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Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University in Chicago in the United States. I'm so excited to have here with me today, Professor Ron de Wit, who is a Professor in the Department of Medical Oncology and the Division Lead of GU Clinical Research at the Erasmus MC Cancer Institute at the University Medical Center in Rotterdam in the Netherlands. Thank you so much for being here with me today, Dr. de Wit.

Ronald de Wit: It's a pleasure.

Alicia Morgans: Wonderful. I wanted to talk with you a little bit about the CARD data and our recent exploration of real-world evidence in patients who are similar to the CARD patients that were presented at ESMO 2020. Can you tell us a little bit, just to remind us, of what the CARD study was?

Ronald de Wit: The CARD study was a head-to-head comparison of cabazitaxel chemotherapy versus either abiraterone or enzalutamide in mCRPC patients who had been exposed to one series of the docetaxel chemotherapy cycle and the alternative AR-targeted agents. So these patients had received either abiraterone or enzalutamide, either before or after one series of docetaxel chemotherapy. And then patients were randomized between cabazitaxel, at the standard dose of 35 milligrams per square meter, plus primary G-CSF prophylaxis to avoid neutropenia complications, versus, again, the alternative AR-targeted agent. The primary endpoint of the study was radiographic progression-free survival, and a key secondary endpoint was overall survival.

A total of 250 patients were enrolled, and the key finding, obviously, was the doubling of the radiographic progression-free survival. It was 8 months versus 3.7 months in favor of cabazitaxel. And also, the key secondary endpoint, overall survival, was robustly in favor of cabazitaxel, so actually, there was a 30% reduction in the risk of death by cabazitaxel chemotherapy. That was basically the key message that I delivered at the ESMO meeting in 2019, and those data were published in the New England Journal of Medicine.

And then we decided to do the posthoc analysis of the real-world data. We collected information from 12,000 patients with mCRPC who had received at least one line of treatment for their metastatic CRPC disease. These 12,000 patients came from Europe, they came from the US, from Japan, and from Brazil. Out of these 12,000 patients, we selected 450 patients who matched the CARD criteria. Now, first of all, I think one of the key findings out of these 12,000 patients were that the majority of these patients actually received both AR-targeted agents in sequence, from the first to the second line, or from the second to the third line despite the concern that was already there worldwide, that crossing off between the AR-targeted agents was not that effective. But still, it happened. In fact, out of these 12,000 patients, more than two-thirds received the crossover between the AR-targeted agents.

Now, of those patients who received cabazitaxel like the CARD population, again, 450 patients, I think if you look at the data, the results were quite similar to what we found in the CARD study. The patient characteristics were a little bit worse, so it is obvious that the physicians chose cabazitaxel because of the worst characteristics of the patients. They had a higher percentage of visceral metastasis, for instance. But if you look at the median duration of cabazitaxel treatment, it was quite similar. So I think the obvious conclusion from the real-world data that I presented at The ESMO 2020 meeting, is that what we found in CARD, is what you can see in the real world. It nicely matches, and that is the benefit of looking at real-world data.

Alicia Morgans: Yeah. So let's dig into that a little bit. So, real-world data can be really valuable for multiple reasons, but one of those is that these patients may more closely reflect the populations that we see in clinic. So from your perspective, how powerful is real-world data? Of course, acknowledging its limitations. Non-randomized, this is the treating physician's choice of therapy. But how powerful is this kind of data when you are making decisions in your practice?

Ronald de Wit: Well, it really helps. It will never provide level one evidence, but the pitfall with interpreting clinical trial data is always those data reflect what is really happening in your daily practice. And I think that real-world data, like what we've presented at the ESMO meeting, shows that it is.

Alicia Morgans: Absolutely. What are your thoughts? Interestingly, a greater proportion of patients in this presentation, this data set, seem to receive a cabazitaxel dose that was 20 milligrams per meter-squared, which of course is different than the CARD trial. Does this, in your mind, help to justify the use of that lower dose with a similar benefit? Or what are your thoughts on that dose difference?

Ronald de Wit: Well, that is a tough question. That is very difficult to answer. We have done two studies to sort out the 21 to 25-milligram dose, and both of these studies showed a more or less similar effect in terms of overall survival, but response rates tend to be a little higher on the 25 milligrams. We have done some posthoc analysis from both studies, PROSELICA and FIRSTANA, and especially in patients who have symptoms at baseline, it seems to be that the eventual outcome is better with the 25 milligrams dose. So if a patient has pain at baseline, I think you need to go for the 25-milligram dose. And if you look at the current data with the primary G-CSF prophylaxis, the incident of neutropenic fever was only 2%, 3%, so it's fairly well-tolerated.

Alicia Morgans: That makes a lot of sense. I think what's interesting, though, is that if you were choosing between an AR-targeted agent, a second AR-targeted agent, in this, maybe, more elderly and somewhat more frail population and cabazitaxel, my takeaway from this data are to get the cabazitaxel into them at whatever dose is feasible for that patient population.

Ronald de Wit: I completely agree because we have now the evidence that the crossover between the AR-targeted agents isn't really effective and the cabazitaxel is. And even though it may be an elderly or a frail patient, you should not lose the window of opportunity of choosing the right drug at the right time. So I think you should try to use cabazitaxel 25 milligrams if possible, and otherwise 20 milligrams, to be on the safe side. But anyway, it is more effective than using the crossover between the AR-targeted agents.

Alicia Morgans: Right. I completely agree. If you had to summarize this data, which I think is so powerful in a real-world cohort, even in the more elderly and potentially more frail cohort, what would your message be to clinicians who are facing patients who have progressed on docetaxel, have progressed on a single AR-targeted agent? What is the message, especially if they are looking at that decision between a second AR-targeted agent and cabazitaxel?

Ronald de Wit: Well, I think that we have to realize that cabazitaxel, is chemotherapy, but the data shows that it is well-tolerated.  The data from the CARD study shows that it is well-tolerated, and it is so much more effective than the crossover between the AR-targeted agents, that it is really a pity not to offer that to the patient. And the real-world data that we have now on all these 450 patients who are currently patients, demonstrates that it is a special population that is quite reflective of your daily practice. More or less, similar characteristics, similar duration of cabazitaxel treatment. So, what we found in the CARD study is a daily practice.

Alicia Morgans: Absolutely. So we should take those opportunities when they are there, not miss that window of opportunity to use a therapy that is clearly, both in the CARD study and in this real-world evidence study, effective therapy for controlling the disease.

Ronald de Wit: I agree. Yeah, Yes.

Alicia Morgans: And it can be safe and tolerable.

Ronald de Wit: Yes, exactly. I completely agree.

Alicia Morgans: Thank you so much for sharing your take on this evidence and for participating in this ongoing research, really to ensure that patients have options for their treatment.

Ronald de Wit: Okay. Has been a pleasure.

Alicia Morgans: Thank you.