Case 3: Treatment After Progression to mCRPC

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Alicia Morgans, MD:Jorge, I know you’re very familiar with the data. As medical oncologists, our antennas kind of perk up when we hear about people thinking about combining radium with other agents, and not thinking about things, as Ken mentioned, such as bone health. What are your thoughts on that, Jorge?

Jorge Garcia, MD:This is sort of bread and butter for us, in our clinic, obviously. But there a few things, before I answer your question, that I think are important. There is the notion that these patients receive ADT [androgen deprivation therapy]/docetaxel, progress, and now we’re going to give them abiraterone, for which there are no data, at least prospectively. We know of the COUGAR-AA-302 data, and the PREVAIL data, right? The radium-223 may be the exception. And we know of the TROPIC data. These are trials that really actually got the approval of these agents in the true castration-resistant setting, but in patients who never had received prior therapy. So nowadays, when you move the oral agents and docetaxel up front, I think the biology of your disease, in my opinion, has to be different. I don’t know if abiraterone is the right agent for this patient. I think most of us will do that just because we don’t have better data.

I think the bigger question is, when you progress on ADT and docetaxel, what would you do? You can do cabazitaxel. You can do oral abiraterone. You can do oral enzalutamide. You could do radium-223. Some people may argue that you can do sipuleucel-T in this context, right? I think that if one makes the decision to do abiraterone, I’m bothered by 2 things. Number 1, his time to biochemical recurrence or development of castration-resistant disease was less than a year, right? On ADT/docetaxel, that’s just no good.

Secondly, how do you define castration-resistant disease? There is a misconception that you need to have pain, radiographic progression, and rising PSA [prostate-specific antigen] to meet the definition for castration-resistant, but that’s not the case. What is defined, as you pointed out, Neal, quite well, is that you must have a testosterone that is under 50 [ng/dL], at least for us in the United States. But, I agree with you. His testosterone on ADT is 43 [ng/dL]. That’s pretty good for a guy who is getting ADT, quote/unquote, right?

But if your testosterone, by guideline, is less than 50 [ng/dL], you only need 1 of those 3: Either a rise in your PSA, or symptomatic progression, or radiographic progression. So I think the treatment choice for a guy like this will be totally dependent, at least in my opinion, based upon, are you progressing because your PSA is rising? Or are you progressing because you now have symptoms and you also have radiographic progression? I think this patient, to me, is a bit different than a patient who only has a rise in PSA after ADT and docetaxel. Both are castration-resistant, but 1 patient may require a different therapy.

Now, I agree with you that sequential oral therapy, although it is still commonly done in the United States… I don’t want to be dishonest. I have used it, sometimes. I’ve used it because it’s hard to justify to patients who don’t have a bed of symptoms, to move them to chemotherapy, in that context.

But I think the CARD data, which are the data from the European region just presented at ESMO [the European Society for Medical Oncology annual meeting] and published just a few weeks ago, clearly demonstrate, once and for all, that if you randomize men who have become castration-resistant, who have actually received abiraterone or enzalutamide, and you cross them over to an oral agent that they didn’t receive before, or to cabazitaxel, people with cabazitaxel have a better rPFS [radiographic progression-free survival], and have a better chance of survival benefit, response, and so forth.

So those data are what I use right now to try to convince my patients that despite their reluctancy for toxicities from chemotherapy, the best data that we have right now—prospective Level 1 data—are that you need to move on to a chemotherapy, in the context of this patient.

And lastly, I want to talk a little about bone health. When I think of bone health, I think it’s relevant for our patients, but I think there are misconceptions about the importance of bone health in the United States, at least for our prostate cancer patients. Is the aim to decrease bone loss; therefore, minimizing the risk of osteopenia and osteoporosis? That’s 1. Or for example, with denosumab in the M0 CRPC [castration-resistant prostate cancer] space, is the goal delaying skeletal progression? Or is the goal of delaying the skeletal-related events only in the castration-resistant prostate cancer space?

I used to be pretty opinionated about the early utilization of bone health agents. But to your question, and I’m sorry that it’s taking me longer to get to your question, the ERA 223 data are the data that, to me, really opened my eyes to the importance of bone health agents. Basically, it was a randomized trial looking at radium-223 as a radionucleotide plus abiraterone against abiraterone plus placebo. And that data demonstrated that there are increasing skeletal-related complications when you do both agents together.

Now, the misconception of that data, to me, is that radium should not be used early. That, I think, is a misconception. It didn’t address that question. It was the question of using the treatments together—an oral agent and radium-223. The data clearly show that there’s a significant issue with fractures and skeletal-related events, speaking to the fact that we may actually be undertreating patients with bone health agents.

So I think that tells me that we have to be far more aggressive with bone health agents earlier. But again, the question is in regard to the doses, the frequency, and the schema you’re going to use for bone health agents in the castration-naïve or castration-sensitive space.

PEACE III, actually combining radium-223 and enzalutamide, demonstrated that there was not a drastic difference in the skeletal-related events if you were actually taking bone health agents. But when you were not, there was a huge disproportion of patients getting complications with fractures and so forth. I don’t know the mechanism of why patients, when they receive combination therapy, have more bone-related issues. But I do know that has to do with bone health, and I think that we still have to try to think a bit more as to why that happens.

Neal Shore, MD, FACS:Yes, there’s an interim analysis of PEACE III that showed that if you give the concomitant denosumab or bisphosphonate, you dramatically delay symptomatic skeletal events. So it’s clearly a phenomenon. But the other thing is, if you go back and think about the RECIST [Response Evaluation Criteria in Solid Tumors] criteria, RECIST was essentially described because of the tumor flare that you see when you give abiraterone and/or enzalutamide. So there’s a tumor flare. You see it in a lot of different therapies. You see tumor flare, and I think there’s a lot that we don’t know about what’s going on in the bone compartment.

And so, is there an opportunity at some point? Is it 30 days? Is it 120 days, when you start abiraterone or enzalutamide, to let the bone readjust and get the homeostasis between blast and class, concomitantly giving a bone health agent, and then you give the radium? That’s why I think layered trials, and on top of the PEACE III trial, which is a concomitant, much like the ERA 223 trial… and we’re involved in putting together a really large trial to look at that and the sequencing concept, which I think could be a differentiator. But we don’t know. We need that data.

Alicia Morgans, MD:I agree, and I think that with PEACE III, the importance was that we saw the level of fracture basically come to 0. So if we address bone health, whether the combination is better or not, I think we can figure it out. But we have to address bone health. I also think that we shouldn’t necessarily be trying our own layering in the clinic, just combining agents, until we get some of these answers. That’s why I think it’s wonderful that you’re actually looking into this, and are really trying to dig more deeply.

Transcript edited for clarity.