Alicia Morgans: Hi, my name is Alicia Morgans. 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 Dr. Karim Fizazi, who is a Professor of Oncology and a GU medical oncologist at Gustave Roussy, in Paris, France. Thank you so much for being here.

Karim Fizazi: It's always a pleasure, Alicia. Thank you for inviting me.

Alicia Morgans: Wonderful. Well, I wanted to speak with you a little bit about the quality of life data that was recently published on the Phase IV CARD trial, and you did both a presentation, and you're the lead author in the paper that came out just a few weeks ago, actually. Can you tell us a little bit about what the CARD trial was, and then we can get into what the data was in terms of quality of life.

Karim Fizazi: Sure. So CARD was basically a very pragmatic Phase IV trial trying to look at a very simple question that we're facing very frequently in the last decade or so in men with advanced metastatic prostate cancer who had failed castration, obviously, but also one AR-axis agent, such as abiraterone or enzalutamide, and one taxane, namely docetaxel. And the question in these men was really what's next while they're progressing. Of course, sometimes you and I would have a nice clinical trial with a fancy new drug and a new concept to propose to these men, but for the large majority of men, especially at this time, this was not the case, and the discussion was really, "Should you use a second AR agent or should you use a second taxane?". 

And of course, in countries where all these drugs are available, it was probably tempting for many, many oncologists to just use the AR drug just because it's easier, just a simple prescription on a piece of paper. The side effects, at least the immediate side effects, are quite limited. And so it's an easy conversation, and you don't need to enter into a hard discussion with the patient about side effects, about his disease being advanced, and all of these things.

So I know that many of us were actually doing that, prescribing abiraterone after enzalutamide or vice versa, in this setting. But actually, we realized from a retrospective study, and it's a large way of course, it's almost everywhere on the planet... that actually using abiraterone after enzalutamide was very rarely associated with efficacy, and even enzalutamide post abiraterone had minimal efficacy, with approximately 20% response rate by PSA, and probably less convincing effect on stronger endpoint symptoms, etc., so time to symptoms, these things. While on the other hand, the experience with cabazitaxel in these men was perhaps more convincing, again both in terms of PSA control and symptoms control. So this is why we embarked on a randomized Phase III trial, testing the two options, again the second AR, whatever that was, enza or abi, with second taxane, cabazitaxel.

A year ago at ESMO, Dr. de Wit reported the first finding of a trial in terms of a primary endpoint, which was radiographic progression-free survival, and also the secondary major endpoint which was overall survival, and both were actually met, which, when I think about it, is not something happening so often in oncology. This is pretty much a third-line or even a fourth-line treatment... we should take into account castration... and seeing overall survival improvement in this setting is really scarce, unfortunately. And that is the case with cabazitaxel, and it was really clear cut. It's not, you know, curves not separating, and you always wonder whether it's meaningful or not. It was very clear.

So what we did also in the trial is that we looked at secondary endpoints of quality of life, symptoms control, burn problems, all these things, and all those seem also to favor cabazitaxel. For example, time to pain deterioration, and it's mostly, of course, bone pain deterioration, was significantly improved with cabazitaxel, as compared to the second AR drug. Also, skeletal-related events were improved, and quality of life... often with quality of life, and you are an expert, Alicia, you see that it's mostly maintained across the board, but when you're looking at various domains, it's actually slightly better, favoring cabazitaxel.

And this is also a very important message because many of our medical oncologist colleagues might think that using chemotherapy will be associated with impaired quality of life due to the side effect of the chemo, but actually, I think we should change our mind and more think that... our main goal is to target the cancer hard in the way that... using the best treatment that we have at a given time, and here it's not an easy situation for men who have already developed resistance to many things. And if truly we are improving patients' outcomes from the cancer standpoint, very likely the rest of their life will be also improved. Because the cancer is so important at this point of time to them in terms of consequences to their life that even if you have adverse side effects, it's actually minimal as compared to the benefit you are deriving from the anticancer efficacy. And actually, the side effects were pretty much the ones we knew from cabazitaxel, mostly some hematotoxicity, which can be prevented GCSF, and some diarrhea, which doesn't happen very often.

For example, the treatment-related deaths were not more frequent with cabazitaxel as compared to abiraterone or enzalutamide in this trial, which is also very reassuring. So, again, I guess in other good news, I mean, to me, this is a new standard of care. To be honest, it already was based on the retrospective data we had. Most often, I was proposing cabazitaxel to my patients in this setting when I hadn't a clinical trial to propose, but I guess this is level I evidence, and it's more convincing and helping colleagues who are not dealing with prostate cancer on a daily basis and also payers, all those things, so I think it's very important to have this trial available.

Alicia Morgans: I completely agree, and what I think is so important is that, not only did you very clearly demonstrate the efficacy, through this quality of life data, you demonstrated tolerability, also improvement in multiple symptoms, and as compared to, say, the nonmetastatic CRPC patient population, in which the cancer is actually really causing a lot of pain or other burdensome side effects, in this setting, in the mCRPC setting, the cancer is the driver of poor quality of life, and so when you control the cancer, it's interesting that the quality of life actually stabilizes or improves in that population, and you can see that decline in the population with an ineffective cancer-directed therapy. So as you said, it has been really our standard of care, but because of practice patterns not necessarily being consistent, it's so important to have this kind of data, I think.

So what would your thought be also on the fact that, in this trial, the cabazitaxel was dosed at 25 mg/m², which I believe is common in Europe and actually has been the initial label, but in the US, many physicians actually reduce that dose to 20 mg/m². Despite that higher dose, still, the quality of life was maintained or improved. What would your thought be there?

Karim Fizazi: Well, to be honest with this regard, I guess I'm a US citizen. I'm also using 20 mg and perhaps [inaudible 00:09:07] to be honest, but you know, 20 mg is actually my standard. I'm using it routinely. I haven't been using 25 for years now. I think the data are very convincing. We have two Phase III trials, basically with 20 and 25 mg face-to-face. At the end of the day, we see that 20 mg, the efficacy remains, and the safety is much better, so I'm indeed using 20 mg in my practice. I think we probably should also, in countries were GCSF is available and when it's not unavailable but also it's available front line because I know in some other countries you have to wait for first neutropenic fever to be allowed to use it, but in countries where that's not the case and you can freely use it, I think we should use it, and actually, this is what I'm doing also in my practice with this drug. Which is easy to handle, to be honest. With 20 mg and GCSF, patients are happy.

Alicia Morgans: I understand. I do exactly the same. And there's definitely conversation about, "Well, maybe you don't need the GCSF if you're having that 20 mg/m² dose," but I have access to it, I use it, and I think it keeps patients out of the hospital. So I agree.

And what's also interesting is the quality of life data from those comparisons of 20 mg versus the 25 versus actually docetaxel suggests that that 20 mg may be even better tolerated than docetaxel in some senses, the fatigue, the nail issues-

Karim Fizazi: Absolutely.

Alicia Morgans: So I have also found that it's been quite tolerable. So as you think about this data and the way that it integrates into practice, what would your final message be to the listeners?

Karim Fizazi: Well, I think that cabazitaxel was nice progress for the field, but unfortunately, that's a drug that came probably too late in the history. It is as it is. And because of that and because when it was basically launched people were already thinking about next-generation drugs, tyrosine kinase inhibitors, new targets, etc., etc., people perhaps didn't pay enough attention to this molecule, which, at the end of the day, is not a good thing for patients. Because we now have very clear evidence that it is an important drug in the armamentarium. It's also soon going to be a generic drug in many countries, so the price and the cost issues might not be one anymore, so I think we should really revisit the way we are integrating this drug in our current armamentarium for patients and we are not forgetting using it. Because it's really helping tremendously many patients, and I think it's a very important message for the future.

Alicia Morgans: I agree. And really we need to recognize and remember that sequencing AR-targeted agents after AR-targeted agents is really not the way to go anymore. This is very clear evidence that you can get both efficacy and disease control, as well as quality of life stabilization and improvement with this agent. Cabazitaxel works, and patients benefit. So thank you so much for your efforts, and thank you so much for your time today.

Karim Fizazi: 
A pleasure. Thank you, Alicia.