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Benefits of Radiopharmaceuticals in mCRPC

Panelists:Raoul S. Concepcion, MD, FACS, Urology Associates; Michael D. Fabrizio, MD, FACS, Eastern Virginia Medical School; Jorge A. Garcia, MD, FACP, Taussig Cancer Institute; Judd W. Moul, MD, FACS, Duke University Medical Center; Charles J. Ryan, MD, UCSF Helen Diller Family Comprehensive Cancer Center
Published: Monday, Feb 01, 2016



Transcript:

Raoul S. Concepcion, MD, FACS:
So, this has been a really great discussion about some very important topics, challenges, opportunities. It’s nice to know that everybody has the same questions and that it’s ubiquitous no matter whether you’re in medical oncology or urology, community or academic centers.

We’re going to shift gears a little bit and again talk about another great new therapeutic option, which is radium-223 and its use in terms of management in metastatic castration resistant prostate cancer. Mike, give us a little overview on radium-223: what it is, mechanistically how it works, how you guys are utilizing it in a big urology practice.

Michael Fabrizio, MD, FACS: So, radium-223 is an alpha particle. It was a compound that actually was initially developed in northern Europe. The compound seeks out areas of the bone with rapid turnover, such as the osteoblastic metastasis that you would see in prostate cancer. The compound is actually 1 cc of medication that is infused; it’s been shown in the ALSYMPCA trial to improve overall survival compared with placebo (14.9 months vs 11.3 months). It’s also has been shown to be a very safe compound. Those were the two primary endpoints in that trial. Very little myelosuppression, very few side effects. In fact, in that trial, about 60% of patients had received previous chemotherapy, so they’re already fairly down the path of advanced prostate cancer, and these patients tolerated the drug very well. It actually looks like it decreases skeletal-related events, as well, with many of the other compounds we’ve talked about in this setting.

Raoul S. Concepcion, MD, FACS: So, Judd, you and I are old enough to have used radiopharmaceuticals in the past, right? For the audience that may not be as well versed, we’ve used this in the past and these are tough drugs. How do you differentiate? Why is radium-223 different from the samariums and the strontiums?

Judd W. Moul, MD, FACS: You’re right. We had samarium, strontium, and Quadramet. The problem with those agents is if, as a urologist, we pulled the trigger for one of those agents back in the day, our medical oncology partners would not necessarily be happy with us because of the risk for myelosuppression. And the concern in that era was 1) no real documented survival benefit, and 2) the myelosuppression may limit the use of chemotherapy.

So they were always a challenge, although they were useful for bone pain. Now, radium-223 is the first radiopharmaceutical that actually has a documented survival benefit, and the risk of myelosuppression is much less. It’s not zero. There is still some risk, but it’s much less, so the drug can be administered a little bit easier and can be done a little bit earlier and doesn’t burn the bridge for chemotherapy.

Raoul S. Concepcion, MD, FACS: As Mike mentioned, ALSYMPCA was the registry trial. It was a multi-national trial. I believe you had to be minimally symptomatic or asymptomatic. You could not have planned cytotoxic chemotherapy to be given concomitantly. However, there were a number of patients who did. What was the number, Jorge, that had actually received prior chemotherapy in ALSYMPCA?

Jorge A. Garcia, MD, FACP: So what Mike said, around 60% of patients.

Michael Fabrizio, MD, FACS: And you could not have visceral metastases, as well ?

Jorge A. Garcia, MD, FACP: Correct.

Raoul S. Concepcion, MD, FACS: No visceral metastases. From a medical oncology standpoint, like Mike said, we know there is still some element of myelosuppression. How does that change your thinking in terms of layering sequencing with potential use concomitantly with taxanes, etc?

Jorge A. Garcia, MD, FACP: I think that one of the challenges with radium-223 is the lack of understanding between what an alpha particle is and what a beta particle is. I think there is still a misconception that it’s a nucleotide that will likely lead to the same myelosuppression without survival benefit, which is not the case. The second issue is that the patient population of ALSYMPCA was a very heterogeneous patient population because some people had chemotherapy before, some people were chemotherapy- naïve.

Now, it is important to remind you that when you look at the ALSYMPCA data, patients with visceral disease were not allowed to be enrolled in the trial. But more important than that is how much pain you needed to have to be enrolled. And in that data, actually around 40% of patients or so were not taking opioids, suggesting that you don’t need to be taking opioids to achieve benefit from this therapy.

The second challenge that I see with radium-223 is, how do you think of it? When do you use it? I fundamentally believe that radium-223 is not either/or. In my personal practice, I think that the radium-223 should be utilized as a continuum of the castration resistant process. And that means that when I make that decision that a patient gets on radium-223, I don’t necessarily have to stop my oral therapy.

In fact, if you look at the best supportive care as how it was defined in the ALSYMPCA data, they allow ketoconazole. Well, I don’t think of abiraterone as a ketoconazole, but I think it’s a much more selective powerful agent, more expensive, but yet leading to similar efficacy, mechanistically speaking. And they also allow AR blockers, probably referring to nilutamide, flutamide, and bicalutamide. But enzalutamide is an AR blocker.

So, for me, philosophically, I think that on most of my patients when I start therapy early, they actually stay on oral therapy and I piggyback and add radium-223 into that context.

Michael Fabrizio, MD, FACS: We do the same thing, and, actually, 4% were on enzalutamide. It just hadn’t been approved.

Jorge A. Garcia, MD, FACP: Correct.

Michael Fabrizio, MD, FACS: To that point, 20% were on abiraterone in this trial, so you could continue these medications.

Charles J. Ryan, MD: The chemotherapy combination is a little more complicated.

Jorge A. Garcia, MD, FACP: Correct, correct.

Charles J. Ryan, MD: But certainly, I think that’s the direction things are going. When I first saw these data a few years ago, we had phase II data that looked impressive and the phase III data were very similar, and I wondered if this would be a therapy that would basically replace zoledronic acid and denosumab. And I think that’s the other sort of avenue to talk about; I don’t think is replaces denosumab.

In fact, if you look at the data from the expanded access program, the patients who took both radium-223 and a RANK ligand inhibitor had a superior outcome. So, it’s not one or the other; it’s sort of additive.

Michael Fabrizio, MD, FACS: And I think it’s important to make note that these patients could be on a baby aspirin or Tylenol for pain. They may be taking this, and a lot of it’s not often times reflected in the medical record medication list. So, you really have to talk to these patients because they may take the Tylenol every day but fail to tell the nurse inputting the data that they’re on this medication regularly.

They just take it for symptoms. And these are the patients you want to use this on the continuum a little earlier. Patients with metastatic disease or castrate resistant benefit from these drugs, particularly radium-223.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity

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Transcript:

Raoul S. Concepcion, MD, FACS:
So, this has been a really great discussion about some very important topics, challenges, opportunities. It’s nice to know that everybody has the same questions and that it’s ubiquitous no matter whether you’re in medical oncology or urology, community or academic centers.

We’re going to shift gears a little bit and again talk about another great new therapeutic option, which is radium-223 and its use in terms of management in metastatic castration resistant prostate cancer. Mike, give us a little overview on radium-223: what it is, mechanistically how it works, how you guys are utilizing it in a big urology practice.

Michael Fabrizio, MD, FACS: So, radium-223 is an alpha particle. It was a compound that actually was initially developed in northern Europe. The compound seeks out areas of the bone with rapid turnover, such as the osteoblastic metastasis that you would see in prostate cancer. The compound is actually 1 cc of medication that is infused; it’s been shown in the ALSYMPCA trial to improve overall survival compared with placebo (14.9 months vs 11.3 months). It’s also has been shown to be a very safe compound. Those were the two primary endpoints in that trial. Very little myelosuppression, very few side effects. In fact, in that trial, about 60% of patients had received previous chemotherapy, so they’re already fairly down the path of advanced prostate cancer, and these patients tolerated the drug very well. It actually looks like it decreases skeletal-related events, as well, with many of the other compounds we’ve talked about in this setting.

Raoul S. Concepcion, MD, FACS: So, Judd, you and I are old enough to have used radiopharmaceuticals in the past, right? For the audience that may not be as well versed, we’ve used this in the past and these are tough drugs. How do you differentiate? Why is radium-223 different from the samariums and the strontiums?

Judd W. Moul, MD, FACS: You’re right. We had samarium, strontium, and Quadramet. The problem with those agents is if, as a urologist, we pulled the trigger for one of those agents back in the day, our medical oncology partners would not necessarily be happy with us because of the risk for myelosuppression. And the concern in that era was 1) no real documented survival benefit, and 2) the myelosuppression may limit the use of chemotherapy.

So they were always a challenge, although they were useful for bone pain. Now, radium-223 is the first radiopharmaceutical that actually has a documented survival benefit, and the risk of myelosuppression is much less. It’s not zero. There is still some risk, but it’s much less, so the drug can be administered a little bit easier and can be done a little bit earlier and doesn’t burn the bridge for chemotherapy.

Raoul S. Concepcion, MD, FACS: As Mike mentioned, ALSYMPCA was the registry trial. It was a multi-national trial. I believe you had to be minimally symptomatic or asymptomatic. You could not have planned cytotoxic chemotherapy to be given concomitantly. However, there were a number of patients who did. What was the number, Jorge, that had actually received prior chemotherapy in ALSYMPCA?

Jorge A. Garcia, MD, FACP: So what Mike said, around 60% of patients.

Michael Fabrizio, MD, FACS: And you could not have visceral metastases, as well ?

Jorge A. Garcia, MD, FACP: Correct.

Raoul S. Concepcion, MD, FACS: No visceral metastases. From a medical oncology standpoint, like Mike said, we know there is still some element of myelosuppression. How does that change your thinking in terms of layering sequencing with potential use concomitantly with taxanes, etc?

Jorge A. Garcia, MD, FACP: I think that one of the challenges with radium-223 is the lack of understanding between what an alpha particle is and what a beta particle is. I think there is still a misconception that it’s a nucleotide that will likely lead to the same myelosuppression without survival benefit, which is not the case. The second issue is that the patient population of ALSYMPCA was a very heterogeneous patient population because some people had chemotherapy before, some people were chemotherapy- naïve.

Now, it is important to remind you that when you look at the ALSYMPCA data, patients with visceral disease were not allowed to be enrolled in the trial. But more important than that is how much pain you needed to have to be enrolled. And in that data, actually around 40% of patients or so were not taking opioids, suggesting that you don’t need to be taking opioids to achieve benefit from this therapy.

The second challenge that I see with radium-223 is, how do you think of it? When do you use it? I fundamentally believe that radium-223 is not either/or. In my personal practice, I think that the radium-223 should be utilized as a continuum of the castration resistant process. And that means that when I make that decision that a patient gets on radium-223, I don’t necessarily have to stop my oral therapy.

In fact, if you look at the best supportive care as how it was defined in the ALSYMPCA data, they allow ketoconazole. Well, I don’t think of abiraterone as a ketoconazole, but I think it’s a much more selective powerful agent, more expensive, but yet leading to similar efficacy, mechanistically speaking. And they also allow AR blockers, probably referring to nilutamide, flutamide, and bicalutamide. But enzalutamide is an AR blocker.

So, for me, philosophically, I think that on most of my patients when I start therapy early, they actually stay on oral therapy and I piggyback and add radium-223 into that context.

Michael Fabrizio, MD, FACS: We do the same thing, and, actually, 4% were on enzalutamide. It just hadn’t been approved.

Jorge A. Garcia, MD, FACP: Correct.

Michael Fabrizio, MD, FACS: To that point, 20% were on abiraterone in this trial, so you could continue these medications.

Charles J. Ryan, MD: The chemotherapy combination is a little more complicated.

Jorge A. Garcia, MD, FACP: Correct, correct.

Charles J. Ryan, MD: But certainly, I think that’s the direction things are going. When I first saw these data a few years ago, we had phase II data that looked impressive and the phase III data were very similar, and I wondered if this would be a therapy that would basically replace zoledronic acid and denosumab. And I think that’s the other sort of avenue to talk about; I don’t think is replaces denosumab.

In fact, if you look at the data from the expanded access program, the patients who took both radium-223 and a RANK ligand inhibitor had a superior outcome. So, it’s not one or the other; it’s sort of additive.

Michael Fabrizio, MD, FACS: And I think it’s important to make note that these patients could be on a baby aspirin or Tylenol for pain. They may be taking this, and a lot of it’s not often times reflected in the medical record medication list. So, you really have to talk to these patients because they may take the Tylenol every day but fail to tell the nurse inputting the data that they’re on this medication regularly.

They just take it for symptoms. And these are the patients you want to use this on the continuum a little earlier. Patients with metastatic disease or castrate resistant benefit from these drugs, particularly radium-223.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: Personalized Sequencing in Castration-Resistant Prostate Cancer: Bridging the Latest Evidence to the Bedside in Clinical ManagementAug 25, 20181.5
Community Practice Connections™: Precision Medicine for Community Oncologists: Assessing the Role of Tumor-Testing Technologies in Cancer CareNov 30, 20181.0
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