Alicia Morgans: Hi. This is Alicia Morgans, GU medical oncologist and Associate Professor of Medicine at Northwestern University in Chicago. I'm so excited to have here with me today a friend and colleague, Dr. Phil Koo, who is the Chief of the Division of Diagnostic Imaging at the Banner MD Anderson Cancer Center in Arizona. Thank you so much for being here with me today, Phil.

Phillip Koo: My pleasure. Great to be here, thanks.

Alicia Morgans: Wonderful. I wanted to talk with you a little bit about some recent updates in radium-223 data as well as some of the clinical implications of using this agent in our patients with mCRPC. So, can we start by reviewing some of the data from ASCO 2020, where we learned about combining radium-223 with sipuleucel-T?

Phillip Koo: Sure. When we think about radium-223, it's a drug that was approved in 2013, so it's around seven-plus years that we've had experience with this drug. Its unique mechanism of action I think lends to this idea of combination therapies. There have been some highs and lows with this idea of combination therapies, but I think one area that's been hypothesized is the idea of combining radium-223 with immunotherapy and this idea of the abscopal effect. I remember hearing about this trial from Dr. Antonarakis from Hopkins about the combination with sip-T and radium-223.

So, at ASCO this year there was a poster that looked at this Phase II randomized prospective trial that accrued roughly 32 patients who were randomized to receive radium plus sipuleucel-T versus sip-T alone. And in those patients who actually received the combination, their PSA response was actually better than those who received sip-T alone, their alkaline phosphatase response was also better, and the time to clinical or radiographic progression was actually much better. I think it was around nine months versus three months in the control arm, with a pretty significant hazard ratio, I believe in the 0.2 or 0.3 range. So, that was exciting to be able to see the two drugs in combination have some sort of synergistic effect.

Interestingly, the primary endpoint was looking at some of these immune responses, and that immune response actually was not higher in the combination arm. So, clearly there's something here that is going on that we're not quite sure what it is, but I think this provides a lot of evidence that this should be explored even further, and this idea of combination, this idea of radiation plus immunotherapy could be something real that really benefits our patients.

And just to clarify, these patients were minimally symptomatic or asymptomatic patients without having received docetaxel in the castration-resistant setting.

Alicia Morgans: Yeah, I completely agree with you, Phil. I think that it's so important when we have the opportunity to see that these combinations might improve things that are actually so clinically meaningful to patients and to clinicians. The progression-free survival endpoint is probably the most important, and that was pretty dramatically different between the combination arm and the single-agent arm. And when we look at things like PSA response and alkaline phosphatase best response, these were actually clinically significantly and statistically significantly better in terms of the combination therapy than the single agent. So really, I think that this is a combination that raises questions and helps us to think about where these agents could go in the future. Is this something that's moving forward as far as you know?

Phillip Koo: I haven't heard any details about the next steps. I think it makes sense to perhaps move this to a Phase III trial and explore this on a larger scale. It's interesting... When you think about radium-223 and all the excitement regarding the first approved alpha-particle therapy, I think it's time to keep pushing that envelope. And I know with various studies there have been sort of a deflation of the excitement, but I think these drugs are so unique, the mechanism of action and sort of the understanding of why it works makes a lot of sense.

The mechanisms of action are very different from our other drugs for the treatment of patients with CRPC. So, this idea of combination I think is something that we shouldn't lose hope with. And I think hopefully the pharmaceutical companies out there continue to support these types of innovative combination trials because I think there's a lot of synergy that can be gained by using a drug like radium-223 with a lot of other drugs out there, and I know there are trials out there that are exploring this, but I think it needs to be continually supported and expanded.

Alicia Morgans: I think that's a really good point. And I think the emphasis on switching mechanism of action is something that has become so clear to us in the metastatic castration-resistant prostate cancer treating community. We have seen multiple studies that really suggest that sequencing AR-targeted agent after AR-targeted agent, even if docetaxel or some other agent is sandwiched in between those two administrations of an AR-targeted therapy, it really does not seem to have a meaningful clinical impact for the patients.

Just to mention some examples, I mean, we've seen this in the control arm of CARD, we've seen this in the control arm of PROfound, and certainly, we have seen hints at this when we've thought about the PLATO study and other studies that have really thought about whether it's going to be helpful for us to do this.

What I love about radium, whether it's in combination with sip-T or not, is that in the appropriate patients it is actually a very nice, completely different mechanism of action that can help certainly improve symptoms but also prolong survival, probably because of this switch and different approach in terms of the mechanism of action. What are your thoughts?

Phillip Koo: I completely agree, and I think a lot of times some physicians might get used to sort of a certain class of drug and just like to be able to switch from a different type of drug within that same class. I think this idea of changing mechanism of action, as you mentioned, there's data now showing why that should be done. I think the beauty of radium-223 is really the tolerability. So, when you do switch that mechanism of action, you're not switching to a drug that patients are really struggling to take.

I think what we've seen over the past seven years is radium-223 is a very highly tolerable drug. The side effect profile is, if we go back to ALSYMPCA, was almost similar to the control arm, which was the best standard of care. So I think in terms of that, it's almost kind of like a nice transition where you give them a five, six-month break, and then you can reinitiate something afterward as well.

Alicia Morgans: I think that's a great point. I think though that sometimes it's not just comfort with a certain mechanism of action, but also sort of a comfort with being able to prescribe an agent on one's own that can help when one is choosing to just move to the next AR-targeted agent. But I think in your system, in my system, and many other systems, we've actually been able to really coordinate this collaboration between nuclear medicine and medical oncology or urology, whoever's treating these advanced patients, to ensure that there's a smooth collaboration, not just a transition of care from one treating service to another, but really a collaboration and a partnership in supporting patients through continued treatment with things like radium-223. How has your experience been, and from your point of view, what are some of the things that are most helpful in maintaining that collaborative relationship?

Phillip Koo: You know, that's a great point, and traditionally oftentimes we think of handing off care or transitioning care ... hoping is it's more than that. It's really this idea of integration, which I think takes it a step further than just coordination because oftentimes patients will go back and forth between different specialties. And if I think about nuclear medicine specifically, there's that diagnostic piece that nuclear medicine can be involved with, then there's the potential with radium-223. Then when we have approval for a PSMA-targeted therapy, there'll be that transition as well. So, that idea of being able to integrate these types of specialties into your team I think makes a lot of sense.

How that could be best done, I think it really varies. I think regardless of the structure of your organization, whether you're an independent practice or an employed practice, whatever it may be, I think there just needs to be a commitment to making it happen. If there's a commitment to making it happen, I think you can find ways to work with another independent practice or potentially a tertiary referral center to find that model that works best for everyone.

And I would hope that those practices out there are willing to be flexible, because these are all new situations that we're all dealing with, and I don't think you can tackle these new situations with traditional thinking. So, it requires all of us to sort of be a little creative, be a little flexible, and work closely together. But again, it really comes back to if we really want to do what's best for the patient and we're committed to that, then this to me is a no-brainer. We have no other option but to work in that integrated fashion.

Alicia Morgans: I think it's an interesting point that you bring up that as we continue to have an evolving radiopharmaceutical landscape when it comes to mCRPC and potentially even earlier in the disease spectrum, we are going to have to really solidify these ties between our groups, and radium is probably something that has actually pulled us together for the last few years to help us actually do that. And whether we build on those skills or not I think is going to be up to us.

Ensuring the communication between these partnerships is really something that, I think at least, helps our group really smooth that transition of patient day-to-day to nuclear medicine and back again, and to ensure that someone takes ownership of laboratory results and takes ownership of different complications is really a discussion that needs to happen, not just for radium but for our future radiopharmaceuticals as well. So, it's something that I hope continues to evolve and is something that's going to be so important to our patients as these treatment options that really take us from a focused mechanism of action to multiple alternatives come into play in the advanced and potentially earlier disease settings.

Phillip Koo: Absolutely. I mean, I agree 100%, and each meeting that comes up you see just this move forward and an increasing level of complexity. I'm not too ashamed to understand that I have limitations as well with regard to my understanding and my abilities to help with these patients. And I think we all do, but the beauty of working together is I think we can fill in those gaps and really offer a product and a service to our patients that can't be achieved alone.

Alicia Morgans: I agree. Well, as you think about this new data from ASCO 2020 and radium-223 generally in terms of its clinical implications, what is your take-home message to the audience?

Phillip Koo: My take-home message is radium-223 is a safe drug and a tolerable drug. We've learned a lot over the past seven years. One highlight that I'll make is bone protection is important. This idea of combination is something that'll hopefully this gives us a signal to re-energize this field of alpha-particle therapies and radium and really discover what it might be able to do for our patients. Hopefully, anyone watching this will get inspired to really elevate this and take this to another level, and hopefully, we'll get the support that we need from the industry as well to move this forward.

Alicia Morgans: Great, and I agree, and continued partnerships between nuclear medicine, medical oncology, urology, and radiation oncology are going to be the way that we improve outcomes for our patients, and that has been reiterated I think multiple times in the last few years as we've seen the development of different therapeutics and really helped ourselves and our patients understand how we can best achieve these good outcomes. So, thank you so much for your time today.

Phillip Koo: My pleasure. Thank you.