Alicia Morgans: Hi, I'm so excited to have here with me today, Dr. Karim Fizazi, who is a GU Medical Oncologist and Professor of Medicine at Gustave Roussy in Paris, France. Thank you so much for being here today.

Karim Fizazi: Thank you, Alicia. My pleasure.

Alicia K. Morgans: Of course. Thank you. So, I wanted to talk with you today about the CARD trial, which is a really exciting Phase IV trial looking at third-line treatment for metastatic CRPC. I'd love to hear what was this trial? And what's so important and different about it?

Karim Fizazi: Right. This is really a situation of men who have been facing quite a lot in the last decade, nowadays that we have both next-generation AR axis-targeted agents, abiraterone and enzalutamide, and taxane with docetaxel, and now also cabazitaxel. So these men had existed already one AR axis-targeted agent, either abiraterone or enzalutamide, and also docetaxel. And when we were facing these men basically in the last years, the big question was should we move to second AR axis-targeted agents? So enzalutamide if he's been using abiraterone for example, or should you go to the second taxane with cabazitaxel? What's best? And of course, you might debate based on the data we had some years ago, cabazitaxel is an IV so it's more difficult to give, et cetera. But retrospective analysis suggested that actually it might be more potent than the second AR axis-targeted agent.

So that was really the case for randomization. So this is why we decided to do the trial, and it was a very pragmatic randomization. [1:38 inaudible] taxane, cabazitaxel or second AR axis-targeted agent. 250 men were randomized in the situations and the primary endpoint was radiographic progression-free survival. Very clearly cabazitaxel wins. rPFS is basically doubled with chemo as opposed to a second AR axis-targeted agent. And on top of that, overall survival, which was a key secondary endpoint, was also significantly and I guess clinically, meaningfully improved with cabazitaxel with a 46% reduction in the risk of death as compared to a second AR axis-targeted agent.

So when you think about it, we rightly said that this is third-line treatment. Actually sometimes it can be fourth-line if you count ADT. We don't have so many examples in oncology while treating epithelial cancers where you do see overall survival being met in third or fourth-line treatment. And here we have one and it's not a small impact, it's actually 36% reduction in risk of death. So it's big. Very important.

Alicia K. Morgans: Absolutely. And I think especially as we're having actually similar agents move from the metastatic CRPC setting, even into the metastatic hormone-sensitive setting, this data is going to be really, really important as we think about next-line treatments generally.
One of the main messages was that cabazitaxel was clearly effective in this population that had received docetaxel and either abi or enza as compared to the alternate AR targeted agent.

Karim Fizazi: That's right.

Alicia Morgans: It was also quite tolerable in this setting as well.

Karim Fizazi: It was, and actually the side effects were as expected, but the GCSF also prevented probably many neutropenic fevers. So that's actually my routine management of men with cabazitaxel using GCSF. Because besides the hematological toxicity, generally speaking, it's a quite well-tolerated agent. Alopecia is minimal. Nausea, vomiting is minimal or absent. Diarrhea can be usually easily managed and that's it. Compared, for example, to docetaxel with a neuropathy, with the nail issues, et cetera et cetera. Generally speaking, it's a quite well-tolerated drug, as far as you are able to manage the hematotoxicity and again, the GCSF helps.

So yes, and indeed even if it's an IV compared with a pill, data on quality of life clearly favored the IV chemo, which means that if you truly have an active agent that fights better against the cancer, your quality of life will be better.

Alicia Morgans: Yes. You actually presented that data at GU ASCO. It was really fascinating to see that the quality of life curves as measured by the FACT-P actually demonstrated an improvement in the quality of life for those patients treated with chemotherapy. I imagine this is because of disease control, whereas we saw actually a continuous decline of patients in terms of quality of life when they were treated with the other AR targeted agent.

Karim Fizazi: Correct. Especially when you focus on what is clearly important in disease-related, pain-related outcomes, and also prostate cancer-specific scales from the FACT-P, you really see a favorable impact of cabazitaxel, over the second AR axis-targeted agent, very clearly. And when you assess pain or using the BPI measure for example, the effect is very clear. 45% of men experience a response while on cabazitaxel as compared to less than 20% in the control arm with abiraterone or enzalutamide. It's a big difference. We all know it's not easy to treat pain, and to achieve a response on pain is not something you have easily. And I think this is very meaningful to patients.

Alicia Morgans: The other thing that's meaningful to patients, and of course related to pain is SREs. So, skeletal-related events were also decreased in the cabazitaxel arm as compared to the other AR agent, which I imagine is both due to the effectiveness of the chemotherapy, but also because the second AR agent was not really effective.

Karim Fizazi: That's true. That's very true. Actually, we saw approximately 40% reduction in the risk of SREs. And of course for those people who don't know what SREs are, we're talking about major pain requiring radiation, or a fracture or spinal cord compression. So those things are truly clinically important to older patients and 40% reduction, again is something on top of VOS, PFS, pain et cetera. Chemo works against the side effect of the other cancer.

Alicia Morgans: Absolutely. I think the importance of changing the mechanism of action was also really highlighted in the CARD trial. So in the control arm, we saw that as you said, the radiographic progression-free survival was really short for that second AR targeted agent. I think it was around two and a half months and granted, these patients were on their first AR targeted agent for 12 months or less, this was an inclusion criteria of the trial.
But when I think about that data, I don't think that this is surprising to me. Number one, because I have seen clinically and I know that the mechanisms of resistance to one AR targeted agent are actually probably in most cases, going to be very similar. But I'm not surprised, and I also would think that I don't think that a longer time of exposure to an AR targeted agent would necessarily mean that the second AR targeted agent should now have a greater chance of response. I'm not sure what your thoughts are? This is hypothetical because we actually don't have that data, in the CARD trial at least. Of course, we have others, but...

Karim Fizazi: I agree with you. I mean CARD really specifically focused on men who had progressed within a year on their first AR axis-targeted agents. So the data applies to these men. But you're very right in the retrospective analysis that we have now a bunch of them out there regarding the use of abi post-enza. Or enza post-abi, even in patients who had received the first agent for quite a long time. The frequency of the second agent is not magic. It's really minimal. Just 5% of men tend to benefit from abiraterone post-enzalutamide and maybe 20-25% maximum from enza post-abi. And when I say benefit, it's just a drop in PSA and typically it doesn't last long, typically two months, three months and it's over.

So I agree with you, even in men who have received these agents for more than one year, When they progress, probably except for a very tiny minority, we should not switch to the other agent and consider something else. A taxane obviously right now, and hopefully in the future some other agents, but we should try to stop switching from abi to enza or enza to abi for a large majority of all the men.

Alicia Morgans: Absolutely. Now I wanted to talk to you too about the patients in this trial. A number of them actually came in with a large amount of pain, which we know and we've already discussed as a hard to control symptom, but it's also a really poor prognostic sign.

So when you're facing patients who are having all this pain, one, what do you do to try to catch them before they get there? But two, is this the population as well that you would certainly want to move forward with something that you think is going to be highly effective? Rather than again, sequencing another AR targeted agent and losing time in that population?

Karim Fizazi: You're actually right and you need to be honest with you. In some patients, I'm not necessarily waiting for clinical deterioration or radiographic progression to switch to my next treatment when I'm managing men with mCRPC. I know that the recommendation in the trials that were done in the past generally say that before switching or doing something else, you should have two criteria out of three: PSA, radiographic, clinical. But to be honest, in some men with a rapidly rising PSA, I know that they're going to develop symptoms very soon, very likely.

So instead of just waiting and say to the gentleman, "I'll see you in two to three months," and then have to face a man on pain, et cetera and some other symptoms... To be honest, I'm telling them, we should consider switching your treatment now. And even if it's chemotherapy, this is actually my practice. If don't want, fine. I'm telling them, "okay, so I'll see you again in two months. But if your PSA keeps rising, then we should consider treatment."

Alicia Morgans: I do the same. And certainly there are patients who choose to defer treatment and for many of these men, they're elderly or they have other reasons why they want to defer treatment. But I always put a caveat on that and say, "yes, okay, we'll follow up in maybe two months, but if you have a symptom, if something changes, please let me know." Because when their PSA is rising so rapidly, it is common that these things happen.

Karim Fizazi: Actually you're very right. I mean, sometimes this timeframe also helps them. You're explaining once that PSA is not good and it's rapidly rising, this should be the right time to switch to your next treatment, and by the way, this is a chemotherapy. And if they're not happy with the idea, providing them an additional one to two months can be a way for them to be self-convinced that indeed, we should do that. So it can help.
But truly in some patients, I just don't know why, because I'm like you— seeing again a patient that was telling you, "oh, it's so painful" et cetera, et cetera, while you saw him two months before— you don't want to see that.

Alicia Morgans: You don't want to see that. Well, I so appreciate you taking the time to review all of this data. And if you had to give one message to the viewers, sort of a take-home message, what would that be about the CARD trial?

Karim Fizazi: Well, I think people have been under-using cabazitaxel in the last decade and I think that's a big mistake. Taxane works in this disease. We have ample data, and now randomized data, indicating that after the failure of AR axis-targeted agent, taxane work. This is true for docetaxel, this is also true for cabazitaxel.

We also have now big data from various trials we discussed indicating that switching from AR axis-targeted agent to the other one doesn't work, so we should just prevent doing that, even if it's easier. It's just a piece of paper to feel, and the patients go away with another pill. We should avoid those things in the majority of men and take the time to sit down with a patient, explain that chemotherapy is the main option for them in their situation when they have exhausted those agents.

Alicia Morgans: Absolutely. We have only so many options for the patients that we treat and care for, and it is really our responsibility to make sure that they have access to and exposure to every opportunity to control their disease. And in the setting, we're not only improving overall survival, but we're also actually improving quality of life as well, reducing pain and preventing skeletal-related events. So I truly appreciate you sharing your expertise and talking with me about this. Just thank you so much for your time.

Karim Fizazi: Thank you.