Case 3: Use of Radium-223 in mCRPC

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Alicia Morgans, MD:It’s really mechanisms of action over time. You just want to get them all in. And so, that raises a question that I hear in my clinic. People come in for second opinions. “Should I have this, or that?” And one of the things that comes up is, “Is radium-223 only for bone pain? Why would I need that, otherwise?” I really do push back on that, because radium-223 also has a life-prolonging mechanism of action that we see works. Ken, you brought it up earlier as being potentially, for this patient with bone-only metastatic disease, a completely reasonable option. And so, as I’m thinking through the list, if it prolongs life and is potentially going to be effective in my patient, it’s absolutely on the list. It’s something that we talk about. What do you think?

Kenneth Kernen, MD:I think it’s critical to use it earlier. Because when we looked at our initial use of it, patients were only getting maybe 3 or 4 treatments before they were succumbing to the disease. We thought, “Hey, we’re clearly not doing something right.” So we’re really trying to incorporate it as early as possible. And again, if you look at the indications, it’s symptomatic CRPC [castration-resistant prostate cancer]. You have to ask the right questions, right?

“How are you today?” “Oh, I’m fine.” That’s not the right question. And that’s where we use FACT-P [the Functional Assessment of Cancer Therapy-Prostate questionnaire], to tease out the symptoms. I would say that there’s probably no man who’s got metastatic castration-resistant prostate cancer who is not symptomatic. It’s up to us to ask the right questions so that he can get the therapy that’s going to prolong his life, and to get that therapy at a time when it’s going to make a difference.

Neal Shore, MD, FACS:I think your point is spot on. I’ve seen some data by urologists who have clinics like you do. There’s a bit of a differential between the use of radium-223 more aggressively prior to instituting chemotherapy. Part of it may be that medical oncologists who perhaps have a longstanding history of using chemotherapy as the go-to are concerned that maybe they won’t be able to give the chemotherapy post radium-223, which has been disproven. I think there are even some who don’t really understand, to your point, that this is a drug being given for survival prolongation. ALSYMPCA clearly showed that.

A paper published inLancetshowed that pre chemotherapy, it’s a 4.1-month median OS [overall survival] versus 3.1 post chemotherapy. The data are really strongly there now. And it’s so well-tolerated. I’m careful to use this wordwell tolerated. We have to be careful about saying these things. But the level of grade 3/4 [adverse events] is really rather remarkably low. And so, I think that’s part of the education that still hampers radium-223.

Jorge Garcia, MD:Neal, if I may interject, I think one of the concerns to your point is that still, even 2, 3, 4 years later after its approval, people don’t understand the difference between a beta emitter and an alpha emitter, right? And people perceive radium-223 maybe as one of those older radionucleotides that we used to use, that were somewhat toxic. They were great for palliative intent, but were somewhat toxic. But also, if you look at the ALSYMPCA data and the makeup of the trial, roughly 40% of people did not take any opioids, right? So that means people who we would have defined as asymptomatic, or minimally symptomatic patients, because they were taking over-the-counter NSAIDs [nonsteroidal anti-inflammatory drugs], but not opioids.

And lastly, the misconception of, “If I get radium-223, and then I come back to chemotherapy, there’s going to be a significant adverse effect profile.” If you look at the grade 3 and 4 events for thrombocytopenia, for neutropenia, thrombocytopenia and anemia, the difference, at least for neutropenia and thrombocytopenia, goes from 1% to 2%. The instance of grade 3 neutropenia with docetaxel, and even febrile neutropenia, is between 6% to 12% with docetaxel in the TAX 327 and SWOG 9916 studies.

So I always argue, if the concern that you have of using radium-223 is an adverse effect, please, give me a better explanation. If you don’t like it, I’m OK with that. But it cannot be toxicity-dependent, right?

And lastly, how do you define who can get radium-223 and who should not? The median number of cycles given in America is around 4. And most people who actually cannot get beyond 4 cycles either started too late or have progression. But I would argue that in the States it is around 4 cycles.

But we don’t know the time to pain control on radium-223. We know a little bit from the early data, but the reality is that if you see someone with pain, and that pain is multi-level, if you will, that patient should not get radium-223. That patient needs systemic chemotherapy.

So when the time to pain control is critical for you and your patient, I would make that distinction between chemotherapy and radium-223. If you have the time, because you have isolated bone pain, you may even do palliative radiation and come back to radium-223; or maybe you start the patient on radium-223. But if someone is actually really crippled with pain, which could have been a patient who could actually enroll on ALSYMPCA, in my clinical opinion, that patient is not an ideal candidate for radium-223. You don’t have the time for radium-223 to kick in and work for that patient.

Alicia Morgans, MD:This is an incredible discussion here, really focusing on mechanism of action, personalizing care. What are your thoughts, Neal? What are your closing thoughts?

Neal Shore, MD, FACS:Closing thoughts, I like to quote Professor Johann de Bono, who says, “It’s getting really complicated.” So mCRPC [metastatic castration-resistant prostate cancer], advanced prostate cancer, I think is really fun, as a researcher and a clinician. And I say that in the spirit of great, exciting new data that we’ve covered today with the trials. Every one of our congresses, you know, internationally, it’s really tremendous. The intellectual vigor of it is incredibly breathtaking to me, which I think also helps this whole overarching concept of burnout that people talk about. You can’t get burned out when you’re getting great new data and options for our patients. But it is complicated, in that you have to keep up with it all. I think the multidisciplinary team is essential. We keep adding more components to it—interventional radiologists, geneticists, counselors. Learning within our own clinics how to counsel. Cardio-oncologists, the pathologists, etcetera. I think it’s a wonderful time. We still have unmet needs, and we need to continue to address them with proper trials.

Kenneth Kernen, MD:For me, I think it’s all about hope. I say this all the time, but I think this is a great time for our patients. There’s a tremendous amount of hope. There are so many new things that are coming out, and that have come out. We’re turning this into a disease of chronicity, so that these patients can get to all those family events that they want to get to. And we just keep telling them, “We want you to keep going, longer and longer, because there are new things that are going to be out there.” That’s the most important thing, I think, for me—the hope for these patients to live longer. And then that goes with the customization of care that goes with it.

Jorge Garcia, MD:To complement that, there is no doubt that because of what we have done over the last 10 years, there has been a drastic shift in mortality in prostate cancer. And I would argue that most patients with castration-resistant disease have perhaps shifted that completely to the right, and more men are living longer. From the biology perspective of prostate cancer, I think that this is the year that we will say, after 2019, that the molecular revolution and the molecular treatment approach for prostate cancer began. I think that PROfound will demonstrate that, and I’m hoping then with more molecular therapeutics we’re going to be able to actually… We haven’t even time to talk about radioligands, and PSMA [prostate-specific membrane antigen]-bound antibodies, and CAR [chimeric antigen receptor] T-cell therapy, and immunologics. I think the future is bright for our prostate cancer patients, and certainly for us who are vested in what we do for a living, trying to help our prostate cancer patients.

Alicia Morgans, MD:Absolutely. So personalization of care, hope for the future, and multidisciplinary care to support our patients both in disease-directed therapies, but in all of the supportive care and counseling needs that they have. This was a really wonderful discussion.

Thank you, Dr Shore, Dr Kernen, and Dr Garcia, for your thoughtful case presentations and a really lively informative discussion.

To our viewing audience, thank you for joining us for thisTargeted Oncology™ Virtual Tumor Board®presentation. We hope today’s discussion was a valuable use of your time, and that you acquired some practical knowledge that you can take back to your clinic.

Transcript edited for clarity.