Phillip Koo: We're thrilled to have with us today, Dr. Wolfgang Weber, who's the Chair of the Department of Nuclear Medicine at the Technical University of Munich, who's a leading authority when it comes to PSMA-based imaging and therapies.

So today we're going to focus on the topic of PSMA-based therapies. And I wanted to get your thoughts with regards to the current state of PSMA-based therapies in 2020.

Wolfgang Weber: Well, I think there is now quite extensive experience with this form of therapy in the clinic. And what I can say, both on the public literature and our own experience, that it is a surprisingly safe therapy. That even in the presence of extensive bone disease, where one would expect tox, because of the bone marrow, it's still quite safe to perform this and that patients tolerate it very well.

And there's also definitely encouraging signs that it is an effective treatment. Although, of course, the Phase III clinical trial is still out there, so we have to wait if this is really confirmed that in the general patient population, this is an effective treatment.

I have very little doubts that in selected patients, it is highly effective. In an unselected patient population, I think we need to wait for the outcome of this trial and see how well the treatment is actually working.

Phillip Koo: Great. So, a lot of the single-site trials that were published on this, you would see these PSMA waterfall plots where there'd be a significant number of patients that did not have a PSA response. And then, recently we saw data presented by Dr. Hofman and his group in Australia, about this idea of FDG positive lesions versus PSMA positive lesions.

Can you talk a little bit about that phenomenon and the impact it has on response?

Wolfgang Weber: Sure. I think, first of all, it's really quite interesting that there are some patients that respond very well to this treatment. And that there are other patients, that on imaging don't look fundamentally different, that don't respond to this treatment. I think there's really a need for a lot of research, to better understand why patients respond very favorably. Whereas other patients don't respond to this treatment.

And of course, one potential explanation is, that there is PSMA negative disease that you see on an FDG PET scan. And that I think has been quite convincingly shown by Dr. Hofman. That this is a group that has a very poor outcome.

However, I think there's also a group of patients that is PSMA positive and all the metastases are PSMA positive that doesn't respond. And I think that's also a very interesting scientific question, why that is? And what one can potentially do to make those patients also benefit from the treatment.

Phillip Koo: Yeah. So this question of PSMA positivity comes up and lots of different points of view, with regards to patients with castration resistance, maybe not having as much PSMA expression. Whereas sometimes you'll hear people say, it actually has greater PSMA expression.

Based on your extensive experience, what are your thoughts on that PSMA expressivity along the course of disease?

Wolfgang Weber: Yeah. I think one aspect is that, while it is convenient and also somewhat necessary for patient management, to say there is PSMA positive and negative disease, of course, this is a whole gray zone. You can have a variability of a factor of 5 or 10, with respect to the intensity of uptake, at a certain point in time.

The other point is that, when we talk about PSMA positive and negative disease, most of the time we talk about PET scan, where the uptake is measured one or two hours post-injection. For the effect of treatment, I think it's equally, or even more important, how long the activity is actually staying in the tumor? So you could easily have a disease, where you have a high uptick initially, but also rapid clearance. And then that's relatively low dose to the tumor tissue.

So I think this issue of PSMA positivity is a much more complex one than one could easily believe, from just looking at those images. And both, because even if the disease is visible on the PET scan with positive contrast, there's still a lot of variabilities of how much the uptake is. And it can easily be a factor of 5 or 10, different in patients that are positive on those images.

And then there's this other aspect that with the PET scan, we're only capturing one-time point relatively early. And for the treatment, we need the activity in the tumor for a week or more. So that's another unknown factor at the moment.

Phillip Koo: Great. Have you had any experience looking at treatment response with imaging? Whether it be a metabolic agent, or something else?

Wolfgang Weber: So we routinely do PSMA PET scans, to monitor our patients that we treat in Munich. Mostly because this is such an experimental treatment, we really don't want to continue treatment when there's any indication that some of the tumors are actually growing.

So what we do, to make it also somewhat cost-efficient, we don't do an FDG PET scan and a PSMA PET scan at every cycle. So what we do, we do a PSMA PET CT scan, with contrast-enhanced CT at every other cycle to check both on the PSMA PET, but also on the CT scan if there's any indication that a tumor is growing. And if there's an indication the tumor is growing, we stop with the treatment.

Phillip Koo: I see.

Wolfgang Weber: And what I find interesting is that, in most of the patient's progression, of course, was disease that is still expressing PSMA.

Phillip Koo: Interesting. So when you look into the future, based on the work that you and your group are doing and based on the other work, where do you think we're headed with regards to therapy? What direction? I know there's a lot of talk about alpha therapies, different conjugates, different types of PSMA. What are your thoughts on where we're going to land?

Wolfgang Weber: Sure. It's a really interesting time right now and there are plenty of opportunities. I think that the biggest first step now is to find out if in a controlled Phase III clinical trial if the clinical benefit of this drug can actually be demonstrated. People believe this is likely to happen, but I think we still need to wait for the results of this trial.

Then the next step is basically beta versus alphas. I think there are certain advantages of both betas and alphas. There are some patients that respond beautifully to alpha therapy, that haven't responded, or have no longer responded to treatment with a beta emitter. And that can be explained by the higher energy of these alpha particles, potentially.

On the other hand, if the data are correct, that the expression of PSMA by prostate cancer can be on a cellular level not homogeneous but quite heterogeneous, then an alpha emitter with a range of 100 micrometers may actually have some disadvantages. Because it doesn't reach all the cancer cells. So I could easily envision, that the ideal scenario, is a combination of alpha and beta therapies. And there also might be specific patient subpopulations that respond better to betas and better to alphas. And along the same lines, also combination with other drugs, such as PARP inhibitors, which will be quite interesting.

Phillip Koo: That's an interesting concept, because with radium-223, I think we've seen some data published that bulky tumors aren't responding as well. And that's probably because of the range of action.

Wolfgang Weber: Right.

Phillip Koo: Yeah, so that's interesting. So, based on your experience with alpha particles, what can you share with regards to the safety profile of these alpha particles?

Wolfgang Weber: Yeah. So what I said in the beginning, that lutetium PSMA is surprisingly well tolerated. The actinium is more toxic. And what is a clinically relevant toxicity is that most of the patients experience dry mouth after two cycles of this treatment, which interestingly is not the case with the lutetium.

So although both ligands are accumulated by the salivary glands, the toxicity is markedly higher with the actinium, or the alpha emitter as compared. So, why that is again, is not entirely clear. But it's definitely a fact. And this is why, at least in Munich, we only use the actinium treatment in patients that have failed the treatment with the beta emitter. Simply because of the safety profile, this is a palliative treatment, with the actinium and with the beta emitters. So side effects are very important.

And so, we always start with lutetium PSMA treatment. And only if this fails, we perform the actinium PSMA.

Phillip Koo: With regards to the salivary gland toxicity, we often hear a lot about the idea of Botox in the salivary glands. Do you have any experience with that or comments regarding the effectiveness?

Wolfgang Weber: We don't have experience with this. There are anecdotal reports, that this might be possible to decrease uptake there. But we have no experience with this.

Phillip Koo: It reminds me of the conversations we used to have with iodine-131 and sucking on a lemon.

Wolfgang Weber: Yeah. It is quite fascinating, that the salivary glands take up so many substances. And it's also... What you do to decrease iodine uptake of the salivary gland is really a long story. And still, there's no consensus, as far as I understand, when and how much you should do that.

Phillip Koo: So I think maybe the story will continue with the alpha particles as well.

Wolfgang Weber: Very likely.

Phillip Koo: Yeah. Well, great. Thank you very much for your time and we look forward to your work in the future.

Wolfgang Weber: Thanks very much.

Phillip Koo: Thank you.