Bone Health in Prostate Cancer - A Conversation with Neal Shore and Oliver Sartor
January 20, 2019
Neal Shore and Oliver Sartor have a conversation on bone-targeted agent therapies in prostate cancer, specifically focusing on the ALSYMPCA phase three trial; the design, findings, the addition of radium-223 and what this trial has led to today. They review a few other current ongoing trials including the PEACE III single arm trial and other current approaches in understanding combination therapies in bone health.
A. Oliver Sartor, MD, is currently the Assistant Dean for Oncology at Tulane University School of Medicine, Medical Director of the Tulane Cancer Center and the Laborde Professor for Cancer Research, with appointments in both the Medicine and Urology Departments.
Neal Shore, MD
Neal Shore: So much has happened in the last year with new data in the metastatic castration-resistant prostate cancer space, trial information, new findings, new therapeutics. One of the areas that I've been fascinated by, and you and I share this interest, is in the bone environment, the compartment of the bone. And as everybody knows, starting back with Paget's seminal findings that the seed and soil phenomenon, and particularly as it relates to prostate cancer cells, they just like finding that the bone milieu, it goes from the homeland of the prostate to the "hostland", as Ken Pienta has said.
When I think about the importance of taking care of bone metastases and being preventative, as well as, proactive in how we can avoid complications of bone metastatic castration-resistant prostate cancer. For medical oncologists, urologists, and radiation oncologists, if we look at the seminal work that you did in the ALSYMPCA trial, and then a lot of the studies that have ensued in a fairly quick time, we're now at sort of an interesting crossroads with a lot of learnings. Your thoughts on ALSYMPCA, its design, the findings, and then we can talk about what that's led to today.
Oliver Sartor: Sure, Neal. It's actually kind of interesting, I might even start going back slightly further. The bone tropic nature of prostate cancer, as you noted, goes way back. And I liked the terminology of the "hostland" because that really captures the important essence of the disease. If you go back to even samarium and strontium, were both targeted isotopes that led to palliation, of course, that led to a concept that maybe you can intervene in bone-dominant disease and perhaps change the natural history. And that was sort of the idea behind ALSYMPCA that we would use radium-223, which is a bone-targeted alpha emitter and possibly be able to alter survival, which was a bit of an audacious goal. So it was designed, and one of the nice things about the elements of the design is it incorporated other therapies that people began to use bone-targeted agents, not as standalones but in combination with other agents while they're managing the patient.
ALSYMPCA incorporated that beautifully with a standard of care being used in both arms so that Phase III and then the addition of the radium-223. And of course what was found, and published a journal and the subsequent FDA approvals were affected is that radium could actually pull on survival and decrease things like symptomatic skeletal events who were important for patients, radiation to bone fractures, to bone and spinal cord compression, et cetera. So ALSYMPCA laid a really nice framework for combining these radiopharmaceuticals with other agents that help to lead to a path forward. And that's why I think that was important. I don't know if you would agree or disagree or add to that framework or just, you know, I want to get your own comments as well.
Neal Shore: No, I would absolutely agree and I think the intriguing nature of the design of ALSYMPCA, was for combining the best standard of care at the time. Whether it was a first-generation androgen receptor inhibitor or a steroid or an estrogen or ketoconazole or external beam radiation for palliative therapy. I really liked the idea as a uro-oncologist, that we would try to be combinatorial. Certainly in medical oncology in so many other non-GU disease states, there's a great synergy of combination therapy. But yet interestingly in the advanced castration-resistant prostate cancer, because so many of our approved therapeutics have happened so quickly, one on top of another. We've been lacking in the appropriate prospective combination studies.
But yet in ALSYMPCA, we saw this design of a very smart way to combine, especially as you point out, radium and alpha particle with the very distinct mechanism of action, different from a novel hormonal agent, different from taxanes, different from immunotherapies and different from just androgen deprivation therapy. So we know that always was very intriguing to me. And then we go forward with, as you say, reaching the high bar that radium-223 in the ALSYMPCA trial demonstrated a survival prolongation, and along with the other drugs that are approved for that indication. So naturally, you take that finding, the relatively ease of administration and it's really remarkably well-tolerated safety profile, and you think to yourself, how do we make that even better for the patients where there's the right fit? So maybe your thoughts on what progressed after the approval of ALSYMPCA.
Oliver Sartor: Well, the thing that was remarkable is the pace of change. And it was not just ALSYMPCA that was coming through, all of a sudden we had abiraterone, we had enzalutamide, the idea of incumbent therapy that was raised in ALSYMPCA began to kind of move into the next level. If we learned from ALSYMPCA that there was substantial improvement in the use of bone health agents in combination with radium showing a decrease in the risk of symptomatic skeletal events and, of course, as you move forward you begin to want to incorporate multiple agents, and that was actually done in a trial called the ERA 223. And here there was a very explicit call-out on the abiraterone front, one of the most popular therapies that has been incorporated into advanced disease, and it was a simple design in ERA 223 to be able to take abiraterone as the base then randomized to either radium or no radium. And what they did with the bone health agents, I think may have been a little problematic and we'll cover that in a little more detail. Once they decided in the trial design is that if you were on a bone health agent that you could stay on it. But if you were not on a bone health agent, that the starting of a bone health agent was not allowed. Now as it turned out, of course, many people use the bone health agents, denosumab, zoledronic acid and the like, but that was only the minority of cases. And what happened in the ERA 223, I think we all know, is that the trial was stopped early because of an increased risk of fractures.
And in the initial analysis, it was actually an increased risk of death, which was quite a surprise. So the IDMC stopped the trial early and now we have the opportunity to look back and we get to learn from that experience. And one of the things we've learned from that experience is that there was a really marked impact of the bone health agents on particularly the fracture rate in association with radium. Now diminish the risk of fractures even in the non-radium arm, the abiraterone arm, was particularly profound in combination with radium. So all of a sudden this concept of starting abiraterone and radium at the same time raise safety concerns that were unanticipated. And I think we also had unanticipated learnings about the importance of the bone health agents in the context of a radium abiraterone combination. And again, I don't mean to sort of wax poetic on it, but I want to get your perspective on that as well and see if you would agree, disagree, add, subtract, or your own way of viewing the ERA 223 data.
Neal Shore: Yeah, it's really interesting that there were several early trials that were done. Phase II open-label studies, I did two. Small numbers, about 40 patients open-label where we combined abiraterone with radium and a separate Phase II where we combined enzalutamide with radium. Niraj Agarwal did a fairly similar study too, and these have been presented and published. And it was interesting, demonstrating that for in these trials, there was an opportunity to have somewhere between a 30 to 90-day initiation of either abi or enza and then layer in the radium. And again, small numbers, open-label and there really weren't any problems at all. In fact, they're sure to be very good tolerability. And I mentioned these because it sort of hearkens back to the design of the ALSYMPCA. That radium was designed as a novel alpha particle because of its unique mechanism of action at the bone cortex, shallow penetration into the marrow, less myelosuppressive effects of earlier agents as you said, strong chance samarium and therefore also an opportunity to combine and do better in the long run for our patients.
Lo and behold, as you have really nicely described in ERA 223, that trial had concomitant or virtual simultaneous initiation of abiraterone acetate with prednisone, with the initiation of a course of radium. So what's interesting, and I think it brought to light is a couple of very important things, as you mentioned, what's the role of having a bone protective agent, whether it's a bisphosphonate or a rank wagon inhibitor such as denosumab, onboard. Clearly there's a benefit both in the combined arm and in the just abiraterone alone arm to having a bone health agent. That was very interesting. The other thing you mentioned, which I thought was really important was the interim analysis said there may be an increase in mortality rate, but I think in the final analysis, or the more up to date analysis presented it ESMO in 2018, that it was not actually statistically significant, an imbalance in the death rate.
But to me it brings to bear a more important question is timing. When's the best timing to combine drugs? Is it simultaneously or is there a benefit to starting a drug such as one of the novel hormonal agents abiraterone, enzalutamide. In the future, it could be apalutamide, it could be darolutamide, and giving the bone a chance to adjust. Is there something going on immunologically with T cell infiltration? With blast and classed interaction? Is there an opportunity for there to create a greater stabilization of bone metastatic sites and then add in a really potent apoptotic agent such as radium? What do you think about that?
Oliver Sartor: Very important point. You and I both pointed out, the ERA 223 began with the simultaneous administration with the radium and abiraterone. And I personally think that there is importance to that timing. Neal, you had published, we had published, with a particular registry study, Fred Saad had published or read a few studies showing that actually the combination of abiraterone and enzalutamide with radium in, what we might call, a layering approach where they were not introduced at the same time, both of them seem to indicate, actually, all of them indicated some benefit. And really not without those safety concerns. So this simultaneously beginning therapy with the abiraterone and radium I think is an important distinction from the other studies that have been reported. And then moving forward, we all know that this needs to be tested prospectively. And I'm going to do a shout out for this guy named Neal Shore, who really did a great job in having additional discussions.
And there was a trial with abiraterone that had been under discussion that I had an issue with there, Neal had we gone to have discussions on enzalutamide and we've now come up with a new trial design to take out this timing issue. And Neal, I want you to discuss this new trial design and the incorporation of bone health agents from the very beginning, which was unlike the ERA 223, and we're not going to be banning the use of bone health agencies, in fact, we're going to be encouraged it. But anyway, I wonder if you might kind of cover this new trial design new concept as we begin to think toward the future.
Neal Shore: Well, thanks. Thanks very much, Oliver. I appreciate that. Yeah, I think together you and I are going to co-PI this trial of patients who have M1CRPC disease, and who have not received either abiraterone or enzalutamide during the CRPC transition. And essentially we're going to highly encourage that patients who have bone M1CRPC disease may have some soft tissue as well, who would be appropriate candidates to receive enzalutamide, will have a two-arm trial. Both arms will receive enzalutamide, we'll make sure that they tolerate the drug. We'll make sure that there's an appropriate PSA response, ideally a decline of 30% or more. And we'll monitor these patients for a full 12 weeks and then make that assessment of tolerability as well as the appropriate PSA response to rule out and remove anyone who has a perhaps primary resistance.
And then patients will be randomized to receive a course of radium or a placebo infusion. And I think that'll give us a really nice opportunity to see and investigate the notion of layering, giving the bone a compartment and opportunity to adjust and then hopefully have a synergistic and beneficial effect. But we have to do this prospectively, as you point out, interestingly, there's another trial that's going on right now called PEACE III very similar but very different in those same agents, similar two-arm trial, prospective, blinded, but they're starting the enza/radium arm simultaneously much like they did in the ERA 223. So I'm very excited about this trial. I'm so happy that you're the co-PI on it with me, and I think this is going to be very important for understanding combination therapy.
Oliver Sartor: Yeah. And one last comment on this, is the bone health is really almost a central focus. Yes, there's enzalutamide, yes there's radium, but the strong encourage when they used for the bone health agents. Either denosumab or [inaudible] which are the two FDA approved AIDS in the space, in an effort to ensure that bone health is a priority for these patients going forward. And I think, that's a little bit different than the ALSYMPCA trial where it was an option, a little bit different from the ERA 223 trial where it was an option. Here, there's going to be a very strong encouragement to be utilizing these agents, and I think that that has the potential to provide even more patient benefit.
Neal Shore: Yeah, no, I fully agree. Well, listen, Oliver, as always wonderful talking with you. Thank you.