Lecture Presentation:

Phillip Koo: Hi, my name is Phillip Koo from Banner MD Anderson Cancer Center in Phoenix, Arizona. Welcome back to another module in this fabulous series on precision medicine in prostate cancer. Today we have with us Dr. Stefano Fanti, who is the Director of Nuclear Medicine at the University of Bologna, in beautiful Italy. And today he's going to be talking to us about radioisotopes targeted therapies in cancer, and he'll give us a nice overview of a little bit of the historical context of radioisotopes in cancer, where I think we could take a lot of lessons as we enter into this new era of targeted therapies in prostate cancer. So thank you very much, Dr. Fanti, for joining us.

Stefano Fanti: Thank you, Phil. It is my great pleasure and honor to be again with the friends of UroToday with you and Neal and Alicia, great experts, and a really great honor to share with you some of, let's say my little expertise regarding the use of radioisotopes for the targeted therapy in cancer centers. As you've mentioned it before, I was trying to do a journey through previous experience that as a nuclear medicine physician we had regarding the use of a radioisotope in other malignancies, and possibly catch the similarities with the prostate cancer, which is just emerging right now.

These are my disclosures, I used to say that the key disclosure is that I'm proudly a nuclear medicine physician. So be aware that you will hear some stories from a nuclear medicine perspective. And as said, we will start a little bit from the past, try to then cover which is the present, again with special reference to the neuroendocrine therapy with the Lutathera®, and then moving a bit in the future, and probably we may then discuss about that with respect to prostate cancer.

Now, the history comes from really very far because there's more than one century that radioactive compounds are using for treating, then it was indeed prostate cancer, the first to be treated. But it was not really nuclear medicine, it was brachytherapy, and brachytherapy is quite simple. You just put some radioactive source just as close as possible to the tumor. You should know where the tumor is located. It should be confined to the organ, so to the prostate. That has been working and indeed it's still done, but it's fully in the hands of radiation oncologists. So it's not part of nuclear medicine, even if it uses radioisotopes. And that gives me the opportunity to make this very important distinction between radiation oncology and nuclear medicine.

That's to say radiation oncology requires the knowledge of the tumor location because you are targeting the tumor using essentially some external beam source of energy in order to kill the cells with a topographic and localization concept. And nuclear medicine is different because you are aimed at targeting the cancer by knowing the tumor biology. So you inject something in the body which goes usually through IV, intravenous injection, and then you target the biological characteristic of the cancer.

And this in turn gives me a chance to play a little bit with the physics of the situation, as a nuclear medicine physician, physics are our best friend. And let me remind you for a little bit, what is a radioactive isotope? Well, it's very simple. It's an atom that has an excess of nuclear energy and that makes it unstable. So in nature, everything which is unstable tends to go in a much more stable situation. So this excess energy is emitted as gamma radiation, or it can be used to create and make and emit a new particle. Now, gamma radiation are essentially energy photons. So it's light essentially, while particles are definitely much bigger and they deliver energy and they can kill the cells when they do deliver this energy.

So again, the gamma-ray it's an electromagnetic radiation and electromagnetic radiation is something that we face in our daily life because the electromagnetic spectrum goes from the microwave to the radio to daily application of that. And of course, in the visible, it's based on this electromagnetic spectrum, as well as infrared, ultraviolet, and at the extreme on the right end, that you can see that for healthcare activities X-rays and gamma rays are there. But they're all different forms essentially of energy or photons. So there's no particular matter.

That's completely different when you refer to alpha or beta particles because they are much bigger and being much much bigger, it's not only about energy, but it's about the capability to really work as a bullet. So these are really our weapons. And that's a figure to make things very simple that I use for my students at the university, that's to say that the gamma emission is absolutely a light, so I can use it to see the cancer because I can have systems to reveal the light that comes from X-ray or gamma-rays. While the particles either beta or alpha are just bombs because they can kill the cell. They can easily kill the cell and they can be used for a therapeutical approach.

Now, step back again to the prostate. There's been a use of radioactive treatment and especially in the late '90s that indeed never came to widespread use, essentially because those therapies were purely palliative. So they have no curative intent. Everything changed with the introduction of radium -23, which is again, radioisotopic therapy that did demonstrate in this trial, which is more than 10 years old indeed, an advantage for the survival of the patient with advanced prostate cancer and bone met. And that's essentially the story for prostate cancer and for isotopes for therapeutical use.

Now, let's move to the concept of theranostic. Theranostic is a nice word. It is not the only domain of nuclear medicine, there are many other parts of medicine that can pretend to have a theranostic, but probably in nuclear medicine, we have a really great example of how we can view. Well, essentially you have the cancer cell, the cancer cell has a number of features, of course, mainly for the bad, a few for the good, including the fact that they do overexpress some proteins, some receptors that we may call as target. So having a target means that if we have a targeting agent, it can label very specifically to it. And so we can bring a radioactive isotope there. And that's the concept absolute of theranostic, because if you bring a diagnostic isotope there, then you can see the cancer. If you bring a therapeutical isotope there, then you can cure it.

So if for example, I have a good target, just like we will see for the neuroendocrine tumor, the sum of a certain receptor. We have an agent which is called the ligand, which is specifically binding, and we use it as a radioactive isotope. For example, a positron emitter like gallium 68 or fluoride 18, then we can image. So we can make a diagnosis with that. But if we replaced that isotope with a big bullet or a bomb if you should prefer, so lutetium, yttrium, or actinium, then you will kill the cancer cell. So you will have a very simple and specific therapeutical effect.

Now, let me try to bring you to the journey of Lutathera®, which is the example that we had in the past decade. Again, theranostic principle, you need the target, which has to be overexpressed in a neuroendocrine tumor, or neuroendocrine neoplasia. And it was very well known. It's somatostatin receptors, there are several subtypes, but especially the subtypes too are incredibly overexpressed in the neuroendocrine tumor. This has been known long, long ago and the cold inhibitor has been used. But what we learned that we got very good ligand, so specific peptides that can bind it to the somatostatin receptor. And then can be linked with the lutetium and gallium all the isotopes that I just mentioned.

So if you have the ligand and you add the gallium, you have nice imaging, and that's an example of imaging with PET of a neuroendocrine tumor. You see the hotspot, which is the localization of neuroendocrine cancer. And that's clearly something which has a lot of similarities with the PSMA imaging because it's absolutely the same concept. That's the same prostate cancer, you have an overexpression of PSMA that can be labeled with gallium, for example, or fluoride and produce PSMA PET images, which has been just simply developed the like 10 to 15 years later as compared to the gallium DOTANOC or DOTATOC imaging.

And for therapy, the concept is the same. If you replace the gallium with lutetium, you would have a very effective therapy. And that's an example you see here, the patient, the many hot spots at the localization of the tumor, and the patient is treated with lutetium DOTATATE and after therapy, there is a great response for a solution in the disappearance of the area of the tumor. And that's absolutely the same concept that is used for theranostics in prostate cancer, using lutetium labeled PSMA. So the concept is perfectly the same.

I told you the journey of Lutathera® started about 20 years ago, the first patients were reported on The Lancet in the very late 90s, so the first report of a series is something like five years later it came from the group in Rotterdam which was really pioneering that, and this is one of the other papers in JCO.

The problem was that at the beginning, there were not robust multicentric trials. So it takes time. Essentially, because there was no big pharma company behind it. There's been a question regarding the possibility to portend, the possibility to produce and deliver it, because you have to deal with the relevant amount of radioactivity, logistical problems, some skeptic points of view by the big pharma that we're not used to that, I mean, as an oncologist, you deal with the pills, you don't deal with the radioactive.

Unfortunately, the word radioactive itself has a bad reputation, to be honest. So there's a bit of let's say, prevention regarding that. But that was overcome when a big company came and played the big game with this trial, that was a registered to a trial, is called the NETTER-1 trial, published on the New England that demonstrated an incredible superiority of lutetium DOTATATE as compared to the standard of care. And that's been a prospectively multicentric international trial, that demonstrated that again, the PFS and overall survival superiority of Lutathera®.

And of course, it led very rapidly to approval by the FDA and the AMA, and it was in 2018, and commercialization of the product. So what was before then, just in few centers, it has then since two years made commercially available, is standard of care, is done almost everywhere in the world for neuroendocrine tumors. And this incorporated into the guidelines as for example, European Guidelines for Neuroendocrine Tumor. Please note that frequently it's referred as PRRT because it's a peptide receptor radionuclide therapy because usually, we use small peptides because they are for some reason more effective of big anti-corporate fragment or other alternatives.

Okay. That's essentially what was for us, the journey of Lutathera®. Again, it took a long time, it took almost 20 years, but it's finally reduced that it is standard of care commercial available. So what you can expect is that a similar journey will be done by a PSMA product. The concept that comes to my conclusion is very simple. What you see is what you treat. Theranostic has got this amazing capability. If you can bring there for some reason, a gamma or a positron emitter isotope, and you can see the spread of the cancer and that's an example of a prostate cancer patient, then absolutely using the same concept you can deliver therapy.

So you have from the very beginning, the proof and the demonstration that the therapy will be effective because you know exactly where you do deliver your therapy. So that's a systemic therapy with an incredible capability of predicting the response. That's an example of a prostate cancer patient. That's pioneering work from Heidelberger, and you can see the incredible spread at the bone and after three runs of actinium therapy, PSMA, a great response of the patient.

So that's been reported by UroToday because the problem was quite similar to the neuroendocrine tumor. It takes a big company to run a good multicentric registered trial, which is now being reported. Well, indeed there are several trials like that. This is the Australian one, which has just been reported at ASCO 2020 a few weeks ago. The probably best known is the VISION trial, which is ongoing very well, it's supposed to be completed before the end of the year. So the status for PSMA is that we are... not me personally, but they are running several trials so with possibly the capability to demonstrate the effectiveness very soon.

So, great potential, incredible potential in a scenario which has numbers, which are not compatible because everybody knows prostate cancer is incredibly more frequent than neuroendocrine. And the concept is very elegant, at least in my view, and is probably keen to be extended to other cancers in the future, because there are new other tracers coming much earlier, of course. PSMA, optimistically very soon, will have a registration and commercial distribution. I guess it makes a great difference for the oncologist. Of course, it's a change in the minds of the way of treating patients, that probably has to be somewhat, let's say helped by us as a nuclear medicine community. Thank you. And of course, happy to get any questions.

Faculty Discussion:

Phillip Koo: Thank you very much, Stefano, for that wonderful presentation. Giving an overview in that historical context, which I think sharing that journey with our medical oncology, radiation oncology, and neurologic oncology community, I think really helps give everyone a background with regards to the potential success here. So my first question I have for Alicia before you ask the question of Stefano is, the NETTER-1 trial was the pivotal trial, the registration trial for lutetium-177 DOTATATE, and it originally reported out pretty significant progression of this survival data, including an interim overall survival benefit as well. And it was just really well received by the medical oncology community and quickly became the standard of care. And in my mind, I think partly because there aren't as many good therapies for metastatic neuroendocrine tumors, how do you foresee this playing out when it comes to PSMA targeted therapies once approved?

Alicia Morgans: So I think that in medical oncology, what we're really looking for is maximal disease control and a balance with low toxicity and good quality of life. And when therapies do that, I think can be adopted very quickly, particularly if they don't have copay restrictions or other things that would restrict people from accessing the drug. My only concern with lutetium as it comes out is that it may have some geographical access issues in the beginning as different centers are rolling out their ability to give this drug, but from a perspective of a clinician and the perspective of patients, I think that this drug similar to Lutathera®, will absolutely be embraced because it makes sense, it doesn't harm patients as many of our other agents can do in our efforts to help them have control of their disease.

And I hope we'll have an improvement in survival. So I think this will be taken up similarly to the Lutathera®. So now I have the opportunity to ask you a question, Stefano. You mentioned you treat what you can see. And I think conceptually that is very attractive as you mentioned, but as we move things like lutetium, if we have access to that in a later phase, if we move that earlier into settings where there's so little disease that perhaps even PSMA scans can not pick up the small cells in clusters, they're not going to be in clusters, they may be a cell here or there, and even that imaging may not pick up something that we can see. Is that a setting where things like lutetium may not function or may not work, or is that just a setting where our imaging capabilities are not as honed as we wish and that agents lutetium may still have some benefit to patients?

Stefano Fanti: Wow, Alicia, great. You challenge me every time, that's my pleasure. Very interesting. And give me a chance to make some considerations, that's to say, regarding imaging, I'm absolutely in line with you. We are aware that the attempt is to move in a much earlier phase the use of lutetium PSMA because the ongoing trials are considering a late-stage disease or a third- or fourth-line of therapy. So patients with essentially advanced stage and so visible findings, but other trials also the Australian one are now pushing to the limit, that's to say, to adding as first-line possibly in combination. So at a moment where imaging maybe even completely negative about maybe the primary or in some cases completely negative.

So there may be some problems related to the fact that indeed to have some visualization, you need a minimum amount of cells. That's to say, our special resolution is not perfect, it's around four to five millimeters and so you need millions of cells. And even if you gain some advantage from the overexpression of the receptors because there is so-called partial volume effect, that to say, if a lot of radioactivity concentrates in one point, I can see things which are really small as two millimeters, but I can never see micrometastasis.

But nonetheless, the therapeutical fact is delivered in any case, because there is no minimum, there is no lower threshold. And again, those are beta particles and in particular, the alpha particles have an effect directly on DNA that kills the cell with a very high likelihood. So the rationale is that I can even go more or beyond what I see. I can treat beyond things that I cannot see because the limitation is mostly for the imaging part. On the other way around there are intrinsic limitations because you need to deliver the radioactive isotope to the area you may like to treat.

So if for any reason there is let's say a necrotic lesion very wide, where the perfusion does not get there. It's very well known that it's not suitable for treating. Some isotopes may slightly overcome with the so-called crossfire effect, that to say that the pathway, so the length of the distance that the isotope goes could be something like one millimeter, two millimeters, even a little bit more that's to say if a lesion is in the range of five to seven millimeters, it can be treated even up to one centimeter. But if you have a really large lesion with some distorted perfusion or some problem to deliver the treatment, that will probably be a permanent limitation. But this is definitely not the case of the early setting of the disease where we are now moving for the, let's say, treat even what you don't see.

Phillip Koo: Great, thank you very much. And I think that's a really great point. From a nuclear medicine perspective, there's very little control after you inject something and for lesions that are large and necrotic, you bring up that great point. And I think there've been some studies using radium that talk about larger lesions and necrotic lesions not being as effective. So Neal, as someone who's had an impact in prostate cancer in multiple stages, what are your thoughts on how we make this not just the potential as Dr. Fanti referred to, but a reality? And how do you foresee these types of therapies integrating into a urology practice?

Neal Shore: Yeah. Thanks, Phil. So Stefano, I just want to echo both Alicia and Phil your presentation was truly brilliant and I love the historical perspective, especially and hopefully for many of our younger listeners, because if you don't appreciate the history of where we were to where we are today, thanks to your leadership and Phil's leadership in the field of nuclear medicine. I mean, we say this a lot, but this is game-changing. And to your question, Phil, regarding urology, absolutely urologist worldwide, Italy, U.S everywhere else will want to embrace this.

What's particularly interesting to me are Stefanos' comments regarding how we always go to the third-, fourth-line of therapy to get an approvable pathway regulatory requirement. And it's invariably based upon the survival data. But I think as you alluded to Stefano, and I as a urologist, when I think about the potential for this type of therapy, for patients who have a PSA relapse or early high-risk newly diagnosed localized disease with likely a component of micrometastatic disease, I'm extremely enthusiastic about these potential studies. And even arguably can we at some point get rid of testosterone suppression and think about a radioligand pharmaceutical to really take care of all the disease known, seen, and not seen as Alicia mentioned.

And then the other thing I wanted you maybe to comment on is, we have many therapies now that have survival prolongation, you can count eight or nine in advanced prostate cancer. And they invariably involve either daily oral medication or a regular infusion cycle. What's pretty appealing to me about radioligand pharmaceuticals is the dosing schedule is very patient-friendly and that even becomes more of a consideration around pandemics, doesn't it?

Stefano Fanti: Yep. If I can comment, I guess that about, let's say, patient tolerance and capability to run the entire course of the planned therapy. I mean, side effects have been evaluated and they are not so different, they're probably even in favor, for example, if you refer to taxane or to other therapies. What's fundamentally different is the approach that patients usually like a lot, that's to say you don't have like for a radiation oncology plan dose of daily visit, or even for the pills, having some [inaudible 24:35] that change really your life. This therapy is, for example, let's say the Lutathera® therapy is based on something like a course every six weeks, and you will have about four courses. So it's very manageable from the point of view of life quality. And again, dealing with the relatively minor, because the severe side effects are really minor, just occur in a minor number of cases. And absolutely the same for lutetium PSMA.

I mean, if you consider that you're planning to have six courses on an interval of six weeks each, and for each treatment, you will stay in the hospital that depends on regulation, but in Europe, you have to be hospitalized for a couple of days, probably in the U.S. would be even less because usually you have also a more flexible regulation. But then it's done, that's to say there's no daily discomfort, even by the psychological point of view, it's very patient-friendly. At least that was my feedback on those patients.

Phillip Koo: Great. So as we bring this module to the close, I want to end with asking each of you and I'll start with you, Alicia, Neal, and then Stefano. One request or hope you have for your specialty colleagues with regards to how we can work together to make this really maximize the potential for targeted radionuclide therapies? Let's start with you, Alicia.

Alicia Morgans: Sure. So thank you. I would say, and this is anticipating that the VISION trial is positive. I am hopeful we'll see when the data comes out. But I would challenge my colleagues to not just give this in clinic, which I think that we will ultimately be able to do, and I'm sure we'll do well, but to continue to think about ways to use lutetium-177 in earlier stages of disease, when we don't struggle with the size of a metastatic deposit. And when we can potentially, as Neal mentioned, cure people and potentially get rid of things like androgen deprivation therapy. I would challenge us to really think about how we can optimally use this as we gain experience with using it if it becomes approved.

Neal Shore: Yeah, I would echo Alicia's really great comments. We have advances oftentimes in healthcare in oncology and GU oncology that are sometimes viewed as incremental. This is a non-incremental, this is a big change. And I would encourage my urologic colleagues in community and academia to say, "Wait a second now, we know prostate cancer has a lot of heterogeneity and there's this burgeoning complexity of options." You have to have a really strong and healthy relationship with your nuclear medicine physician community, or radiation oncology community or you've got to embrace this because if you don't, you're going to fall behind.

This is really important. Patient advocacy groups are going to be clamoring for this. And it really has to do so much with leadership that Stefano and Phil and your colleagues have brought. So we benefit, Alicia and I benefit, patients benefit, researchers benefit. So that would be my message to my urology colleagues.

Stefano Fanti: Well, I'm really happy and delighted by your great commands, because I guess we need the input from great clinicians, great urologists, oncologists, and so on. I guess again, that the journey has led us to be part of the MDT for neuroendocrine tumors, for like five to 10 years. Again, we started with diagnosis, and then we are fully involved with therapy. And I guess it should be the same for prostate cancer. I'm already part of the MDT, but of course, I was just invited for the PSMA PET reporting at the beginning. And right now it starts to be also about therapy and probably as a nuclear medicine community, we suffer a little bit of weakness, that's to say we have never been prime time players, I used to say we are pundits of medicine. And some trials have not been really brave enough as Alicia mentioned it too.

So we always start with late-stage disease, so the situation if not an orphan situation where it was at the same time more challenging, but at the same time easier to recruit the patient because they have exhausted alternatives. Probably we have to make with your help, a change in our mentality. So move to earlier therapy, to be more participating, more proactive in the MDT, and together with radiation oncologists. And these are the differences that oncologists and urologists who consider to easily refer patients, just like they do with radiation oncologists while it doesn't matter, it could be radiation oncologists or nuclear medicine physicians to deliver the lutetium. It's not the problem of any specialty doing that, and for the patients, it's important that the treatment is available at the right moment.

Phillip Koo: Great. Thank you very much. All wonderful comments and suggestions. I think speaking for nuclear medicine, we've really had the privilege to hear from visionaries in nuclear medicine, Johannes Czernin and Michael Hofman who we've referred to multiple times, Thomas Hope and Stefano Fanti. And for the nuclear medicine physicians that might be listening to this precision medicine forum, I encourage you all to get inspired by this, and we need more of these types of leaders in our field to really help meet the Dr. Morganses and the Dr. Shores and the Dr. Sartors and the Dr. Vogelzangs where they're at to really push this forward in that multi-T model. So thank you all for your wonderful comments and your engagement and leadership in making this all a reality. Thank you.

Alicia Morgans: Thank you.

Neal Shore: Thank you.

Stefano Fanti: Thank you very much again.