Alicia Morgans: Hi, I am so excited to be joined today by Dr. Phil Koo and Dr. Neal Shore where we're talking about radiopharmaceuticals and optimal sequencing in real patient cases. Thank you both for joining me.

Phillip Koo: Pleasure.

Neal Shore: Pleasure.

Alicia Morgans: Wonderful. So let's get started in our case. So Dr. Koo, can you talk us through the case, please?

Phillip Koo: Great. Thank you, Alicia. So this is our second case and this is a 63-year-old man who was diagnosed with de novo metastatic prostate cancer in January of 2020, Gleason 9 prostate cancer with a PSA of 4.4 at the time of presentation. He was initially treated for metastatic hormone-sensitive prostate cancer with enzalutamide plus ADT. He experienced PSA progression and end progression of bone metastases and then was diagnosed with metastatic castration-resistant prostate cancer, then was subsequently started on denosumab and docetaxel in October of 2021. And then he presents again now with progression of bone-only metastatic disease, and this shows the bone scan showing his distribution of boney mets. So I know there are a lot of different therapies you could consider in this space, maybe we can go over that, but also think about this discussion about radium versus lutetium 177 PSMA in this setting.

Alicia Morgans: Great. So thank you so much. Now, this is clearly an aggressive prostate cancer, obviously diagnosed as de novo metastatic disease and also with a really low PSA at the time of diagnosis with metastatic disease. So I think starting off suggesting that it's going to be a bad actor and clearly it was and we see that the patients already had progression of disease now through ADT enzalutamide and ADT docetaxel. Luckily, I just want to point out and comment that it was called out that the patient has received a bone health agent, which is so important and is a really critical piece of ensuring that patients are taking care of from a whole-patient perspective to reduce skeletal-related events, so that's great.

But thinking through options, I think of course we need to think about radium, we need to think about lutetium, I would also suggest that we keep in mind that cabazitaxel may be an option here too, depending on how that patient is progressing. Sometimes that is the most important option in my clinic, when patients are presenting with visceral crises, for example, or something that's more of a catastrophic progression. In this case, the patient really seems to have bone-only progression, which gives us the opportunity to potentially still use radium or certainly to use lutetium. I wonder, these are not decisions that I typically make just on my own, I'm sure I've mentioned shared decision-making before and I could talk through the pros and cons here, but I wonder, Dr. Shore, what are the pros and cons of each of these radiopharmaceuticals, if you're thinking it through and talking it through with the patient?

Neal Shore: Yeah, I appreciate that. Maybe kind of put a little bit of a real-world spin on it, but if I can just parenthetically say this is certainly in 2022, the type of patients who I would've started on triplet therapy, young man, obviously aggressive disease, based upon what we saw with the ARASENS data where triplet therapy was clearly beneficial with ADT doce, and daro surpassed ADT doce, and then PEACE-1, ADT doce abi versus ADT doce in high-volume patients clearly was also superior. And as you point out this low PSA, Gleason 9, Grade Group 5, this is aggressive disease, blew through it pretty quickly, got the docetaxel, so now, yes, here's this patient, he's still young, probably still fit, good performance status.

I would tell this patient, "Look, we've got radium 223, I could get you started on this next week." It's a one-minute infusion. It's been around for over 10 years now. My radiation oncologist, my nuc med radiologist. Not a problem in terms of supply chain, and access reimbursements are not an issue. These are all the practical things. There's no pre-med, there's no post-med. The precautions in terms of traveling and moving around are pretty straightforward with just universal GI precautions. The safety tolerability profile of low-grade GI and the need to monitor a CBC monthly, it's all very achievable.

Now lutetium 177 PSMA is a great new advancement for us, and it is approved for this patient who's got mCRPC and has progressed with bone-dominant disease, progressing on doce and an AR pathway drug per the VISION study. But right now we're still having some supply chain issues, and there's a long wait to get patients onboarded. I'm fortunate we're a site, we're approved, we have patients, but the waits is a bit long. I know that's being addressed and I'm hoping that by mid-portion 2023, end of 2023, that supply chain issue has been vanquished. There's still some reimbursement issues that are getting sorted through by some payers, I think that's also a short-term issue. It's a great therapy. Trials are looking at moving up PSMA RLT, specifically lutetium pre-chemotherapy mCRPC, but that's not going to help this patient right now who's sitting knee-to-knee to me right now in the clinic.

The radium is once a month for six cycles, the lutetium 177 is once every six weeks up to six cycles. There are some additional precautions for the patients when they get lutetium in terms of how long they have to stay at the clinic, additional radiation precautions with family members, and even some would argue some travel issues. Interestingly, our German colleagues, they hospitalize patients. Fortunately, we don't do that or nor do I think we have to, but those are some of the real-world considerations. There are some concerns regarding off-target issues with lutetium that can affect salivary glands. There are very, very low percentage of issues regarding renal function. Both of these drugs can affect the bone marrow, so that's an important consideration for monitoring white count, red blood cell count, platelet count.

Phillip Koo: So Alicia, Neal brings up some great points about access and logistics. How do you as a medical oncologist sort of take all that into account as you sort of plan out your next steps?

Alicia Morgans: So I think that access issues become some of the prime issues when you, as Neal said, are sitting toe-to-toe with somebody and this patient's disease is probably progressing pretty rapidly because really the patient just started docetaxel a few months ago and must be progressing very rapidly, really with minimal to no response to docetaxel, or we wouldn't already be thinking about another treatment. So at least in my clinic at this time, it takes me several months to actually get lutetium, that's after I get a PSMA PET, so I don't think this will be a long-standing issue. But right now, if I need to treat the patient right now, I'm really thinking about radium or cabazitaxel.

And I have mentioned before, but we'll just reiterate, that there are windows of opportunity sometimes for some of the treatments that we have, and right now imaging would suggest that we have an opportunity to use radium. I can use cabazitaxel in the future most likely, unless this patient has a poor performance status or has some sort of marrow issue or some reason I can't use chemotherapy, those are usually barriers that we can overcome. So to have the option to use radium now, since I won't be able to get lutetium in most places rapidly, might be the best option. But I do think that over time, as we have better access to all of these agents and are really able to kind of get what we need at the moment we need it, or a little bit closer to the moment, these decisions will become maybe less reliant on access. But at this point in time, this is a real-world issue that really does affect our clinical decision-making.

Phillip Koo: And I think for us, that did sort of come into play with regards to next steps, and due to these issues, access and logistics, I think we did move forward with radium. And then one question that comes to mind is, as a urologic oncologist, medical oncologist, I think you guys are always sort of playing chess and trying to think what's the third step, the third move from now, and one question that always comes up is, all right, if you give radium how long before you could give lutetium? And I don't think there's any real good data there, but any advice that you guys have for the listeners with regards to sort of gaps in between radiopharmaceutical therapies?

Neal Shore: Yeah, it's a really important question. Let me just go on record as saying Dr. Morgans, she plays three-dimensional chess, I play checkers when I'm playing. So yeah, we do have some nice work. Even within the VISION trial, there were a percentage of patients who had radium beforehand. They waited six months, it had to be six months out. I think that was just sort of somewhat arbitrary, and those patients did fine. There had been some other studies published from Europe, also in the US, similarly demonstrating patients doing fine. You have to be judicious. I think as Alicia was pointing out earlier, if the patients had extensive amount of chemotherapy, if they had extensive amount of bone marrow involvement, you're probably going to want to give it some time and monitor the marrow by getting CBCs and seeing what's going on. You have to balance that with progression of disease, right?

And so that's tricky, and I think that, as we said earlier, we want to give in, apply to patients, expose them to novel mechanisms of action while their performance status and their lab parameters are still viable. So I think to answer you directly, I'd probably wait somewhere at least another month post-radium, maybe ideally six to eight weeks, and continue to monitor the CBC, but depending upon the aggressiveness of disease and the shared decision-making discussion, how risk-intolerant or risk-seeking is the patient?

Alicia Morgans: I would agree with that. I think you do need to make sure that your CBC has recovered so that you're meeting parameters that might be those safety parameters that we think about with lutetium. So generally, I think about a hemoglobin over 10 and generally, I think about platelet counts over 100,000, but I would say that we are waiting for and expecting groups to put together some clear recommendations that are maybe expert consensus to just give us a little bit of guidance 'cause right now it's really just safety parameters based on our own best experience and best advice, but at least an expert consensus will give us some group-think around how we should best move forward.

Phillip Koo: Great. Yeah, I agree. I think we're still learning here, and a lot of those baseline values are taken from the trials, but I think there is probably some room to be a little more aggressive with some of those lab values. And for us, personally, I think it's really hard to come up with a cutoff in terms of timing, and it is that shared decision-making process and understanding the risk. So it's great insights. Thank you very much.

Alicia Morgans: Thank you.