question and provides evidence that cabazitaxel is the next line of therapy for these patients. The trial’s primary endpoint, imaging-based disease progression, was reported in 73.6% of those who received cabazitaxel and in 80.2% of those who received abiraterone or enzalutamide. Patients treated with cabazitaxel had a longer imaging-based progression-free survival (8.0 months vs 3.7 months) and a longer duration of treatment (22 vs 12.5 weeks).
Because there is clinical evidence of cross-resistance between different ASTIs, the value of sequential therapy has been unclear. Emergence of androgen-receptor splice variant 7 (AR-V7) mutational status in circulating tumor cells is associated with poor outcomes with secondary androgen-signaling inhibitor therapy, and may be an indicator of resistance to subsequent androgen-signaling inhibitors.1,2 In the PROPHECY trial, the response rates to subsequent androgen targeted therapy in patients with AR-V7 mutations ranged from 30% to 40%.3 Understanding how AR-V7 mutational status may impact such outcomes will certainly help define whether a subgroup exists in whom use of second-line androgen signaling inhibitors may be considered.
The patients enrolled in the current study appear to represent a subgroup of patients with biologically aggressive disease or with inherent resistance to ASTIs. The patients included in this study progressed within 1 year of androgen targeted therapy, which is representative of a more aggressive population of patients who may be hormone insensitive and derive more benefit from chemotherapy. Initial androgen deprivation therapy was given for 13.7 and 12.6 months to the cabazitaxel and enzalutamide/abiraterone arms, respectively, prior to developing castrate-resistant prostate cancer. Patients enrolled in this study also previously received docetaxel, deselecting those who are taxane-resistant and therefore may be less likely to respond to additional taxane-based therapy. Detection of AR-V7 splice variant expression in circulating tumor cells, consideration of biomarker data, and sensitivity to taxanes may help guide decisions regarding the use of sequential androgen-targeted agents; however, there has been no clear data to guide such an approach. It is also important to consider that, because this is a European study, the approved dose given in this trial was 25 mg/m2. The PROSELICA trial previously demonstrated noninferiority of 20 mg/m2 compared with 25 mg/m2, with fewer adverse events, which is the dose now utilized in the United States.4