IMbassador250: A Study of Atezolizumab in Combination with Enzalutamide in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) - Christopher Sweeney

June 2, 2020

Alicia Morgans and Christopher Sweeney discuss the IMbassador250 trial results presented at the AACR 2020 virtual meeting.  IMbassador250 is a phase III trial in patients with metastatic castration-resistant prostate cancer (mCRPC) comparing atezolizumab plus enzalutamide vs enzalutamide alone. Dr. Sweeney says that the study conclusively showed that adding atezolizumab to enzalutamide after abiraterone, did not demonstrate a clinical benefit. Dr. Morgans and Dr. Sweeney discuss the use of biomarkers and the development of effective treatment plans for metastatic prostate cancer patients.


Christopher Sweeney, MBBS, Professor of Medicine, Harvard Medical School, Medical Oncologist, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

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, this is Alicia Morgans, GU medical oncologist and Associate Professor of Medicine at Northwestern University in Chicago, Illinois. I am so excited to have here with me today a friend and colleague, Dr. Chris Sweeney, who is a Professor of Medicine at Harvard Medical School, as well as being a GU medical oncologist at the Dana-Farber Cancer Institute. Thank you so much for talking with me today, Chris.

Christopher Sweeney: Thanks for having me.

Alicia Morgans: Wonderful. So, I wanted to really pick your brain about a recent presentation at the virtual American Association for Cancer Research or AACR meeting that occurred just shortly ago. You presented some really exciting information or interesting information in terms of clarifying our understanding of the IMbassador 250 trial in which you looked at enzalutamide and atezolizumab in metastatic castration-resistant prostate cancer. Can you tell us a little bit about the setup of this trial and what you found?

Christopher Sweeney: This was a study of the hormone switch versus hormone switch plus PD-L1 inhibition. Specifically, patients recruited to this study were those who had enzalutamide after prior abiraterone and about 50% could have had prior docetaxel in the castration-resistant prostate cancer setting. Half the patients got the hormone switch, enzalutamide after abiraterone alone, and the other half got the combination of enzalutamide plus atezolizumab. We can go into the rationale for why we did a Phase III study in a little bit, but first, let's just get to the point.

The study was really informative in terms of how negative it is. So there was no evidence that adding atezolizumab PD-L1 inhibition to enzalutamide after abiraterone prolonged the time to PSA progression, prolonged the time to radiographic progression, and had no impact on overall survival. So as the study was designed, it was negative in terms of telling us we should not be adding atezolizumab to enzalutamide in the setting, but it was informative in telling us that we've got a lot of work to do of how to bring advanced immuno-oncology based therapies forwards to prostate cancer.

Alicia Morgans: I think that's so important and although it was a negative trial, I think that this really informed a question that has been lingering in the prostate cancer world. Now, there was a study by Julie Graff who is out of OHSU in Oregon, where she looked at patients who had progressed on enzalutamide and actually added pembrolizumab and saw that there might be some responses. I think that really stirred the pot in terms of getting the prostate cancer community really interested in whether these checkpoint inhibitors might help in combination with enzalutamide, in particular, to add the benefit.

Maybe synergize with these androgen receptor directed therapies to synergize for survival endpoints and other improvements in outcomes in the metastatic CRPC setting. So having this trial though negative, I think, was so important in helping us understand things in that realm. Now, this was an unselected population. Did you find in any of the subpopulations or by using biomarkers that certain populations might do better or worse?

Christopher Sweeney: You asked a very good question, Alicia, about the role of biomarkers, and is there a subset within the prostate cancer patient community that has a chance of benefiting from monotherapy with PD-1 or PD-L1 inhibition? The answer is there are clear small case series showing meaningful and durable responses to patients who have MSI-high tumors, or tumors with mutations of CDK12. So that definitely does exist.

So let's take a step back and ask the question. Why did we go straight to a Phase III study? We do know that there is evidence of immune modulation resulting in benefits in prostate cancer with sipuleucel-T. We also see some longterm responders to CTLA-4 inhibition in the randomized Phase III studies. We also saw some patients who did respond to PD-1/PD-L1 inhibition, but it was in the 5% range. So the question was there are some patients, but who are they? We could look for those patients in the randomized Phase III.

So the randomized Phase III got us an opportunity to look at and perform a conclusive study if it was going to be positive or negative. This is conclusively showing that adding atezolizumab to enzalutamide after abiraterone did not impart a benefit. There were side effects associated with it. The enzalutamide side effects were equal in both arms. But those with the PD-L1 inhibition had single-digit [inaudible] of many organs be it the colon, the lungs, the adrenal glands, the thyroid, as we expect. In total, about 11% of those with those had that side effect profile, and there were also three patients who've died from it. So in all honesty in the overall patient population, there were side effects without benefit.

Getting back to the question about, can we analyze biomarkers? And the answer is yes. The randomized Phase III design allowed us to look at whether the market was prognostic or predictive. What we can see is that there was no evidence of a meaningful number of patients who had a profound response that could cause any tail or separation of the curve in those who got atezolizumab. Suggesting that the CDK12 patient population with mutations of the CDK12 and their tumors, all those without MSI-high is a very small patient population that we can't discern in overall survival curve.

Or it could also be that these patients who have these variants respond well to enzalutamide. That doesn't mean to say that if they got enzalutamide and did well with that in this setting they may actually also respond to sequential monotherapy with these agents, but this is work that has yet to be done. So we have a lot of work to do on how to work out what is the best immune modulation strategy for prostate cancer. I don't think it is the end of the story. I think we're just beginning to elucidate what strategies to take forward and which ones to not take forward.

Alicia Morgans: So I love that you pointed out that it could be that patients who have CDK12 abnormalities or MSI-high may actually respond so robustly to enzalutamide that there's no clear additive benefit of atezolizumab but that if used sequentially there may still be a benefit from atezolizumab as compared to some other treatment or certainly, as compared to palliative treatments or best supportive care.

So that is important, I think for everyone to recognize that this is not the end of the story for PD-1/PD-L1 agents checkpoint inhibitors in metastatic castration-resistant prostate cancer, but it does fill in a hole, I think really nicely. It's wonderful that there were over 750 patients on this trial to help answer this question. Now, this trial was presented at AACR virtually, and that is a brand new thing for us in prostate cancer and GU oncology in general. I'd love to hear your thoughts on how that worked and how you really communicated the finding from your trial given the lack of standing at a podium in front of a large room as we normally would see you.

Christopher Sweeney: So the most important thing to appreciate is that the great effort that AACR went to, to actually adapt and get this going was a huge undertaking and they should be given all credit. I think they were basically, at least in the oncology space, the first in class to actually adopt this platform. They did an amazing job.

The reason for pushing forward is the role of information dissemination. So a number of us were aware of this negative result and we wanted to disseminate it as quickly as possible. So we chose the next deadline, which was the AACR and we got it out there, albeit in the virtual platform. It may have actually reached more people in real-time. From what I can tell at any one time they had about 40,000 patients registered... Sorry not patients, 40,000 participants register and watch the virtual presentation.

As I understand, it was about 20,000 at the one time people logged in to see the plenaries on the first day, on the Monday morning of the virtual platform presentations. So it was a great way to disseminate the information as quickly as possible. The presentations were all pre-recorded to minimize every technology glitch. The speakers were all in a green room of sorts, namely, they were all online. Whereas all the participants were only available to see the presentations but they could send in questions. The chairs did a fantastic job of taking all the questions that came in and they well answered in real-time by those of us in the green room, if you would, via the chat function. So I think it met the objective of information dissemination as quickly as possible and doing it in a professional manner as quickly as possible.

The other thing, the reason to get this information out as quickly as possible is having noticed that there were side effects with the immune modulation, Alicia. We should also just address the notion that there is a lot of potential use of these PD-1 and PD-L1 agents inhibitors off-protocol. Somewhat of as the New York Times article talked about as desperation oncology, the last-ditch effort. I think that's what this study says. In patients who do not have MSI-high or CDK12, one should probably avoid using these agents off-protocol. Again, the virtual presentation allowed us to disseminate this information as quickly as possible.

Alicia Morgans: I really appreciate that you had that opportunity and AACR had to pivot very, very quickly in order to do this. I commend them certainly for their ability to do it effectively. Really just to reiterate your notion that one of the important reasons to disseminate this information is to prevent harm to patients for giving them the benefit of the doubt, as I always hear or frequently hear. "Let's give them the benefit of the doubt and try this, just try this therapy, because it may help."

That actually may not be the best thing for our patients as there are patients who will experience toxicities and complications that may certainly impair their quality of life and potentially even shorten their life. If there is no evidence of benefit, we're not really giving them the benefit of anything, and certainly not the benefit of the doubt. So I think that is very important and I really appreciate you bringing that to light. So if you had to sum up this Phase III trial that you've done and you've presented and the findings, what would your message be to the listeners?

Christopher Sweeney: Adding PD-1 or PD-L1 inhibition, at this stage with this drug was PD-L1 inhibition, does not add to the hormone switch approach. There may be some patients who benefit from enzalutamide after abiraterone, but it's a smallish number. We know from the CARD trial that we should be using cabazitaxel in this patient population, especially if they did not have a robust response to their prior abiraterone. So the choice when a patient has a disease that progresses after abiraterone is enzalutamide alone if they had a durable response as a potential hormone switch. But be careful and make sure you do not try too long and too hard and miss the opportunity to give the cabazitaxel, or if they had a poor response to abiraterone, go straight cabazitaxel. Also, if you're going to use a PD-1 or PD-L1 inhibitor, you use it on trial.

Alicia Morgans: I think those are very strong and important messages and I appreciate you summing everything up. Thank you so much for sharing your insights with us today.

Christopher Sweeney: It's my pleasure. Thank you very much.