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CARD: Sequencing Therapies in Metastatic Prostate Cancer

Panelists: Dan George, MD, Duke Cancer Center; Joe M. O'Sullivan, MD, FRCPI, FFRRSCI, FRCR, Queens University Belfast; Charles Ryan, MD, Masonic Cancer Center; Christopher Sweeney, MBBS, Dana-Farber Cancer Institute; Bertrand Tombal, MD, PhD, Cliniques Universitaires Saint-Luc
Published: Wednesday, Dec 18, 2019



Transcript: 

Dan George, MD: You brought up an important point, and it’s a really important segue to the other very informative study that was presented at ESMO [the European Society for Medical Oncology Congress] about using therapies that are ineffective and the cost of switching to a therapy that doesn’t work. In oncology we have to extrapolate and we have to practice where there are no data, because many of our cases go beyond the clinical trial space.

But Bertrand, there was a study also presented of sequencing different therapies, the CARD study that was presented at ESMO and published in the New England Journal of Medicine. I wonder if you could walk us through those results. What are the clinical implications of that study?

Bertrand Tombal, MD, PhD: Basically, I think the change in the next months is indeed coming from 3 papers. The first 1 is Kim Chi’s, paper on back-to-back ABI [abiraterone]–ENZA [enzalutamide], which is clearly showing that there is very little benefit of backing up androgen receptor inhibitor pathway 1 after the other. So far it was an alternative that was validated because, as you said, we have to carry on with the patient. Besides the precision medicine approach, there is another approach, which is to say, what is the role of second-line taxane, and especially cabazitaxel?

The CARD trial came very late in the development of cabazitaxel because I think the main excuse to the company working in prostate cancer is that they never anticipated that we would have like 5 drugs,  creating once again a very unstable landscape.

Dan George, MD: Five oral therapies that would be used in sequencing. This was not necessarily the way they were developed.

Bertrand Tombal, MD, PhD: The idea behind CARD was to recognize that, indeed, we should consider that the standard treatment of advanced prostate cancer is to receive at some point 1 of the hormones and docetaxel. That’s where sequencing starts. Because as mentioned by Chris, the triplets, the doublets—we know moving to the same olaparib stage, what do you do when you progress on abiraterone-enzalutamide?

The idea of CARD was to test that…having on 1 side the pragmatic, what we all do, which is to give the other AR [androgen receptor] pathway and taking cabazitaxel in parallel to that. The dose is 25 mg, because you have to understand that when we planned this trial, we basically planned the trial before we have the result of the other trials. Then patients are randomized, switching to receive cabazitaxel.

First, there is the control arm. Once again, as mentioned by Chris, consistency doesn’t work. Or it works for a few months. Then what is the difference with cabazitaxel? You increase PFS [progression-free survival] by 2. That was the primary end point.

You hit all the intermediate, traditional end points, such as PSA [prostate-specific antigen] decrease, PSA progression-free survival. That’s new. You provide an overall survival, let’s say a 40-person increasing overall survival, which is a few months, exactly like in the same ballpark as the olaparib. Clearly that study should be considered positive. I would say hopefully it will be practice changing in a way that people finally recognize that switching the AR pathway inhibitor should be a rare exception rather than 1 they should do. Clearly it puts back in the fact that when you have progression on the AR pathway, physiologically speaking, especially for all those patients who won’t hit the magic bullet, going to cabazitaxel is an option that actually may increase overall survival versus switching the AR pathway. There is a lot of discussion.

Dan George, MD: Just to summarize, this is a randomized study in patients with metastatic castration-resistant disease, prior treatment with docetaxel at some point—hormone sensitive or metastatic in prior treatment with either enzalutamide or abiraterone. They could have gotten any order of sequence of that. It could have been the docetaxel, then the AR-targeted therapy, or the other way around.

They were randomized, it was not quite fifty-fifty, but there was good representation of both sequences, and then randomized either to cabazitaxel, as you said, or the other hormone agent they hadn’t gotten, and we see this doubling of progression-free survival.

Bertrand Tombal, MD, PhD: Almost doubling.

Dan George, MD: It is almost doubling in the significant overall survival benefit, in line with these other studies, clinical experiences. What more do we need to say: it is time to change practice, and no more of this AR in sequence therapy? Chris, are there exceptions that we should be thinking about? Does this end the discussion or where are we with this?

Christopher Sweeney, MBBS: No. So I think 2 things. One is, we need to get over chemotherapy phobia.

Dan George, MD: Yup.

Christopher Sweeney, MBBS: Having said that, not everyone is a chemotherapy candidate, so you have to choose; your patients won’t. As we know, even with docetaxel and hormone-sensitive castration-resistant and cabazitaxel, the real-world experience, toxicity goes up, efficacy goes down. You’ve got to choose your patients well, who you’re going to use cabazitaxel on. It’s very clear. If you’re not having a great response to your prior AR, you’ve got some AR-independent disease, you’ve got clinical characteristics, and you don’t need AR B7 to tell you that. Give them the chemotherapy if they’re chemotherapy fit.

If they’ve had a long response to abiraterone, and their PSA is going up a little, there are data to support the hormone switch, or even actually thinking that’s the patient to sneak in radium because they’ve got some Tylenol or acetaminophen. They’ve got some symptoms. But you can sneak in another agent if they’ve had an indolent disease. But as Eminem said, you sometimes have “1 shot, 1 opportunity,” and you need to get the chemotherapy. This is because a lot of those patients in CARD got chemotherapy later, but not enough and not effective enough.

Bertrand Tombal, MD, PhD: To be precise, the CARD trial includes patients who progress within 1 year of the ARPI [androgen receptor signaling pathway inhibition]. So it addressed that group of patients with a rapid progression. The second comment made by Chris, a little more than 40 people received cabazitaxel at progression. We have very little information about the relative tolerance of receiving cabazitaxel up front versus after another line. But I think to me, the benefit of these 2 trials today goes more for the fact that we should think about adding a hormone. That, to me, should once again be the rare exception. We now have now 3 drugs: radium, cabazitaxel, olaparib.

Transcript Edited for Clarity

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Transcript: 

Dan George, MD: You brought up an important point, and it’s a really important segue to the other very informative study that was presented at ESMO [the European Society for Medical Oncology Congress] about using therapies that are ineffective and the cost of switching to a therapy that doesn’t work. In oncology we have to extrapolate and we have to practice where there are no data, because many of our cases go beyond the clinical trial space.

But Bertrand, there was a study also presented of sequencing different therapies, the CARD study that was presented at ESMO and published in the New England Journal of Medicine. I wonder if you could walk us through those results. What are the clinical implications of that study?

Bertrand Tombal, MD, PhD: Basically, I think the change in the next months is indeed coming from 3 papers. The first 1 is Kim Chi’s, paper on back-to-back ABI [abiraterone]–ENZA [enzalutamide], which is clearly showing that there is very little benefit of backing up androgen receptor inhibitor pathway 1 after the other. So far it was an alternative that was validated because, as you said, we have to carry on with the patient. Besides the precision medicine approach, there is another approach, which is to say, what is the role of second-line taxane, and especially cabazitaxel?

The CARD trial came very late in the development of cabazitaxel because I think the main excuse to the company working in prostate cancer is that they never anticipated that we would have like 5 drugs,  creating once again a very unstable landscape.

Dan George, MD: Five oral therapies that would be used in sequencing. This was not necessarily the way they were developed.

Bertrand Tombal, MD, PhD: The idea behind CARD was to recognize that, indeed, we should consider that the standard treatment of advanced prostate cancer is to receive at some point 1 of the hormones and docetaxel. That’s where sequencing starts. Because as mentioned by Chris, the triplets, the doublets—we know moving to the same olaparib stage, what do you do when you progress on abiraterone-enzalutamide?

The idea of CARD was to test that…having on 1 side the pragmatic, what we all do, which is to give the other AR [androgen receptor] pathway and taking cabazitaxel in parallel to that. The dose is 25 mg, because you have to understand that when we planned this trial, we basically planned the trial before we have the result of the other trials. Then patients are randomized, switching to receive cabazitaxel.

First, there is the control arm. Once again, as mentioned by Chris, consistency doesn’t work. Or it works for a few months. Then what is the difference with cabazitaxel? You increase PFS [progression-free survival] by 2. That was the primary end point.

You hit all the intermediate, traditional end points, such as PSA [prostate-specific antigen] decrease, PSA progression-free survival. That’s new. You provide an overall survival, let’s say a 40-person increasing overall survival, which is a few months, exactly like in the same ballpark as the olaparib. Clearly that study should be considered positive. I would say hopefully it will be practice changing in a way that people finally recognize that switching the AR pathway inhibitor should be a rare exception rather than 1 they should do. Clearly it puts back in the fact that when you have progression on the AR pathway, physiologically speaking, especially for all those patients who won’t hit the magic bullet, going to cabazitaxel is an option that actually may increase overall survival versus switching the AR pathway. There is a lot of discussion.

Dan George, MD: Just to summarize, this is a randomized study in patients with metastatic castration-resistant disease, prior treatment with docetaxel at some point—hormone sensitive or metastatic in prior treatment with either enzalutamide or abiraterone. They could have gotten any order of sequence of that. It could have been the docetaxel, then the AR-targeted therapy, or the other way around.

They were randomized, it was not quite fifty-fifty, but there was good representation of both sequences, and then randomized either to cabazitaxel, as you said, or the other hormone agent they hadn’t gotten, and we see this doubling of progression-free survival.

Bertrand Tombal, MD, PhD: Almost doubling.

Dan George, MD: It is almost doubling in the significant overall survival benefit, in line with these other studies, clinical experiences. What more do we need to say: it is time to change practice, and no more of this AR in sequence therapy? Chris, are there exceptions that we should be thinking about? Does this end the discussion or where are we with this?

Christopher Sweeney, MBBS: No. So I think 2 things. One is, we need to get over chemotherapy phobia.

Dan George, MD: Yup.

Christopher Sweeney, MBBS: Having said that, not everyone is a chemotherapy candidate, so you have to choose; your patients won’t. As we know, even with docetaxel and hormone-sensitive castration-resistant and cabazitaxel, the real-world experience, toxicity goes up, efficacy goes down. You’ve got to choose your patients well, who you’re going to use cabazitaxel on. It’s very clear. If you’re not having a great response to your prior AR, you’ve got some AR-independent disease, you’ve got clinical characteristics, and you don’t need AR B7 to tell you that. Give them the chemotherapy if they’re chemotherapy fit.

If they’ve had a long response to abiraterone, and their PSA is going up a little, there are data to support the hormone switch, or even actually thinking that’s the patient to sneak in radium because they’ve got some Tylenol or acetaminophen. They’ve got some symptoms. But you can sneak in another agent if they’ve had an indolent disease. But as Eminem said, you sometimes have “1 shot, 1 opportunity,” and you need to get the chemotherapy. This is because a lot of those patients in CARD got chemotherapy later, but not enough and not effective enough.

Bertrand Tombal, MD, PhD: To be precise, the CARD trial includes patients who progress within 1 year of the ARPI [androgen receptor signaling pathway inhibition]. So it addressed that group of patients with a rapid progression. The second comment made by Chris, a little more than 40 people received cabazitaxel at progression. We have very little information about the relative tolerance of receiving cabazitaxel up front versus after another line. But I think to me, the benefit of these 2 trials today goes more for the fact that we should think about adding a hormone. That, to me, should once again be the rare exception. We now have now 3 drugs: radium, cabazitaxel, olaparib.

Transcript Edited for Clarity
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