Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute in Boston in the US. I am so excited to have here with me today, a friend and colleague, dr. Shahneen Sandhu, who is an Associate Professor and a GU and Melanoma Medical Oncologist at the Peter MacCallum Cancer Center in Melbourne, Australia. Thank you so much for being here with me today.

Shahneen Sandhu: Thank you for having me.

Alicia Morgans: Wonderful. Shahneen, you did a fabulous talk at GU ASCO 2022, where you really helped us as a field of clinicians, investigators, and patients too, think through PSMA imaging and treatment, really this transformative technology, and we appreciate your expertise in this area. I'd love to talk to you about that and really just pick apart some of the main themes that we heard about from you. One of the most important from a clinically relevant perspective, as well as where we go with PSMA treatments in the future, is that one size of treatment, one dose of treatment, one schedule of treatment may not be right for all patients. Can you tell me a little bit about that?

Shahneen Sandhu: Thanks for asking this question. I suppose this is something that nuclear medicine physicians have thought about a lot more than medical oncologists, but I think we need to think about it as well. One of the challenges, as you rightly point out, is we are using these treatments largely, currently in the context of metastatic castration resistant disease, and mostly when patients have exhausted most therapies. So the bulk of the disease is often very high, and yet we use the same dose or the same activity for somebody who's got four spots of disease compared to somebody who's got 60% of the bone marrow replaced with tumor.

It's clear that this agent relies on the internalization of the radionuclide to deliver the radiation. One could assume that if you've got a bigger volume of tumor, delivering a bigger dose at first time point may be valuable and certainly wouldn't cause additional toxicities because of that huge volume of disease. So I think we just need to do an extra body of work to try to think about how we define dosimetry on the first PSMA pet scan and maybe personalize the dose a bit based on the volume of disease. And that may also be relevant for schedule as well.

Alicia Morgans: And that makes a lot of sense. Can you tell us how does that work? This is a beta emitter. Tell us a little bit about that, and tell us how the volume of tumor maybe affected differently with a beta emitter, at least LUTs, a beta emitter, I should say then maybe PSMA targeted alpha emitters that may it come in the future.

Shahneen Sandhu: I suppose the alpha emitters have got a very short wavelength. The beta emitters have got a slightly longer wavelength, but the energy levels of an alpha emitter are far more potent than a beta emitter, so it causes more definitive tumor killing with an alpha emitter than with a beta emitter. The benefits of the beta emitter is in addition to hitting that the tumor itself, there is a spillover effect on some surrounding tissue, whereas an alpha emitter can be more specific. So if you've got really small volume disease, I think alpha emitters can be very useful. These larger burdens of disease, beta emitters can be useful, but the issue, however, is that beta emitters largely cause some double strand breaks, but they cause a lot of single strain breaks as well, which are not necessarily going to be lethal for the cancer. And so being able to think about the concept of desensitization, particularly in someone who's got high volume disease is also valuable.

Alicia Morgans: Thank you for talking that through. I'd love to hear next about your thoughts on the dynamic nature of PSMA expression, because as we're trying to get the right dose for patients, we're also trying to time our treatment to be a time when the patients prostate cancer cells are actually expressing the largest amount of PSMA possible because that's how we're getting the treatment to the disease. Can you talk us through the different disease states in prostate cancer and how PSMA expression may be different in those states and different as it compares to, or as, as the cells respond to different treatments?

Shahneen Sandhu: I think we know that this is a target that is almost ubiquitous in prostate cancer. We know it's there in the context of primary disease. We also know that it, that it becomes more over expressed in the context of castration resistant and more advanced and more aggressive disease, but what's emerging in the field is an understanding that clearly the receptors are dynamic and can be modulated by targeting a range of different things, including targeting androgen receptor signaling. In the context of hormone-sensitive disease, we found that when we've done imaging in patients who've just started their androgen deportation therapy or an androgen deportation therapy in conjunction with an androgen receptor pathway inhibitor, such as abiraterone or enzalutamide, there's actually quite rapid down regulation of the receptors. So one could imagine that by day nine or day 14, once you've started the ADT, the AR responsive of tumors are going to respond incredibly well and there's this massive down regulation, and that has a bearing on if you want to come in and use Lutetium PSMA in the contacts of hormone sensitive disease.

I think it would be prudent to know that there's a target there. Otherwise, all you're doing is blindly delivering treatment that is not going to be taken out up by the tumor because that expression has been lost. It's a different story in the context of castration resistant disease, where using some of these antigen receptor pathway inhibitors in the setting of CRPC actually up regulates those receptors. So there, it becomes easier to use those agents, up regulate the receptors, and possibly even deliver better doses of radiation to the tumor, because you've got better receptors. They're taking up more of the radionucleotide and delivering a big, the dose of radiation to the tumors. One of the things I tried to highlight in the presentation is you see this pan out in the vision study, and this was in the supplementary material where actually the hazard ratio of the subset of patients that had treatment in conjunction with an androgen receptor pathway inhibitor was better than and the subset of patients that did not. So something to consider as we start to use this in clinical practice, given there is enough safety data for the combination.

Alicia Morgans: I think that's such a relevant point as we look forward to the approval of Letitia. Will we in clinic combine it with a second line AR targeted agent and patients who have already had progression on one? Because as you said, that's how the study was done, and we certainly have the safety tolerability data. So it seems like a reasonable approach and definitely food for thought for us in a clinic. So, the final point that I wanted to really explore with you is where we go in terms of patient selection. Is patient selection from now ever forward going to be based on PSMA pet, should it be based on something else? Do we need an FDG pet? When where do we go in the future? Is imaging going to be enough?

Shahneen Sandhu: Yeah, the way I would consider this is when you've got a tool that allows you to be more precise, then use the tool. That's the way I would think about it in a very simplistic way. It's really just the same. Herceptin would've failed if we actually didn't pre-select patients essentially on the basis of her two expressions. So it's the same sort of broad concept. I would say PSMA pet scans should be here to stay. We should try to figure out, does the patient have adequate target? That definition of what is an adequate target, no doubt, will evolve as our understanding evolves. I think in the context of monotherapy, it is important to know that there is a target, because otherwise, a subset of patients will get treatment that doesn't benefit them for very long, at all. The value of a FDG pet scan, one of the things we're learning as we're doing more of these FDG pet scans, is we're finding that actually there's a considerable subset of patients that actually have mixed disease.

Not surprising, really, that it's heterogeneous and there are a subset of patients that will have large volumes of disease that is PSMA negative, and some proportion will be PSMA positive. In our experience, those patients also don't benefit for very long, but again, it's going to take a little bit of understanding about how we use these, these novel pet imaging. The point I'd like to make is despite really some of these tools, including the PSMA pet scans, and certainly we've used this consistently in the trials that we've done in Australia, but despite that, the point I'd like to make is actually a proportion of patients, about approximately in excess of 20% to 30% of patients, despite having high PSME uptake that is concordant with FDD disease will still not respond.

They've got primary refractory disease, and trying to understand what's driving that subset of patients is important, and in time I hope it will be a combination of pet scans and molecular data that will define the subset of patients that should get this treatment and also understanding the outliers. The subset of patients that actually have these marvelous responses that are durable for a year don't need another lot of treatment. Understanding actually what drives that would also allow a more personalized approach with these sorts of new therapies.

Alicia Morgans: I could not agree more. I think that patients and clinicians alike would love to know better what to predict when they're going into a setting where they're trying a new therapy. Is it going to work? If not, why? If it is going to work, will it work for a long time or a little time? These are all really important questions. I appreciate that you and your team continue to do the work, both in terms of Lutetium studies and clinical trials, but also from a molecular perspective and relatives, because this is where we really need to go as a field. So, I just want to congratulate you again on a fantastic talk at GU ASCO 2022, and thank you so much for taking the time to talk it through with us today.

Shahneen Sandhu: Thank you. It's pleasure to do so. Thank you so much for asking me.