Optimal third line therapy for mCRPC is unknown. The majority of patients will receive one ART targeted therapy with abiraterone acetate plus prednisone or enzalutamide and docetaxel chemotherapy. The CARD trial129 tested the efficacy and safety of cabazitaxel versus the alternative ART therapy in patients with mCRPC who progressed after two prior therapies. The primary end point was imaging-based PFS. Secondary end points included survival, response, and safety. A total of 255 patients were randomized, and progression or death was reported in 73.6% in the cabazitaxel group compared with 80.2% in the group that received a second ART (HR=0.54; 95% CI: 0.40 to 0.73; p<0.001). The median OS was 13.6 months with cabazitaxel and 11.0 months with the androgen-signaling-targeted inhibitor (HR for death=0.64; 95% CI: 0.46 to 0.89; p=0.008). The median PFS was 4.4 months with cabazitaxel and 2.7 months with an androgen-signaling-targeted inhibitor (HR for progression or death=0.52; 95% CI: 0.40 to 0.68; p<0.001). A PSA response occurred in 35.7% and 13.5% of the patients, respectively (p<0.001), and tumor response was noted in 36.5% and 11.5% (p=0.004). Adverse events of grade 3 or higher occurred in 56.3% of patients receiving cabazitaxel and in 52.4% of those receiving an androgen-signaling-targeted inhibitor. It is important to note that the CARD study enrolled an enriched group of patients with advanced mCRPC, with more than two thirds having disease-related pain. There may be clinical settings as in long-term response to the initial agent (abiraterone acetate/enzalutamide) or asymptomatic patients with disease progression in whom a therapeutic trial of the alternative agent is reasonable. Cabazitaxel significantly improved a number of clinical outcomes, as compared with an additional ART (abiraterone acetate or enzalutamide), in patients with mCRPC who had been previously treated with docetaxel and the alternative androgen-signaling-targeted agent (abiraterone acetate or enzalutamide). The magnitude of this benefit, improvement in multiple secondary endpoints, and other evidence demonstrating that sequencing serial ART therapies has limited efficacy suggests that cabazitaxel chemotherapy remains an important option for mCRPC patients in the third line.