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Impact of the CARD Trial for Treating Metastatic CRPC

Insights From: Daniel Petrylak, MD, Yale University; Nicholas Vogelzang, MD, Comprehensive Cancer Center
Published: Friday, Mar 27, 2020



Transcript:

Nicholas Vogelzang, MD: If you explain these things to the patients, what I often tell the patient is: “Look, the cancer that we started treating you with way back when with androgen deprivation therapy and perhaps docetaxel, now after AR [androgen receptor] inhibition the tumor has evolved. The tumor is now a different tumor.”

We saw the Stand Up to Cancer Dream Team biopsies from UCSF [the University of California San Francisco] showing that a good 20% are neuroendocrine, and there’s no particular clinical feature that predicts for neuroendocrine. So do you have a trigger point for when you’re going to use, for example, cabazitaxel? Let’s talk briefly about that evolution. How early are you using cabazitaxel?

 
Daniel Petrylak, MD: I’m looking at the CARD trial. I think that’s the way I’ve based my practice in the past. The CARD trial was a study that looked at sequential treatments in castrate-resistant disease. Generally we would use a next-generation antiandrogen like abiraterone or enzalutamide first. Then go on to docetaxel. And the question has always been with our patients, what’s the next step that is right? A lot of people will try another next-generation agent. ABI [abiraterone] versus ENZA [enzalutamide], ENZA [enzalutamide] versus ABI [abiraterone]. Or of course go on chemotherapy. And the thought was, well chemotherapy is more toxic, we don’t want to use it in this situation.

But the CARD trial helps answer that particular question. It actually was a very clinically relevant study. Patients who had received either ABI [abiraterone] or ENZA [enzalutamide], then docetaxel, they received the opposite antiandrogen in a randomized fashion, and it was compared to cabazitaxel. And lo and behold, cabazitaxel had a better radiographic progression-free survival, overall survival, better PSA [prostate-specific antigen] decline rate, and also better objective response rate. It seems the cabazitaxel is a superior drug in this particular situation to enzalutamide.


Nicholas Vogelzang, MD: And lending a lot of credence to the idea that the tumor has evolved away from androgen receptor dependence into this more neuroendocrine, more chemotherapy responsive. Have you identified or maybe potentially used the idea that if you have a BRCA or one of the driver mutations, are you thinking that these should be given chemotherapy earlier?

Daniel Petrylak, MD: Yes.

Nicholas Vogelzang, MD: I’ve always wondered about that because my limited experience with BRCA is that they can get long responses to androgen inhibition. But sometimes they’re very short, and then you’re going, OK, I need to treat these guys, and chemotherapy is right there for you.

Daniel Petrylak, MD: This is I think one of the key points about DNA repair. One of the things that we never really, I guess one of the surprises I had in the last couple of years, is that we administer drugs such as abiraterone and you look at the DNA repair enzymes, there’s a downregulation. The same thing with androgen blockade. I could never really rationalize why we were giving radiation therapy plus hormone therapy together. I couldn’t understand the mechanism for that. Now it makes complete sense. By giving combined radiation therapy, hormone therapy, for localized disease you’re downregulating some DNA repair enzymes, you’re making the tumor more sensitive to radiation therapy, and there’s your mechanism. I think we’re understanding more about the biology not only of late-stage disease, but early stage disease by these particular agents.

Nicholas Vogelzang, MD: Going back to the CARD trial, is this practice changing?

Daniel Petrylak, MD: Absolutely, yes.

Nicholas Vogelzang, MD: In say for example, the patient you and I talked about hypothetically, you’ve given them say docetaxel up front for metastatic, or abiraterone up front for metastatic, along with LHRH [luteinizing hormone-releasing hormone] agonists. You’re then moving into a resistant, an AR independent, and you’re going to do SIP-T [sipuleucel-T], and then you’re going to not do a second-generation enzalutamide, or are you? Do you use it the duration?


Daniel Petrylak, MD: The duration, I think this is something that the CARD trial did not account for. One of the things I think we’ve all seen anecdotally is if you respond for a long period to an initial next-generation antiandrogen, you have a lot more likely chance of responding to the second one if it’s a long duration. I’ve had some patients who I’ve treated with multiple hormone treatments. I had 1 patient recently who had been on ketoconazole and hydrocortisone for almost 7 years, and then we put him on abiraterone, prednisone for another 3, and then he got some mileage out of enzalutamide afterward. So biologically what’s different about this patient?

Nicholas Vogelzang, MD: Right. Suggesting that it’s addicted to the androgen receptor.

Daniel Petrylak, MD: Exactly.

Nicholas Vogelzang, MD: There’s something about some of these tumors where they stay androgen sensitive, or at least somewhat androgen sensitive.

Daniel Petrylak, MD: Yes.

Nicholas Vogelzang, MD: The difference in the CARD trial was that they were required to be independent of androgens as based on lack of, or short duration, but not necessarily short duration response to androgen inhibition.

Daniel Petrylak, MD: Exactly.

Nicholas Vogelzang, MD: It’s a challenge, isn’t it, to know what to do.

Daniel Petrylak, MD: It is. You’ve got to tailor to your patients. Now the other issue, too, of course that I think is very important is should you be adding carboplatinum to cabazitaxel based upon The University of Texas MD Anderson Cancer Center data? I tend to do that in a patient who may have liver or visceral disease. And the MD Anderson data are very exciting. It’s being confirmed in a larger randomized trial right now. That’s also another avenue.

Carboplatinum or the platinums have been always there, and they’ve always had a level of activity. We don’t necessarily think about those up front, but these are something we have to think about.

Nicholas Vogelzang, MD: I had a funny anecdote from one of my friends who was trying to get cabazitaxel, got it approved; he wanted to add carboplatin. And when he told them that he was going to give carboplatin and cabazitaxel, they said, “We’re not paying for either one.” He said, “Wait a minute, carboplatin is cheap, and we’ll be happy to eat that cost.” They said, “No, you can’t give the combination.”

Daniel Petrylak, MD: I’ve had something similar where patients have had the cabazitaxel approved, but the carboplatinum disapproved, for you know $300. They said, “Fine, we’ll pay for it.” That’s actually very interesting. It’s unfortunate that the drug satraplatin that we used a number of years ago, that we didn’t understand the DNA repair path. Because I think that trial that Cora Sternberg, MD, Oliver Sartor, MD, and I did would have been a positive study that had....

Nicholas Vogelzang, MD: We saw those small number of patients who had dramatic responses, and the FDA’s look at it was that it didn’t have enough power to show a survival advantage, even though there was a tail. We probably missed an opportunity there.

Daniel Petrylak, MD: Absolutely. I actually tried to recently get that drug for a patient. You can’t get it anymore.

Nicholas Vogelzang, MD: You can’t get it, it’s not available. That’s disappointing. But it’s sad to think that the insurance companies are not letting us use carboplatin, which is well established, and it’s very sporadic, do you notice that?

Daniel Petrylak, MD: Yes, exactly.

Nicholas Vogelzang, MD: One company will say, “We’ll let you use CARBO [carboplatin],” and the other will say, “No, you can’t.”

Daniel Petrylak, MD: I had a patient who, well unfortunately this patient passed away, but he had a CHEK2 mutation, and he unfortunately could not qualify for any of the PARP [poly ADP ribose polymerase] inhibitor trials because of his platelet counts. He actually sued his insurance company; he lost.

Nicholas Vogelzang, MD: He lost.

Daniel Petrylak, MD: Unfortunately he passed away 2 weeks after that event. This again is showing us, we’ve got so much information, and how do we use that, and how do we convince the people who are paying that this is useful? The rapidity of the knowledge is logarithmic. Unfortunately, everything else is lagging behind in getting these to our patients.

Nicholas Vogelzang, MD: Certainly the insurance companies and third-party payers are not necessarily understanding what we are learning. The faster we learn, the harder it is for the insurance companies to keep up.
                                                                                                       
Daniel Petrylak, MD: Perhaps we need as academicians to educate them and help them understand because our patients really deserve this.

Transcript Edited for Clarity
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Transcript:

Nicholas Vogelzang, MD: If you explain these things to the patients, what I often tell the patient is: “Look, the cancer that we started treating you with way back when with androgen deprivation therapy and perhaps docetaxel, now after AR [androgen receptor] inhibition the tumor has evolved. The tumor is now a different tumor.”

We saw the Stand Up to Cancer Dream Team biopsies from UCSF [the University of California San Francisco] showing that a good 20% are neuroendocrine, and there’s no particular clinical feature that predicts for neuroendocrine. So do you have a trigger point for when you’re going to use, for example, cabazitaxel? Let’s talk briefly about that evolution. How early are you using cabazitaxel?

 
Daniel Petrylak, MD: I’m looking at the CARD trial. I think that’s the way I’ve based my practice in the past. The CARD trial was a study that looked at sequential treatments in castrate-resistant disease. Generally we would use a next-generation antiandrogen like abiraterone or enzalutamide first. Then go on to docetaxel. And the question has always been with our patients, what’s the next step that is right? A lot of people will try another next-generation agent. ABI [abiraterone] versus ENZA [enzalutamide], ENZA [enzalutamide] versus ABI [abiraterone]. Or of course go on chemotherapy. And the thought was, well chemotherapy is more toxic, we don’t want to use it in this situation.

But the CARD trial helps answer that particular question. It actually was a very clinically relevant study. Patients who had received either ABI [abiraterone] or ENZA [enzalutamide], then docetaxel, they received the opposite antiandrogen in a randomized fashion, and it was compared to cabazitaxel. And lo and behold, cabazitaxel had a better radiographic progression-free survival, overall survival, better PSA [prostate-specific antigen] decline rate, and also better objective response rate. It seems the cabazitaxel is a superior drug in this particular situation to enzalutamide.


Nicholas Vogelzang, MD: And lending a lot of credence to the idea that the tumor has evolved away from androgen receptor dependence into this more neuroendocrine, more chemotherapy responsive. Have you identified or maybe potentially used the idea that if you have a BRCA or one of the driver mutations, are you thinking that these should be given chemotherapy earlier?

Daniel Petrylak, MD: Yes.

Nicholas Vogelzang, MD: I’ve always wondered about that because my limited experience with BRCA is that they can get long responses to androgen inhibition. But sometimes they’re very short, and then you’re going, OK, I need to treat these guys, and chemotherapy is right there for you.

Daniel Petrylak, MD: This is I think one of the key points about DNA repair. One of the things that we never really, I guess one of the surprises I had in the last couple of years, is that we administer drugs such as abiraterone and you look at the DNA repair enzymes, there’s a downregulation. The same thing with androgen blockade. I could never really rationalize why we were giving radiation therapy plus hormone therapy together. I couldn’t understand the mechanism for that. Now it makes complete sense. By giving combined radiation therapy, hormone therapy, for localized disease you’re downregulating some DNA repair enzymes, you’re making the tumor more sensitive to radiation therapy, and there’s your mechanism. I think we’re understanding more about the biology not only of late-stage disease, but early stage disease by these particular agents.

Nicholas Vogelzang, MD: Going back to the CARD trial, is this practice changing?

Daniel Petrylak, MD: Absolutely, yes.

Nicholas Vogelzang, MD: In say for example, the patient you and I talked about hypothetically, you’ve given them say docetaxel up front for metastatic, or abiraterone up front for metastatic, along with LHRH [luteinizing hormone-releasing hormone] agonists. You’re then moving into a resistant, an AR independent, and you’re going to do SIP-T [sipuleucel-T], and then you’re going to not do a second-generation enzalutamide, or are you? Do you use it the duration?


Daniel Petrylak, MD: The duration, I think this is something that the CARD trial did not account for. One of the things I think we’ve all seen anecdotally is if you respond for a long period to an initial next-generation antiandrogen, you have a lot more likely chance of responding to the second one if it’s a long duration. I’ve had some patients who I’ve treated with multiple hormone treatments. I had 1 patient recently who had been on ketoconazole and hydrocortisone for almost 7 years, and then we put him on abiraterone, prednisone for another 3, and then he got some mileage out of enzalutamide afterward. So biologically what’s different about this patient?

Nicholas Vogelzang, MD: Right. Suggesting that it’s addicted to the androgen receptor.

Daniel Petrylak, MD: Exactly.

Nicholas Vogelzang, MD: There’s something about some of these tumors where they stay androgen sensitive, or at least somewhat androgen sensitive.

Daniel Petrylak, MD: Yes.

Nicholas Vogelzang, MD: The difference in the CARD trial was that they were required to be independent of androgens as based on lack of, or short duration, but not necessarily short duration response to androgen inhibition.

Daniel Petrylak, MD: Exactly.

Nicholas Vogelzang, MD: It’s a challenge, isn’t it, to know what to do.

Daniel Petrylak, MD: It is. You’ve got to tailor to your patients. Now the other issue, too, of course that I think is very important is should you be adding carboplatinum to cabazitaxel based upon The University of Texas MD Anderson Cancer Center data? I tend to do that in a patient who may have liver or visceral disease. And the MD Anderson data are very exciting. It’s being confirmed in a larger randomized trial right now. That’s also another avenue.

Carboplatinum or the platinums have been always there, and they’ve always had a level of activity. We don’t necessarily think about those up front, but these are something we have to think about.

Nicholas Vogelzang, MD: I had a funny anecdote from one of my friends who was trying to get cabazitaxel, got it approved; he wanted to add carboplatin. And when he told them that he was going to give carboplatin and cabazitaxel, they said, “We’re not paying for either one.” He said, “Wait a minute, carboplatin is cheap, and we’ll be happy to eat that cost.” They said, “No, you can’t give the combination.”

Daniel Petrylak, MD: I’ve had something similar where patients have had the cabazitaxel approved, but the carboplatinum disapproved, for you know $300. They said, “Fine, we’ll pay for it.” That’s actually very interesting. It’s unfortunate that the drug satraplatin that we used a number of years ago, that we didn’t understand the DNA repair path. Because I think that trial that Cora Sternberg, MD, Oliver Sartor, MD, and I did would have been a positive study that had....

Nicholas Vogelzang, MD: We saw those small number of patients who had dramatic responses, and the FDA’s look at it was that it didn’t have enough power to show a survival advantage, even though there was a tail. We probably missed an opportunity there.

Daniel Petrylak, MD: Absolutely. I actually tried to recently get that drug for a patient. You can’t get it anymore.

Nicholas Vogelzang, MD: You can’t get it, it’s not available. That’s disappointing. But it’s sad to think that the insurance companies are not letting us use carboplatin, which is well established, and it’s very sporadic, do you notice that?

Daniel Petrylak, MD: Yes, exactly.

Nicholas Vogelzang, MD: One company will say, “We’ll let you use CARBO [carboplatin],” and the other will say, “No, you can’t.”

Daniel Petrylak, MD: I had a patient who, well unfortunately this patient passed away, but he had a CHEK2 mutation, and he unfortunately could not qualify for any of the PARP [poly ADP ribose polymerase] inhibitor trials because of his platelet counts. He actually sued his insurance company; he lost.

Nicholas Vogelzang, MD: He lost.

Daniel Petrylak, MD: Unfortunately he passed away 2 weeks after that event. This again is showing us, we’ve got so much information, and how do we use that, and how do we convince the people who are paying that this is useful? The rapidity of the knowledge is logarithmic. Unfortunately, everything else is lagging behind in getting these to our patients.

Nicholas Vogelzang, MD: Certainly the insurance companies and third-party payers are not necessarily understanding what we are learning. The faster we learn, the harder it is for the insurance companies to keep up.
                                                                                                       
Daniel Petrylak, MD: Perhaps we need as academicians to educate them and help them understand because our patients really deserve this.

Transcript Edited for Clarity
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