Julie N. Graff: Great to be here.
Tanya Dorff: Thanks for having us.
Neeraj Agarwal: So let's talk about the radioligand therapy. You are experts. There are a lot of areas where there are no evidence and we would like to get your perspective on how you are using these therapies, how you are managing them, sequencing them, and so on where there is no evidence and we are looking at you to give us some guidance. So I'll start with Tanya first, regarding lutetium therapy, what is the baseline scan you are usually doing before starting the treatment?
Tanya Dorff: So we're fortunate to have very close collaboration with our nuclear medicine physicians and they will overread the PSMA PET scan to make sure it meets VISION criteria, which is how we select our patients for lutetium PSMA therapy. They usually do want it to be within a window of two to three months at most from the time where we're thinking about that as a treatment option.
Neeraj Agarwal: Any role of CT and bone scan before starting treatment?
Tanya Dorff: That's an interesting question. So when there are liver metastases, there sometimes is a need for better anatomic imaging of the liver just to make sure that if the liver metastases are PSMA avid, that there are not also non-avid PSMA liver metastases because that can be hard to see just on the PSMA PET/CT scan. So sometimes the NucMed team will come back and say, "We think in this case an MRI or a dedicated liver contrast CT would be helpful." Bone scan, less so. Primarily bone scan we do use for radium 223.
Neeraj Agarwal: Okay. Any role of SPECT scan?
Tanya Dorff: We do SPECT scans. We don't do them on every patient. I think there are institutions that do them every patient at a set number of doses and that does provide valuable information, but I think that also is a resource issue and patients have to come back the next day and we do use PSMA PET to assess response at more regular intervals than maybe others. So the SPECT can fill that gap if it's not feasible to follow with PSMA pet. But we do have a conference where we sit down with nuclear medicine and review patients how they're doing on their lutetium and PSMA treatment and there are cases where there's either an uncertain outcome clinically by symptoms or by PSA and we might want the SPECT or sometimes even going into it, NucMed will flag that this patient based on how their PET scan looks. I think a SPECT would be helpful right after the first dose to determine whether drug got to disease. So it's very, very helpful. But I recognize we're in a unique situation as an academic cancer center with an international rock star nuclear medicine physician who can really help us do that.
Neeraj Agarwal: Definitely. I agree with you. This is so different from the real world. I have patients who come to me and they tell me that they were not reimbursed for the second PSMA PET scan, or, "We got them done, but they got the denial letter," that it was not reimbursed. And there are other things, but coming back to just to cover the base on the type of scan, just to clarify, PSMA PET scan is there, we do it to make sure target is being expressed by the cancer cells so that lutetium will be effective and SPECT scan is to make sure that drug is going to the target and effectively being delivered into the target. So coming to Julie, I do CT scan and bone scan at baseline and during follow-up because as Tanya mentioned, one of the reasons says if they have non-PSMA avid metastasis emerging PSMA PET scan may miss them, so I do them. Also, second reason is because PSMA PET scan may not be reimbursed, so then I'm left with nothing to monitor the patients. What is your practice for these patients?
Julie N. Graff: Well you bring up some really good points. I just wanted to start by saying if someone comes in for the SPECT scan, they're radioactive. There might have to be special considerations for that. I imagine. We don't do that, at least at the VA where I work. We try to get a CT quality PET, so like a combination CT PET for PSMA testing. I'm not very, very dependent upon bone scans. They're just not great scans, they're not specific and things can be there that are actually gone because there's healing. So I've just been, I have not been doing serial scanning. Actually I do do serial PSA because it's easy to get. If I did serial CT scans, I don't know if I'd do it like every other cycle, so every 12 weeks or I just don't know how much it would affect treatment. And also these patients, they're pretty sick and the treatment makes them tired.
Neeraj Agarwal: And these are really reflecting the real world practices out there. They're so variable right now. Even within a practice, these paradigms can be different for different types of patients. Patients who can afford PSMA PET scan every two months versus who cannot be reimbursed for their PSMA PET scan. And that is a nice segue to the next part, which is do you take treatment breaks from lutetium therapy based on the response on the PSMA PET scan versus do you stop this treatment earlier if you do not see any response on the PSMA PET scan? So I'll start with Tanya.
Tanya Dorff: Yeah, so that's exactly why I do serial PSMA PET scans and I do recognize it's a costly resource and patient time. So I don't always do it at the same time. I look at the PSA response and I do the PSMA PET when I'm ready to ask a question of it. So for instance, if PSA drops so significantly, it's very, very low after two doses. The question for the PSMA PET scan at that point is there still target, is there anything for the lutetium PSMA to go after and treat? Or sometimes the PSA isn't changing but the patient feels better or vice versa, the patient's not feeling better, the PSA's maybe improved a little or maybe it's up and we do the PET scan to determine is there response or not. Because if there's not response, then we would usually terminate treatment. But if it's stable with some other kind of conflicting information between the PSA and the patient, because sometimes that can be hard to interpret. So then we would continue. But we do use a little bit of a tailored approach even though it's not proven to be the right way to do it, we know that there's more toxicity when you keep giving the lutetium PSMA in the absence of target.
Neeraj Agarwal: Because it's going to go somewhere else.
Tanya Dorff: Right.
Neeraj Agarwal: Right. That's great. Thank you. And that's why we are talking here discussing this, seeking what experts do because there are no guidance out there. So Julie, coming to the other spectrum, you are starting to treat a patient with lutetium. This drug has side effects like any other drug. And after say two cycles, patients PSA continues to rise and patient doesn't seem to be doing better, but there is no obvious evidence of disease progression. But PSA has clearly say doubled or risen. These are real world scenarios. What is your take on continuing treatment, switching to something else and why?
Julie N. Graff: I would not make a treatment decision on PSA alone and in the trials, they didn't take people off for PSA rises for most of our treatments. So I would want to see radiographic progression or if the patients become very symptomatic and having a really hard time with the treatment, I'd have a low threshold for stopping it or holding it at least. I also wanted to mention when we talk to our patients about what to expect, they usually want to know how many cycles we're giving. And I have to say in the very early studies it was four cycles and then it was like four to six cycles. If I have a patient who after three cycles has a really good response, he's very unlikely to want to stop, assuming he's tolerating it and the data really are four to six cycles anyway. So just putting that out there.
Neeraj Agarwal: Yeah, no, that's a great comment. So if patient doesn't want to take a break, it's hard to take a break.
Julie N. Graff: Mm-hmm.
Neeraj Agarwal: Yes, that reminds me, or that's a very nice segue to the next part of the question. Patient received six cycles of lutetium, did well for four months or five months, came back with PSA progression, CT scans show disease progression. You do a PSMA PET scan again and patient is positive, SUV is high. Say, just came up with a value, SUVmax is 15. What is the role of repeat treatment with lutetium in your perspective?
Tanya Dorff: So I think we don't know. There are ongoing clinical trials that will answer that question, but for me, first do no harm. I think it's hard to give additional doses without knowing that there's some benefit or what the trade-off is between benefit and toxicity. So I don't do it outside of a clinical trial, but I'm fortunate to have access to the ReLU trial at UCLA where they're asking that question about giving up to six additional doses. And then there are also the actinium-225-PSMA trials, which we know from the European experience switching to the alpha-emitter PSMA targeting can be effective. We don't know how that compares to other approaches. And of course we have other PSMA targeting trials with antibody-drug conjugates and other new forms of treatment-
Neeraj Agarwal: And CAR-T cells and T-cell engagers. Yeah.
Tanya Dorff: I think the best option is a clinical trial ideally because that's how we will learn what's the best strategy, but we do have to think about toxicity and kind of diminishing returns. And why is there that PSMA-avid disease that when we were already treated with PSMA targeting, if you think back to Radium, remember it was initially approved with six doses and then they asked the question would more be better, six versus 12 and it was not better. So I really think there is equipoise about whether more will be better. There probably are some patients for whom it is, but we need to figure out who they are.
Neeraj Agarwal: Absolutely. So summary of this is no roll off re-challenge with Lutetium, based on the current evidence and patients should be exploring clinical trials if they want to get more lutetium, 177 specifically in this context in the context of small molecule delivery. Talking about radium, Julie, we all have used radium in the past. We saw the PEACE-3 data with radium, ENZA combined with radium was superior to enzalutamide, both in terms of PFS and overall survival. So definitely exciting data. Do you use radium before lutetium, after lutetium and if yes, which patients?
Julie N. Graff: That's a hot seat question. I really don't use radium at all to be honest with you. In the face of lutetium, it's really hard to know its role honestly. And I know a lot of people get enzalutamide for newly diagnosed metastatic disease. So it's different I think, than the trial.
Neeraj Agarwal: And we really appreciate that answer because radium use definitely went down after lutetium therapy came up. And it is widely used now. Dr. Sartor was talking just a moment ago that it's hard to follow or measure response on Radium, which doesn't help our patients. If they cannot see what is going on. The PSA is not going down, scans are not getting better. So there are certain issues, but then we have a life-prolonging therapy in the clinic, and there are a lot of patients. We may not see them, but there are a lot of patients who have not seen ARPI in the past. Patients who may not have progressed on ARPI. For example, a limited-duration ARPI given in the context of radiation therapy. And there are seven clinical trials which are ongoing right now. The DHL, HOPE-CAP, PRIMORDIUM, ARASTEP, ATLAS trial, all those trials are using ARPI for one year, two year, three year durations. And we'll be seeing a new wave of patients who are exposed to ARPI in a pre-MCRPC setting, but they have not truly progressed on ARPI. So I think we will see actually increasing number of patients who may be eligible for what we call as, who will meet the eligibility criteria for PEACE-3 trial, at least based on my opinion.
Let's say you have a patient who has not progressed on an ARPI and a patient is coming to you, SUV is 10 or SUV is high. Let's not talk about SUVmax one value. Patient has a high SUV tumor and healthy otherwise, and you have the option of ENZA plus radium and technically ENZA plus lutetium or lutetium only. What will be your preference?
Tanya Dorff: Yeah, it's challenging. I mean, a lot of this comes down to shared informed decision-making. There was a survival advantage in the PEACE-3 trial and someone who's got bone-only disease and has not seen an ARPI, I would consider using the ENZA and radium, especially if the PSMA PET is not overwhelming in terms of activity because we do know that that's one good predictor of benefit or response to lutetium PSMA is how much avid disease or how avid the disease is. But I agree with Julie that there's sort of a diminishing role because lutetium, PSMA is such an active drug. And then we also have the other ARPI combinations coming online such as with PARP inhibitors for select patients. So it is becoming more complex. So I think we have to look at our patients and talk through the different options. Sometimes it comes down to what a patient can do, what's feasible for their lifestyle, what sorts of side effects or quality of life they're looking for or looking to avoid. So I think they were strong data and it should be one of the options we present to patients.
Neeraj Agarwal: Absolutely. Yeah. Well, we had a great discussion. We talked about selection of patients for radioligand therapy. We talked about treatment, how long to treat them, how to select patients for a given treatment, when to take a treatment break based on the response or lack of response. So a lot of data we discussed in a short time. So thank you for doing it. Any last minute, last comments, Julie?
Julie N. Graff: Yes. Thank you for that. I think we need to look very carefully at these combination trials. So whether it's radium plus enzalutamide versus enzalutamide alone, I think that's the wrong trial design. It should be the combo versus sequential where everyone gets to see both drugs. Sometimes it's at the same time, sometimes it's back to back.
Neeraj Agarwal: Thank you. Tanya, any last comment?
Tanya Dorff: There are never perfect data. I do think it's helpful that we have data for safety of lutetium after radium, and I'll be really eagerly awaiting some data about whether one can use radium safely after lutetium, because I do think there are differential impacts on marrow. And I think as much as possible, it's always nice to be able to inform our patients about the safety aspects as well as the expected benefits when we're thinking about what to use first in a situation where we're hoping to use many sequential lines of treatment.
Neeraj Agarwal: Absolutely. Well thank you very much for being here.
Julie N. Graff: Thank you.
Tanya Dorff: Thank you.