Alicia Morgans: Hi, I'm so excited to be here with Dr. Phil Koo and Dr. Neal Shore. We're talking today about radiopharmaceuticals and where they fit into the landscape of treatment of metastatic castration-resistant prostate cancer. Thank you both so much for being here with me today.

Phillip Koo: It's a pleasure.

Alicia Morgans: Great. Let's get started with some patient cases. Dr. Koo, would you mind introducing the case please?

Phillip Koo: Great. Thanks, Alicia. So this case comes courtesy of my colleague, Meera Raghavan. So the first case is a 78-year-old man who was initially diagnosed in 2013 with a Gleason 4+3, Gleason grade 3 prostate cancer, pathologic T4N0. The patient was treated with radical retropubic prostatectomy with pelvic lymph node dissection. And due to a detectable postoperative PSA, he received salvage radiotherapy as well. He then went on to start intermittent ADT in 2015, and during a period of ADT, the PSA started to rise, and then imaging demonstrated numerous bone mets in 2017. So the patient was subsequently diagnosed with metastatic CRPC with symptomatic bone metastases. So I guess the question for the two of you is, what options would you consider for this patient now that they're metastatic CRPC?

Neal Shore: Well, it's a great case on so many things to talk about here. Yeah, I mean, isn't it interesting? It's a Gleason grade group 3 and yet went on. Yeah, it went on to have bad positive margins, but negative nodes. Maybe a second opinion might have seen a preponderance of grade group 4s or 5 in here. So this is an aggressive biology. Nodes are negative. Presumably, it was a reasonable node dissection. The detectable postoperative PSA, gets salvage therapy. It's always really interesting the timing of that. Why intermittent versus continuous? That can be debated too. So this is clearly a patient who's moving quickly. And even though now we're into 2023 and it's 10 years ago, this patient's disease was progressing rather fast. And even with T suppression, the patient develops resistance in about two years time, probably even less than that, and then gets bone metastases and is symptomatic.

So a kind of fascinating case, but that's why these cases are great. And so now, here's someone who is presumably looking for first-line mCRPC treatment with bone predominant metastatic disease. I wonder if the patient had been followed a little bit more aggressively, that some other options could have come into the discussion, but nonetheless, now here you are. So I'm going to kind of stop with that sort of circumscribed tangential review. And Alicia, this is probably a typical case that could come to you, or in the surrounding area, and they say, well, what do we do at the Farber?

Alicia Morgans: Yeah, and I think great points Neal, because if this patient had had a PSMA PET scan, which obviously was not available in any wide extent back in 2017, or before 2017 I guess, back in 2015. You'd think that perhaps if this was biochemical recurrence and was conventional imaging negative, maybe we would've seen PSMA PET positive disease, which would've allowed us maybe to do an ADT and an AR targeting agent in combination, which is often what we're doing for metastatic hormone sensitive disease. But it's always easy to look backwards and hindsight is 20/20. In this case, we have first-line mCRPC in a patient who really has symptomatic disease, and has only seen ADT before.

So what are our options here? Certainly, we would think about potentially using ADT with an AR targeted agent, abiraterone and enzalutamide being approved in this setting. We also know that sipuleucel-T is a potential option for patients with mCRPC, but because this patient has symptomatic bone metastasis, I would say that that's not going to be a favorite choice. And in fact it's probably the wrong option, because really, with a symptomatic patient, that's not really the option that we should be reaching for.

We could consider docetaxel chemotherapy in this setting. But I would say, a lot of patients, particularly an older patient, may choose not to really jump to docetaxel as their first-line setting. If this patient is severely symptomatic, it's possible that that's going to be the right choice. And so, we'd need to review the imaging, and really review the case very thoroughly, perhaps in a tumor board multidisciplinary setting, because sometimes that is still the right choice.

And then of course, there's radium. And I think this is an interesting opportunity, because we have bone only metastatic disease, symptomatic, presumably related to the bone metastases, whether that's fatigue or bone pain where it's not really clear. It may even be weight loss and cachexia related to just cancer progression. So understanding those symptoms, and understanding that radium is an option regardless of the symptom burden, is also I think, really intriguing. So lots of options for this patient. Lots of opportunity for shared decision-making.

Phillip Koo: It's always interesting to sort of hear all of your perspectives on these cases, because it's enlightening for me, as a nuclear radiologist, to hear all the subtleties and these details that you guys pick up. I think it's also interesting that, as you mentioned, back then, we didn't have access to PSMA imaging, and how our world has just changed over the past year or so. But you're right, we're seeing more and more of these types of referral cases, where maybe things would've been different had time and access to certain tools been available back then.

So this patient went on to get radium-223, and they completed their six cycles, which isn't unexpected, given the fact that this is sort of a little earlier use of radium-223. They completed that in March of 2017. They also had palliative radiotherapy to the lumbar spine for symptomatic back pain. And I forget if this was concurrent or immediately after, but again, I think concurrent would be fine as well. They started abiraterone in 2018. Disease progression and was switched to enzalutamide interestingly, in February, 2020. Went ahead and got docetaxel from September 2020 through December 2020 for six cycles, and then went on to get another six cycles for a total of 12 cycles of docetaxel. And then the PSA again started to rise. So I'll turn it back to you guys again, and think to hear your thoughts on treatment options at this point.

Neal Shore: Yeah, a lot of really cool things in this case, and really greatly appreciate Dr. Raghavan presenting and putting the case together. And as Alicia says, it's always great to use the retrospectroscope, and be critical of all sorts of decision-making. And it's always an opportunity to shine when you have the cool light of day to say, oh, here's what we should have done. Or so interesting here, we did a series of studies, Phase II studies, roughly 40 patients combining one set of mCRPC bone dominant, abiraterone and radium, another separate Phase II study of enzalutamide with radium. We published both of these in CGU Clinical Genitourinary Cancer, and sort of came to a very interesting concept that, the notion of layering an AR pathway inhibitor for a couple of months and then starting radium, we found tremendously good tolerability. We didn't see any significant skeletal related events in doing it in that regard, or fragility fractures. And very importantly, all of our patients had bone health agents.

We know in larger studies such as the ERA 223, that wasn't a particularly good strategy, but we're still waiting to see a final readout, hopefully by the end of next year, from PEACE-1, on combining enzalutamide with radium. So that actually is a strategy that can be done today. There is no warning against using that, enzalutamide that is, in conjunction with radium. And if you're of the belief that you want to maximize novel mechanisms of action. So that's something to consider again, looking at this in hindsight. I am not at all a fan of switching novel hormonal agents, sequencing novel hormonal agents. Today, this patient, certainly in 2020, should have genetic testing. We'd really like to know if this patient has a homologous recombinant repair gene alteration.

But even now with new data that's come out with from the PROPEL trial, and even the MAGNITUDE trial, and then most recently TALAPRO-2, we're seeing some benefit, specifically with TALAPRO-2 and PROPEL, of all comers benefiting from combining a PARP inhibitor with a AR pathway inhibitor or drug.

The docetaxel here, I'm impressed that the patient went on for 12 cycles. I use a lot of docetaxel. I'm not adverse to dose reducing from 75 to 60 milligrams per meter square, occasionally even 50, and increase the timing to every two weeks. We see this done in Japan very frequently. It leads to better tolerability, especially in the elderly. So this is a really great case, where so many different approved therapies could be applied when the patient's performance status and his bone marrow were all at a point in time where tolerability could be achieved. And so now you're looking at consideration for either cabazitaxel or a PSMA RLT such as lutetium-177.

Alicia Morgans: Yeah. And I would just pick up on those threads and say, it looks like this patient really had significant bone pain. If the patient needed palliative radiation, which could be concurrent, could be sequential, you can actually do either option during treatment with radium. It sounds like this was really the best way to try to address that bone pain quickly. The patient probably had great marrow reserve at that point, had really never seen anything other than hormonal therapy. And so, that's a nice opportunity to use a medication that is targeting where the disease is for this particular individual who has bone only metastatic disease, and getting that drug in and that window, particularly for patients with bone pain. I think that's a really a great option.

It's interesting to me, just thinking back about the pandemic, I wonder if there were thoughts around COVID, when that patient did the switch from one AR targeted agent to another AR targeted agent. That's a little before I was really thinking about the pandemic on a day-to-day basis in my clinic, but it's right around the time when a lot of people were afraid to use chemotherapy. And that, of course, only lasted for a few months. I think we realized that we could safely give chemotherapy despite COVID-19. But I wonder if that had something to do with it. Because I, like Dr. Shore, would not advocate for AR targeted agent followed by AR targeted agent.

And then, in terms of the options, I agree completely with Dr. Shore. It seems like it's either going to be lutetium PSMA 617, or we're going to use cabazitaxel. And again, another opportunity I think for shared decision-making. But what I think is a positive thing, or that we have to consider, of course, is what the marrow reserve is on for this particular patient, because the patient's had a lot of chemotherapy. I don't usually make it to 12 cycles, and sometimes that can cause some cytopenias.

Neal Shore: You make a great point about when you're giving radium-223, and you really want to get in at least five of the six cycles. In some of these patients, you can get palliation the data ALSYMPCA has shown that. But it's absolutely appropriate to be able to also give the concomitant palliative radiation therapy as well as a anti-resorptive, a bone health agent. So I think that's, a lot of our colleagues still forget that that's absolutely acceptable. So that was really great that that was done. I assume that combination led to an improvement in quality of life and amelioration of the pain, which then allowed for sequencing to an AR pathway drug.

Phillip Koo: Yeah. And Neal, to your point, I still get calls and questions about concomitant radiation therapy, palliative radiation with radium and yeah, again, all the data shows that it's fine.

So it's interesting. We received this patient at this point for consideration of lutetium-177 PSMA 617, and we had similar concerns. This patient had seen radium six cycles, and had 12 cycles of docetaxel, but their blood counts were fine. And so, we felt very comfortable moving forward with this. So this was their bone scan. And then we got the PSMA PET to confirm the PSMA expression. And what you see is sort of a discrepancy that there's more lesions seen on the PSMA PET versus the bone scan. You see these localizing to the bones, and some nodes as well. And the patient did go on to get lutetium-177 PSMA 617. And this shows the first three cycles, the PSA response, and some decreased activity in those sites of disease. And the story's still being told right now, so good. And so far, we haven't had any issues with the patient's marrow. Which again, we weren't expecting it, but 12 cycles of docetaxel did make us consider pause. So good. Any other closing comments or thoughts here?

Alicia Morgans: Yeah, I just want to mention, that I think this was a really nice case where we saw that we could use therapies where we have the window of opportunity, and are able to get the most bang for our buck, get all of the cycles in, for example of radium, and then still have the opportunity to safely deliver lutetium later on in the disease course. I think it's important for us to recognize that we can use these per their label when appropriate, that either one could be an opportunity for a patient. And ultimately, what I think about when trying to see any patient is, how do I get as many of these drugs into my patient as possible? I want to give them every opportunity on as many treatment options as I possibly can. What do you think Dr. Shore?

Neal Shore: Oh, I 100% echo that. We have 12 live prolonging therapies right now in the US from the FDA, and it basically correlates to seven novel mechanisms of action. Seven novel mechanisms of action. In 2003, all we had was ADT. 2004, we had microtubule inhibitors in the form of taxane docetaxel. So think about that. So I 100% love what you just said, because that's why I don't like and don't recommend the sequencing. Let's go to something that's novel. We all know the bane of existence of all of our colleagues who treat cancer is the development of resistance. So always trying to come up with a novel mechanism of action. And that's pretty much how I explain it to patients. That's why radium, which is an alpha particle and lutetium PSMA, which is beta, and the differences additionally in terms some of their delivery and their mechanism. But the fact is that, there is that difference. And doing it, as was said by Phil when the patient's bone microenvironment, the bone compartment, was still robust is that's the key art of medicine that we can't lose sight of.

Alicia Morgans: Great. Well thank you both for talking this through. And Phil, please be sure to thank your colleague. Excellent case for discussion.

Phillip Koo: Okay, thank you.