Alicia Morgans: Hi. I am so excited to talk today with Dr. Cora Sternberg, who is a Professor of Medicine at Weill Cornell and the Clinical Director of the Israel Englander Institute for Precision Medicine also at Weill Cornell. Thank you so much for being here.

Cora Sternberg: Thank you. It's a pleasure to be here.

Alicia Morgans: Thank you so much for talking with us about the CARD trial that I think is going to change the landscape of treatment of mCRPC around the world. Tell us a little bit about this trial.

Cora Sternberg: For patients with metastatic castration-resistant prostate cancer, we've been lucky that after docetaxel we've had a number of other agents approved recently and the androgen receptor-targeted agents, such as enzalutamide and abiraterone, have been widely used, particularly in Europe. This study was done in Europe from 2015, and 2018 when there was enrollment. What we saw happening was that particularly in elderly patients, many people were giving one androgen receptor-targeted agent after another. We know from the PLATO study by Attard that giving enzalutamide and then adding one abiraterone doesn't work. We know from other studies that it really doesn't work to give two androgen receptor-targeted agents in a row.

But we had no real proof of that and we didn't know whether or not it was better after chemotherapy with docetaxel and an androgen receptor-targeted agent, whether it was better to go to another antigen receptor-targeted agent or cabazitaxel. What we did was we randomized 250 patients who had received at least three cycles of docetaxel chemotherapy and had received at least one androgen receptor-targeted agent. In that time period, it was either enzalutamide or abiraterone. They could have received it before or after the docetaxel because as you know, people are receiving more and more docetaxel for hormone-sensitive prostate cancer and also abiraterone for hormone-sensitive prostate cancer, but it was patients who didn't respond to abiraterone for more than 12 months. This study is limited to that category of patients.

The patients were randomized in a one-to-one fashion. What we saw was the primary endpoint was radiologic progression-free survival. There we saw a doubling in favor of cabazitaxel, a 46% reduction in the risk of radiologic progression if patients were randomized to cabazitaxel as opposed to the alternative androgen receptor targeting agent. Even more exciting in this study was an improvement in overall survival, a 36% reduction in the risk of death if patients received cabazitaxel as compared to the other androgen receptor-targeted agents. All of the ways that we looked at it on... 

If we looked at if the patients had androgen receptor response for less than six months or more than six months, if their performance status was zero to one or two, or if they've gotten the chemotherapy before or after the androgen receptor-targeted, no matter what subgroup we looked at, cabazitaxel was better than the androgen receptor-targeted agents.

A number of the patients who are older than 75 years old. There was not really increased toxicity with either agent, the toxicity was pretty similar. Patients were on cabazitaxel a lot longer than they were on actually on the androgen receptor-targeted agent. 

There were more infections with cabazitaxel, but there were more heart problems with the abiraterone or enzalutamide. Actually, most patients when they went off study they went off for progression of disease, not because of side effects. I think what we have now is for the first time a head-to-head study in the third-line setting, making it very clear to us that the sequence of treatment should be cabazitaxel rather than another androgen receptor-targeted agent.

Now, this study was conducted in Europe, and in Europe, the dosage of cabazitaxel is 25 milligrams per meter squared. We gave everybody 25 milligrams per meter squared of cabazitaxel with GCSF. 

That may be one of the reasons why there was not a lot of infections. After the PROSELICA study, the test was done where they compared 25 milligrams per meter squared to 20 milligrams per meter squared. I know in the United States that's often used, but there actually were higher response rates with the 25 milligrams per meter squared. That's since the study was done in Europe and that's the dosage that was used, but I think probably either one could be used. We're going to do more biomarker work. Everything we looked at in terms of PSA response, pain response, quality of life also was all in favor of the cabazitaxel.

I think that this study was really a very, very positive study, and I think it's going to be practice-changing.

Alicia Morgans: I agree. I think it's important as you emphasized that although there were similar rates of adverse events between the two arms, there's actually a longer duration on therapy in the cabazitaxel arm. There were many patients who were actually older and receiving that higher dose of cabazitaxel than the one that we typically use here in the United States.

Cora Sternberg: Absolutely.

Alicia Morgans: Despite all of those things, we found that this was a tolerable treatment for those patients and helped them live longer, had, as you said, better improvement in pain and other adverse events and other secondary outcomes I should say. I think that I completely agree with you. I wonder how do you use this data in your own practice? Where do you fit cabazitaxel in knowing that there are other treatment options, but I would imagine you're not using another AR targeted agent?

Cora Sternberg: No, I would not use another AR target agent after this study. I mean, the majority of patients that went on this study went on with pain progression. I mean, these were patients who were sick, a lot of them. They hadn't responded to an AR agent for more than 12 months. Those patients after participating also in the PLATO Study, I saw how they did not respond by adding on another one. I think that giving cabazitaxel after an AR agent makes a lot of sense. This maybe can reset the mechanism somehow and then give the other AR mechanism, AR targeted agent afterwards. There's other studies showing that patients who get all three agents or all four even, including docetaxel, do better than patients who only get two drugs. 

Of course, those patients lived longer.

In my practice, I would definitely after an AR targeted agent and docetaxel give cabazitaxel at this point. There's less toxicity actually with cabazitaxel than with docetaxel in terms of neuropathy. It's very well tolerated actually.

Alicia Morgans: I agree. It's actually very well tolerated in my patient population as well, and I find that symptomatic patients actually feel better when we get their disease under control because it's the disease that's causing many of the symptoms.

Cora Sternberg: Exactly.

Alicia Morgans: If you had to give a take-home message, what would that be for the audience after the CARD Trial?

Cora Sternberg: Well, I think that it's very clear that we have a head-to-head trial in the third-line setting in patients who have received docetaxel and an androgen receptor-targeted agent and that could have been before or after docetaxel. The best thing to do would be to give cabazitaxel rather than another androgen receptor-targeted agent as your next line of treatment.

Alicia Morgans: Absolutely. Really switching that mechanism of action I think is going to be critical.

Cora Sternberg: I agree.

Alicia Morgans: Sandwiching an AR agent around docetaxel does not resensitize you to the second androgen receptor-targeted agent. Cabazitaxel can be tolerable in this patient population, even at higher doses than we typically use here in the United States. Really we need to change that paradigm and I think this trial does that.

Cora Sternberg: This trial, absolutely, is paradigm-changing.

Alicia Morgans: Absolutely. Thank you for sharing your expertise and for your hard work in the CARD trial.

Cora Sternberg: Pleasure to be here as always.

Alicia Morgans: Thank you.

Cora Sternberg: Thank you.