The Emerging Role of Chemotherapy in Metastatic Prostate Cancer - Episode 9
Daniel Petrylak, MD: The CARD study was a trial that compared cabazitaxel with next generation antiandrogen therapy in men with castration-resistant prostate cancer. Sequencing is a complex issue in the treatment of men with castrate-resistant disease, and the CARD study was one of the first trials to help answer this question. Patients with castrate-resistant prostate, who had progressed either on abiraterone or enzalutamide, as well as docetaxel, were randomized to receive either cabazitaxel or the alternative antiandrogens. If they received enzalutamide, they received abiraterone in the study; if they initially received abiraterone, they received enzalutamide in the study. Patients had to have progressed within 1 year on abiraterone or enzalutamide as their first next-generation antiandrogen treatment. The CARD trial demonstrated a radiographic progression-free, as well as overall, survival benefit in favor of cabazitaxel compared with the alternative antiandrogen. The data were then further analyzed in terms of prognostic factors, in terms of other factors that may have influenced the overall outcome, because again, this was a small randomized phase 2, and small differences in patient populations could have actually accounted in part for this survival benefit and the radiographic progression-free survival. What was looked at was the metastatic disease at the diagnosis, whether they had metastatic disease at diagnosis, or whether they were localized and then developed metastatic disease, visceral metastases, Gleason score, prior therapy with curative intent, and type of progression. Other covariates that were looked at were hemoglobin, lactate dehydrogenase, visceral metastases, the Gleason score, the alkaline phosphatase, and the PSAs [prostate-specific antigens], and these were all were all in terms of the absolute value log of 10. At a significance level of 0.1, this multivariate analysis was used as a way to determine whether these variables were significant. What fell out in this analysis was treatment with cabazitaxel was the most significant, with a hazard ratio of .628, followed by neutrocytes to lymphocyte ratio, hemoglobin, as well as PSAs. Cabazitaxel treatment seems to trump these prognostic factors in terms of our patients.
They also looked at a variety of different variables in terms of overall survival, from the development of metastatic disease from the time of castration resistance to the time that patients go on study. There was a survival rate in favor of cabazitaxel. This analysis helps weed out those patients who may be slower progressors. The overall survival from the time of the second LET [life-extending therapy] to initiation OS [overall survival], again, it was in favor of cabazitaxel in this situation. The office concluded that the data were robust, and that cabazitaxel was a reasonable option in those patients who failed docetaxel as well as an antiandrogen within 12 months.
Practical implications are that we have a way to sequence our patients with castrate-resistant disease, and we didn’t really have good guidance. In fact, what was used before were quality of life issues. People argued that because somebody was being treated with a next generation agent sequentially, we all know that responses are not necessarily the best in a sequential fashion. In other words, abiraterone after enzalutamide, or enzalutamide after abiraterone usually has a lower response rate and a shorter duration of response, if they do respond. The tendency was to put patients on oral agents because it was easier and better tolerated. I think, here, the survival benefit does seem to cancel out any effects that may have.
One of the major questions that is involved in the CARD trial is the types of toxicities that you would expect to see, is there a difference between older patients versus younger patients. The CARD data were based upon age and split the group into patients either less than 70 years of age, or greater than or equal to 70 years of age. The interesting thing that was noted was that any grade 3 or grade 4 AE [adverse effect] was similar, about a 6% difference in favor–higher in cabazitaxel in those younger than 70, and it’s about 8% in those greater than 70. There doesn’t seem to be that much of a difference between them.
Transcript Edited for Clarity