The Combination of Pembrolizumab and Radium-223 in Metastatic Castration-Resistant Prostate Cancer (mCRPC) - Atish Choudhury

February 26, 2021

Joining Alicia Morgans to discuss a plenary abstract presentation from the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) is Atish D. Choudhury, MD, Ph.D. Dr. Choudhury and colleagues presented the results of a phase II study to assess the safety of the combination and differences in immune cell infiltrate in bone biopsies (bx) and preliminary clinical activity of radium-223 + pembrolizumab vs. radium-223 alone.  


Atish D. Choudhury, MD, Ph.D., medical oncologist and clinical translational investigator within the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, Co-Director of the Prostate Cancer Center at the Dana-Farber/Brigham & Women’s Cancer Center

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist and associate professor of medicine at Northwestern University in Chicago in the United States. I'm so excited to have here with me today, a good friend and colleague, Dr. Atish Choudhury who is a medical oncologist and investigator within the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, as well as being the co-director of the Prostate Cancer Center at the Dana-Farber/Brigham and Women's Cancer Center in Boston. Thank you so much for being here with me today, Atish.

Atish Choudhury: Thanks so much for this invitation. I'm really excited to talk about this study.

Alicia Morgans: Wonderful. Well, thank you, and thank you so much for sharing your insights. We wanted to review with you a phase two study that you presented at ASCO GU 2021, in which you added pembrolizumab to radium for patients with metastatic CRPC. Can you tell us a little bit about it, please?

Atish Choudhury: Yes, absolutely. So this is an investigator-initiated study that was actually started by Dr. Lauren Harshman, who is a former faculty with us here at Dana-Farber, as well as Dr. Larry Fong, who is over at UCSF. So the idea behind this study is that, as you are probably aware, and your viewers are probably aware, radium-223 is an approved treatment for metastatic prostate cancer, metastatic to the bone, but it rarely is associated with actual radiographic responses or PSA responses. Pembrolizumab is a PD-1 checkpoint inhibitor that has shown some benefit in a subset of patients with metastatic prostate cancer, particularly those with mismatch repair alterations in their tumors. But as a single agent, also has pretty modest clinical activity.

Atish Choudhury: And so our hypothesis here was that radium-223 might increase the immunogenicity of mCRPC metastatic prostate cancer to the bone, and increase the activity of a PD-1 agent like pembrolizumab to see more clinical response than you might see with either agent alone.

Alicia Morgans: Which is, I think so interesting and exciting. I'm really excited to even hear how this ends up working out. You were fortunate to do a randomized phase two, right? So you were able to compare the two arms and really understand whether pembrolizumab was adding anything. Can you tell us a little bit about that?

Atish Choudhury: Yeah, so it was a two to one randomization with a total sample size of about 45 patients and the primary endpoint wasn't actually a clinical endpoint. It was actually differences in CD4 and CD8 T-cells in bone biopsy specimens from baseline to eight weeks and looking at the differences between the treatment arms.

Atish Choudhury: So about 31 patients were allocated to arm A, which was the combination of radium with pembrolizumab. And 14 were allocated to arm B, which was radium-223 alone. And so the study design is that patients received the combination of radium and pembrolizumab for three cycles of radium. So the radium was given every four weeks and the pembrolizumab was given every three weeks.

Atish Choudhury: If patients achieved stable disease or better, they stopped the radium and continued on pembrolizumab alone. And at the time of progression, if it was a bone-only progression, then they could receive the last three doses of radium. Whereas the patients in arm B received six doses of radium alone.

Alicia Morgans: Wonderful. And just to mention and really congratulate you and your co-authors, that it's not easy to get so many patients into a study and then have all of those patients undergo a biopsy to look at this kind of a primary endpoint. So congratulations on such an innovative design, but also, on really motivating the patients and your co-investigators to ensure that this could actually get done. And what did you find?

Atish Choudhury: Yes, so again, the primary endpoint was about CD4 and CD8 T-cells and bone marrow biopsies. And so this was done in collaboration with the Fong Lab at UCSF, as we've mentioned. And what we saw was that in both arms of the study, in these paired biopsy specimens, some patients had increased density for infiltration and some patients had decreased sense, likewise. Some patients had an increase and some patients had a decrease, and it really didn't seem to correlate very well with which arm of the study they were on.

Atish Choudhury: So of the 42 patients who wound up getting treated on the study, 26 patients had paired biopsy specimens to analyze, which is about 62%. Which again, you are aware, you are in this field, it's difficult to have that high percentage of patients who actually have the valuable paired biopsies. And so it was interesting to be able to do the assays for the immune infiltration, but it turned out that it didn't look like there was much impact of the pembrolizumab or the radium in an obvious way on the total number of CD4 and CD8 T-cells that we're seeing in the biopsy specimens.

Alicia Morgans: Okay. Well, in addition to that, did you do any secondary endpoints to look at markers of disease control or characterize the patient outcomes in any other way?

Atish Choudhury: Yes, absolutely. So we also looked at PSA responses. And there were three patients who experienced a PSA response of over 50%, and all three of those patients were in the arm of radium and pembrolizumab. So about 3 of the 29 patients experienced a PSA response. So about 10%, which is kind of what is seen with pembrolizumab alone in this population. There were no PSA responses that were seen with radium-223 alone.

Atish Choudhury: When we looked at the secondary endpoints of radiographic progression-free survival and overall survival, they were actually rather similar between both arms of the study. So the radiographic progression-free survival was about six months in both arms. And the overall survival was about 16 or 17 months in both arms.

Atish Choudhury: And so this study wasn't powered obviously to look at clinical outcomes, but there wasn't much of a signal that it was different between the two arms at this time.

Alicia Morgans: Okay. Well, did you look into MSI status, TMB, in the patients in this study, or is that work that is still being completed?

Atish Choudhury: Yeah, so that is work that is still being completed and it is in progress now. So there's a rich biomarker plan associated with this study. So we are going to be looking at some sequencing of the pre-treatment tumor biopsy specimens, as well as dedicated cell-free DNA sequencing from pre-treatment and on-treatment specimens as well. And we are also going to be doing some RNA sequencing on the pre-treatment biopsy specimens as well, to look at all of those things that you've mentioned, including the tumor mutational burden, the MSI status, and to look for immune biomarkers in the RNA sequencing data, to see if there is inflammatory milia in the bone microenvironment that might have correlated with the patients who had a longer progression-free survival compared to the ones who didn't.

Alicia Morgans: Okay. That's great. And I certainly would expect nothing less from the collaboration with the team with you guys at the Dana-Farber and the Fong Lab. Really, of course, very interested in these immune signatures among other things. And so, I really do look forward to seeing and hearing that data in the future as it unfolds.

Alicia Morgans: So if you had to summarize this work, which at this point, as far as I can see, does not show necessarily a clear benefit with adding pembrolizumab to radium, but certainly is something that will whet our appetite for the correlatives that are to come, what would your summary be?

Atish Choudhury: Absolutely. So what we saw was that pembrolizumab and radium-223 can be safely combined. The adverse event profile that was seen with that combination wasn't different than what you would expect with either agent alone. Again, as we saw there wasn't much evidence for a change in the immuno [inaudible 00:07:53] or in terms of benefit to clinical outcomes, but certainly this could be a backbone to a strategy where you add maybe a third agent like a vaccine, and it would be reasonably safe to try.

Atish Choudhury: So I think we do need to investigate a lot more to understand the patients who experienced some benefit on both arms of the study, to understand some biomarkers that correlate with that response, and then think of some common editorial [inaudible 00:08:21] strategies that might lead to more benefit than these two drugs in themselves.

Alicia Morgans: Wonderful. Thank you so much for the efforts that you and your team have put forth. We're always excited to hear about your work and to hear your thoughts on how we can consider it in the context of the current treatment landscape. I really appreciate you sharing that and for giving us a taste of what has happened at GU ASCO 2021. Thank you so much for your time today, Dr. Choudhury.

Atish Choudhury: Oh, I really appreciate this invitation. Thank you so much.
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