Radium-223 plus Enzalutamide vs Enzalutamide Alone in Metastatic Castration-Resistant Prostate Cancer - Benjamin Maughan

March 9, 2021

Benjamin Maughan, MD joins Charles Ryan, MD in a discussion on investigational therapy currently being testing of a combination of enzalutamide and radium-223 compared to enzalutamide alone, both FDA-approved therapies for metastatic castration-resistant prostate cancer (mCRPC). This was a randomized study, patients were randomized to standard of care and enzalutamide or six cycles of radium plus the standard of care, enzalutamide. The study tested the hypothesis that combination therapy is more potent and leads to greater clinical benefit than sequential single-agent therapy. At the 2021 GU ASCO Symposium the final efficacy and safety results for this trial were presented.


Benjamin L. Maughan, MD, PharmD, Assistant Professor in the Division of Medical Oncology at Huntsman Cancer Institute, the University of Utah, Salt Lake City, Utah, United States

Charles J. Ryan, MD, the President and Chief Executive Officer of The Prostate Cancer Foundation (PCF), the world’s leading philanthropic organization dedicated to funding life-saving prostate cancer research. Charles J. Ryan is an internationally recognized genitourinary (GU) oncologist with expertise in the biology and treatment of advanced prostate cancer. Dr. Ryan joined the PCF from the University of Minnesota, Minneapolis, where he served as Director of the Hematology, Oncology, and Transplantation Division in the Department of Medicine. He also served as Associate Director for Clinical Research in the Masonic Cancer Center and held the B.J. Kennedy Chair in Clinical Medical Oncology.

Read the Full Video Transcript

Chuck Ryan: Hi, I'm Chuck Ryan from the University of Minnesota, and I'm delighted today to be joined by Benjamin Maughan, who is an assistant professor at the University of Utah's Huntsman Cancer Institute, where he is a member of the GU oncology program there. They presented recently a phase II study of radium-223 plus enzalutamide versus enzalutamide alone. Of course, radium combinations have been a hot topic of conversation and over the last couple of years and continue to be studied. Welcome, Ben. I'm eager to hear about your study. Tell us a little bit about it.

Ben Maughan: Well, thank you. I'm so happy and privileged to be here to talk about this research. This is a pretty exciting investigational therapy that we were testing of a combination of enzalutamide and radium compared to enzalutamide alone, both FDA-approved therapies for metastatic castration-resistant, prostate cancer. Based on a lot of the seminal work that's been done over the past 10 years, looking at combination therapies in the metastatic hormone-sensitive space with things like LATITUDE and CHAARTED, and TITAN, effectively, we are testing the same hypothesis, that combination therapy is more potent and leads to greater clinical benefit than sequential single-agent therapy. That is the concept that we are evaluating in this clinical trial. It was a randomized study, so patients were randomized to standard of care and enzalutamide or six cycles of radium plus again, the standard of care enzalutamide. Interestingly though, we, chose, well.  I guess I would say one of the challenges with radium therapy is that there is no good marker of response.

For most patients, PSA rises while they are on therapy, despite having a proven overall survival benefit, as demonstrated in the ALSYMPCA trial. Most patients have a decrease in their alkaline phosphatase, so you can not use that as a sort of surrogate PSA if you will because radium is only approved for patients with bone-only metastases. There is no radiographic response that you can see. You can measure disease progression on a scan if they have a new soft tissue lesion or new bone metastasis consistently over time, but there is no good way to really measure response, which is important when you are talking about these discussions with patients. They want to know, is this helping me or not? So, to also help address that issue, we were evaluating a pharmacodynamic endpoint in this study, looking at the change in bone metabolism markers, and then seeing how that correlates with clinical endpoints like PSA responses or progression-free survival, those more well-defined clinical endpoints. That is how we designed this study.

Chuck Ryan: What were your bone metabolism endpoint markers and are these things that clinicians should be looking at in the radium patients that they treat in the standard of care setting?

Ben Maughan: Yeah. That's a great question. The markers that we picked are standard lab tests that you can get for patients that you are evaluating for osteoporosis, for instance. Now, to sort of simplify it, there were a number of bone markers that we evaluated, but the primary endpoint was an evaluation of a single one of these bone markers, N-telopeptide, to see if there was a significant change of response with that marker. And, again, we did evaluate a number of other ones, bone-specific alkaline, phosphatase, [inaudible], and some others. Now, I will say it is intriguing that there are some other clinical trials, for instance, a radium trial in kidney cancer that took a similar approach and evaluated a lot of these same bone markers. Again, there was a demonstration of clinical benefit.

There was a SWOG clinical trial following the same concept, proving that patients who have a decrease in these bone metabolism markers also tended to have a better clinical response to therapy. This concept has been reproduced a couple of times, but I will say it's not something that I would recommend is done yet as a standard of care, simply because for the most part, these are signal finding or pilot phase two studies that have been done. We really need to see this validated in a large prospective phase three cohort.

Chuck Ryan: So, in your standard of care setting, when you would use radium, for example, you do not follow N-telopeptide and those types of markers to determine if you are getting a benefit from the radium?

Ben Maughan: Correct. I still sort of struggle in the dark, like the rest of us. Yeah.

Chuck Ryan: Yeah. Good, good. One of the challenges that came up in the previous study where abiraterone was combined with radium was there was an excess of fractures. It led to study termination, but post-talk analysis essentially revealed that if a patient is taking a bone-targeted therapy and the radium and the abiraterone, that sort of fracture risk was mitigated or went away. Did you control for bone-targeted therapies in this study? What are your thoughts on that sort of issue?

Ben Maughan: Yeah. That is a really critical issue that I think up until recently when the ERA 223 trial was published, I think it was a very underappreciated aspect of how we should be thinking about and taking care of our patients with bone metastasis in prostate cancer. The fracture rate in the ERA 223 trial in those patients without bone protective therapies, was very high. I wish I remembered the exact number, but I want to say it was in the 35% range.

Chuck Ryan: I don't remember either.

Ben Maughan: It was extraordinarily high. Again,, this included all types of fractures, pathologic fractures, fragility fractures, fractures from mechanical [inaudible] and trauma, and all sorts of etiologies. Again, it's important that we understand, it is not just pathologic fractures that are a problem for these patients. And as you correctly pointed out, when they compared that against the patients who had bone protective therapy, the fracture risk went almost to zero in the patients that were on abiraterone. It was still slightly higher for the patients who were on combination radium plus abiraterone, but it was still less than 10%. I want to say less than 5%. Then most importantly, because of that data, PEACE III, which has not fully reported yet, which is a similar clinical trial looking at the combination of enzalutamide and radium in a prospective phase three study, they published their results of bone fractures. And they created an amendment requiring the use of bone protective therapy. They then reported on the bone fracture risk pre-amendment versus post amendment. There was a similar finding. And again, it's been sort of demonstrated now in a prospective way that this is very important to do.

That being said, in our particular trial, as a standard of care, we've been doing this for a little while. All patients on this trial in both arms received bone protective therapies, except for two patients. That's because the patients declined to participate in it. It was one in each arm. The fracture rate that we saw in our study, admittedly, it's a small study, but we saw two fractures. One was due to a mechanical fall in the combination arm. Then the other one was a pathologic fracture, again, in the combination arm.  One was a rib fracture, that was the mechanical fracture. Then the pathologic fracture was a T9 vertebral fracture. Again, the fracture rate was low and it just underscores the value and importance of bone health in these patients.

Chuck Ryan: The take-home message from your study is what?

Ben Maughan: The take-home message from our study is that this combination appears safe. The monitoring of bone metabolism markers is an intriguing aspect. Ultimately, before we can move forward with doing a combination like this in the standard of care, we need to see the results validated or demonstrated in the prospective study PEACE III which I anticipate reading out anytime soon. I'm hoping that we can also collaborate with those investigators to validate these bone metabolism marker findings. The signal is that the combination was effective and safe. We will see.

Chuck Ryan: That's great. Well, congratulations on that. I think you are in a very interesting window in this disease and in this space, because when radium first came out, I remember people who were involved in the radium study saying, "Well, it's a bone-targeted therapy with the implication being, maybe they don't need the bone-targeted therapy with it." Now, we know that wasn't the case then, that you do need a bone-targeted therapy. Also, people said, "Well, there's no reason why we can't just op priori combine it with abiraterone or enzalutamide because they have totally different mechanisms of action. We could probably benefit patients absent a clinical trial." Now, we know we needed to do those clinical trials because there is the potential for harm, or there was the potential for harm. Now, you have gotten sort of to that next, you've gotten over that hump a little bit, where you say, "Okay, we've identified perhaps where the area for potential harm is, and we are ready to move on with an efficacy study."

But I come back to the idea that both of these remain standard of care therapies, and then in certain settings, some may wish to combine them outside of the context of a clinical trial. I don't at this point. It puts you and your work in a very interesting and very necessary space. I congratulate you on that. I hope that you and the PEACE investigators are able to combine the data and come up with some really intriguing, definitive answers that can help guide therapy and maximize the benefit of these two important agents that have both proven to improve survival in combination with one another. Thank you for taking the time Ben Maughan, one of our rising stars in GU oncology. Always a pleasure.

Ben Maughan: It's wonderful to talk to you again, Chuck.
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