Transcript:Jorge A. Garcia, MD, FACP: Perhaps the biggest controversy right now that we have when we think about using radium-223 is the timing and the patient phenotype. So, one of the biggest concerns right now is I don’t want to put you on radium-223 before chemo because if I go and give you radium-223, the likelihood of you developing myelosuppression when you receive subsequent chemotherapy is going to be greater. And, if you look at the ALSYMPCA data and the expanded access data, the incidence of grade 3 and 4 neutropenia in the ALSYMPCA was around 1% to 2% for chemo-naïve patients.

And for those patients who went on to actually get chemotherapy, it was around 3% to 4%. And I just remind the group that if you look at the incidence of grade 3 and 4 neutropenia when we use taxanes in TAX 327, SWOG 9916, and the early chemotherapy data, it’s been 5% to 7%, so it’s not really drastically different in that context. I think that earlier may actually be probably the right opportunity for this compound rather than using it later.

And secondly is how long it takes you to have pain control, something that actually hasn’t been published. And, in reality, when I think of who is a great candidate for radium-223, if you have a lot of pain needs and you need rapid pain control, I personally don’t believe radium-223 is the right agent. You can actually get rapid pain control with systemic chemotherapy within a week of therapy. If you look at the median time to pain control on the phase I/II data, it’s around three cycles.

Michael Fabrizio, MD, FACS: Three to four doses, that’s right.

Jorge A. Garcia, MD, FACP: Because sometimes patients don’t have three months to wait to have pain control.

Michael Fabrizio, MD, FACS: That’s correct.

Jorge A. Garcia, MD, FACP: So, I think it’s an important point to re-emphasize to the group, which is early may be better because you have the time to actually invest in the therapy and not rush controlling pain.

Raoul S. Concepcion, MD, FACS: With that being said though, if you had a patient with multiple bony metastases, let’s say it’s high-volume, and you do have one specific spot that clearly is the symptomatic lesion, a lot of people will also start radium, as well as give local external beam into that area for pain.

Michael Fabrizio, MD, FACS: Yes, you can do that.

Raoul S. Concepcion, MD, FACS: I’m just going to change the discussion here a little bit. I think we all agree that it’s a huge mistake to wait until these patients become incredibly symptomatic, vis-a-vis opioid use, to institute this therapy. I think we all agree we need to better define what those windows are. We talked a little bit in the last segment about primary and secondary resistance mechanisms.

I’d be curious to hear the panel’s discussion about how we’re not doing anything to the androgen receptor, given the fact that this is a calcimimetic agent but it still has a survival benefit. Routinely we’ll start an androgen access modulator, whether it’s abiraterone or enzalutamide. Do any of you worry by concomitantly starting abiraterone or enzalutamide, could we be forcing a mutation if a patient just has primarily bony disease and causing these cells to develop this secondary resistance mechanisms, or am I overthinking this?

Jorge A. Garcia, MD, FACP: No. We have these patients who have great responses to oral therapy, and you have to be scared of how they progress because they develop very unusual sites of metastases. They develop visceral disease, lung disease.

One of the biggest challenges right now in the castration resistant setting is how do we develop resistance to these agents? And Chuck alluded to that earlier—there may be glucocorticoid receptor mutations and so forth—but without understanding truly how these things happen, it is very hard to understand how people will evolve and progress. But I’ll tell you that when you see patients who actually have had great responses to oral therapy and they progress, they, to me, become AR-nulled.

They’re not driven by AR anymore, and the reality of it is how much of that will be impacted by radionucleotides. I don’t think we really understand whether or not the combination will lead to early resistance or not. I think it’s mostly a clinical type of management. I mean, who would ever thought that an alpha emitter would actually lead to survival improvement, right?

Michael Fabrizio, MD, FACS: Yes.

Jorge A. Garcia, MD, FACP: None of us were expecting that.

Raoul S. Concepcion, MD, FACS: And we now can’t use your PSA.

Jorge A. Garcia, MD, FACP: Correct.

Raoul S. Concepcion, MD, FACS: Four week, eight week, 12 weeks because we know that for the most part in the trial, there was not a PSA reduction.

Charles J. Ryan, MD: It’s a different category of therapy, yeah.

Raoul S. Concepcion, MD, FACS: Right.

Jorge A. Garcia, MD, FACP: Well, 16% of patients on ALSYMPCA had a PSA decline greater than 50%, so there is a small percentage of patients who do have PSA declines. But I would argue that when you see a patient and you make that choice of starting radium-223, you have to explain to the patient that PSA cannot be followed in the context of that treatment.

Judd W. Moul, MD, FACS: For those urologists who manage castrate-resistant prostate cancer, I still think there’s a lot of confusion about where to sequence radium-223. And just to follow up on the question I asked before, the gentleman who goes on oral therapy, enzalutamide or abiraterone, suboptimal response, poor response at 12 weeks, do you ever sequence radium-223 at that point or is that too early? Where’s the sweet spot?

Raoul S. Concepcion, MD, FACS: We know that in the US that the approval for radium-223 is for those patients who are minimally symptomatic. So what Mike and I discussed offline is that, as urologists, how many patients do we have that are walking around who are close to super scans but clearly have 10-20 bone mets who are completely asymptomatic. And they’re a walking time bomb, as far as I’m concerned.

Judd W. Moul, MD, FACS: Or they’re stoic individuals. There are a lot of guys.

Michael Fabrizio, MD, FACS: That’s right, exactly.

Judd W. Moul, MD, FACS: There are a lot of guys who basically just are tough guys. They don’t admit that they have pain, even though if you ask their wife or their daughter, it’s usually the daughter who’s all over the Internet; they’ll admit that dad does have pain. But he comes in. I had a physician recently who is still practicing medicine in his early 80s and is trying to manage castrate-resistant prostate cancer so he can maintain his practice. And he needs these products, but he refuses to admit that he has pain.

Charles J. Ryan, MD: Again, if you ask somebody do you have pain, that’s one approach where you’re going to get a yes or no answer and patients understand the implications of having pain. They’re smarter than we are about these types of things. But there are objective ways you can figure this out. Alkaline phosphatase if it’s climbing, LDH if it’s climbing, albumin if it’s dropping. These are all validated markers of disease progression and morbidity. And as a practical point, I always ask people what they do with their day and how differently is that from six months ago.

Michael Fabrizio, MD, FACS: Describe your day.

Charles J. Ryan, MD: You’ll be surprised, and that’s where the daughter chimes in and says, “Dad, you’re taking three-hour naps.”

Michael Fabrizio, MD, FACS: And he takes five Tylenol or six Tylenol a day. And then the other thing to remember, and it’s the recurrent theme for this entire discussion, is that overall survival in these patients was better with a better ECOG status, a lower alkaline phosphatase. Once again, hitting these patients earlier in their disease, theoretically. And so I think you really have to ask.

Transcript Edited For Clarity