Transcript:Raoul S. Concepcion, MD: Ash, from a scientific standpoint, why is it that prostate seems to have this predilection for bone? What is it about that?

Ashley E. Ross, MD, PhD: So, I can’t speak with huge expertise here, but when you look at the chemotactic molecules on prostate cancer, they do tend to be very similar to things that get expressed with bone remodeling and also to going to lymphatics as opposed to the visceral metastasis. The visceral disease is a completely different category. It may have to do more with these neuroendocrine small cell—type features. And I think that’s why you look at trial data or you look at your patients that are fundamentally treated differently. No one knows evolutionarily why SDF-1 and these other factors are expressed on the prostate, but it does make the idea of targeting the bone particularly more palpable. And also, when we talk about disease that we can see and whether the microcosm of disease is different than the lone metastasis, I think there is a difference. If you look at some of the papers that are now using deep sequencing delaying clonal evolution, we see that these metastases are going to these different areas. They seem to be educating themselves and then going out or even back to the primary.

And so, having an agent like the radium-223 that can target the bone niche may actually alter the way that the metastatic progression happens. How will we target the soft tissue in the same regard? Is it going to be like the 177lutetium-labeled PSMA (prostate-specific membrane antigen) compound? They’re doing some of that in Europe. I’m skeptical because there’s a little bit of a specificity issue there. But in terms of metastasis-directed therapies, can we use something that alters the process by which the prostate cancer targets its way to the bone? I don’t know if that’s going to be the solution because if you think about that kind of therapy, it would be something you’d be on chronically to prevent an event from happening, to prevent the cells going through an EMT transition to get out into the bloodstream. It would become more stem-like, be more mesenchymal-like, and then be this MET (mesenchymal to an epithelial) transition back into the bone. I don’t think that would work, but perhaps doing something that exposes the cells out of their microenvironment to make it more susceptible to therapeutics, causing that transition from mesenchymal to more epithelial so it can be susceptible to a therapeutic agent. That’s an interesting strategy people like Dr. Pienta have been trying to explore, but there hasn’t been that much headway. Maybe there’s more to come.

Raoul S. Concepcion, MD: Again, I think what’s interesting is that you hear from these radiation oncologists all the time—it’s a great concept—about this abscopal effect, where they radiate, you get androgen spread. So, to me, I think we can actually talk about this. Does that open up the world for the use of radium-223 to take advantage of the abscopal effect and then combine it with an immunotherapy?

Ashley E. Ross, MD, PhD: I believe in the abscopal effect strongly. In the melanoma space, there’s a great case report by maybe the most famous case reporter of our time, this Postow report, where the lady was on ipilimumab therapy but progressing, and she had a metastasis that was near her spine. They radiated stereotactically, and suddenly, there’s regression of metastases in the lungs, metastases in the mediastinal, all that stuff. In fact, I’ll disclose here, I have a clinical trial that’s ongoing for metastatic prostate cancer using cryoablation to the abscopal effect with PD-1. There’s a lot of interest in radium-223, combining it with a less toxic immunotherapy. And so, I think there’s an interest in anti—PD-1 therapy with radium-223. I’m not sure, but is that trial off the ground yet?

Alicia K. Morgans, MD, MPH: I don’t know that it’s launched, but it’s moving forward.

Ashley E. Ross, MD, PhD: By concept, I think that particularly with an immunotherapy that has some toxicity but nowhere near the pneumonitis or colitis of anti-CTLA4 therapy, this is the type of pilot that we have to explore. I think combining it with radium makes a lot of sense.

Raoul S. Concepcion, MD: Do prostate cancer cells express a lot of PD-L1?

Alicia K. Morgans, MD, MPH: No.

Jorge A. Garcia, MD: That’s actually one of the challenges. Prostate has been the “orphan child” when you look at it immuno-oncology (I-O) agents. The ipilimumab data were from a negative trial. Right now, looking at nivolumab and pembrolizumab in the context of prostate cancer, the data so far doesn’t appear to be that great compared with melanoma, head and neck, lung, and so forth. What is it about the prostate cancer and the immune-infiltrating tumor cells, however you define those? I really don’t know, but I’m not sure PD-1 therapy or I-O therapy by themselves independently will actually really pan out to be truly effective in prostate cancer. And I think, to your point, there is far more excitement to do combination trials looking at radiation plus I-O therapy, whether it’s brachytherapy plus a PD-1 or it is external-beam radiation therapy plus PD-1, because of the comments that you just made.

With radium-223, one of the biggest challenges is that we truly don’t understand how it works and whether it is that transition from epithelial to mesenchymal. I really don’t know, but it’s pretty powerful to know that a big fat molecule compared with the old parameters can actually target your bone and actually drastically lead to survival improvement. I think that most of us are still inquiring about why that is the case, but I’m not sure that we truly know. And one of the challenges with radium-223, again, is just lack of science. This is no different than sipuleucel-T. We know that sipuleucel-T makes people live longer, but what is the immunogenicity of how it does it? So, it’s not really well understood.

Transcript Edited for Clarity