Dr. Manish Shah (Host): Welcome to Weill Cornell Medicine, CancerCast conversations about new developments in medicine, cancer care, and research. I'm your host, Dr. Manish Shah. And today, we will be talking about prostate-specific membrane antigen, or PSMA, therapy for prostate cancer.

Our guest today is Dr. Scott Tagawa. Dr. Tagawa is a friend of mine for many years. He is the Director of the Genitourinary Oncology Program and Medical Director of the Genitourinary Oncology Research Program at Weill Cornell Medicine/NewYork-Presbyterian Hospital. He is a global leader of drug development and PSMA-targeted therapies for prostate cancer, and has led numerous clinical trials in prostate, kidney, and bladder cancer.

Dr. Tagawa's work has led to several therapies receiving FDA approval, and he is a key opinion leader in genitourinary malignancies. And, he actually led a very pivotal phase III study that was recently published in a conference in Germany last year. So, Dr. Tagawa, Scott, welcome.

Dr. Scott Tagawa: Thank you very much for the invitation. Happy to be here.

Dr. Manish Shah: So, let's start off with just some basics about prostate cancer and how it develops, how it's initially treated.

Dr. Scott Tagawa: For those that don't know, the prostate is a gland that sits between the bladder and the urethra, that's how we urinate. And outside of skin cancers that are associated with sun, it's the most common site for cancer to develop in someone who was born with a prostate. Generally, we talk about men with prostate cancer.

Fortunately, most of the patients that are diagnosed do not actually die of prostate cancer. The majority of patients we can watch closely, called active surveillance, or intervene and treat with typically surgery or radiation or something that's to the prostate itself. That then leads to control for the rest of their life. But unfortunately, some walk in the door with cancer that is already spread or develop recurrent disease, and that can lead to death. And just because of the numbers of being the most common, it's almost always in the top two to three causes of death due to cancer in men in the United States.

Dr. Manish Shah: I'll take a step back and walk through that a little bit. So, I don't think we've actually defined what cancer is. It is essentially an uncontrolled growth. And there are some cancers that are benign, meaning that you have uncontrolled growth, but it's really self-limited to that area. It doesn't spread anywhere. And there are some cancers that are very aggressive and then it starts to spread, and then grow in those other places that it spreads.

The prostate, this gland, lies in the pelvis between the bladder and the urethra, and as your urine flows, it goes through the prostate. So, oftentimes people may have what we call benign prostatic hypertrophy, so a little bit of growth in the prostate. It's not cancer, but it can cause a little bit of blockage, and so people may have difficulty urinating. So, that's a very common thing that happens.

When there's cancer in the prostate, it can be quite indolent and low grade. You might have cancer, but it won't actually change your survival. You'll die of other diseases, heart disease or whatever else, because the cancer itself is not going to spread, or it could be managed very directly with local treatments. But because it's so prevalent, a small proportion of patients that have the more aggressive type, this is still relatively prevalent.

Dr. Scott Tagawa: I would say most of the time we can tell which category a tumor/patient is going to fall into. And that's partly because of developments through research in terms of looking at new things under the microscope, new things in terms of genes, and new things in terms of imaging or scans. Now, we get it right the majority of time, but it's not a hundred percent, which is one of the reasons we want to continue the research.

Dr. Manish Shah: So, tell us about PSA and PSMA, because that can be confusing as well.

Dr. Scott Tagawa: So, three letters for PSA, prostate-specific antigen. So prostate, we already talked about. Specific, hopefully, people know what that is, but just the idea was that this is going to be specific for prostate and possibly prostate cancer. Antigen just really means it's a protein. And that can be very different things, but we just think of this as a protein. And for PSA, it's made inside prostate and prostate cancer cells that may be secreted, meaning leaves the cells into other fluids. So, much of the time, we use that as something that leaves the cell, goes into blood, and we do a PSA blood test. That's the main type of blood test that we use for screening for prostate cancer.

For someone with prostate cancer, we tend to use that for monitoring. So going up, generally speaking, we say that is bad. Stable or going down, we generally say that is okay. That's more consistent with cancer control. So that's that protein that starts inside the cell and then leaves the cell.

We just add the letter M in the middle of that. So PSMA, so the ‘PSA’ still have the same meanings, prostate and specific and antigen. M is for membrane. So rather than being inside the cell and coming out, it's stuck to the membrane or that's the surface of the cell. So, the only way that leaves typically is when the cell leaves. And we can detect that in blood. So if there's a cell that is circulating in blood that we call a circulating tumor cell, one of the ways we can identify that as a prostate cancer cell is by checking for PSMA.

But what we've learned to exploit over the last several decades is using that as a way to both diagnose and treat prostate cancer. And, this is what has been the first in terms of FDA approvals. We can inject something into the blood. It circulates it around and only goes to PSMA. And what is attached to it is something that lights up. And we can do a scan. And the most common way we use that is what’s called a PET scan. And there’s PET scans that look at sugars, PET scans that look at other things. This is one looks at PSMA. So, this was one of the major advances. It’s really shifted almost everything that we have with this ability to detect. That's called a PSMA PET.

PSMA, is what we would call a cell surface protein. So, it's this protein that's on the cell but doesn't leave the cell, it's stuck to the membrane. And we can exploit that to target something that happens to be, for the most part, on prostate cancer and prostate with only limited distribution in the rest of the normal body.

Dr. Manish Shah: That's really a great explanation. So, is it the exact same protein that is intracellular and excreted versus the one that's membrane-bound? Or it just happens to be the same letters, but a slightly different protein?

Dr. Scott Tagawa: Nope. They happen to use the same letters and words, but they are different. There are forms of PSA that are really restricted to staying on the cell. But PSA, which most people recognize as a blood test, it does leave the cell. So, that's PSA. PSMA, that M has stuck to the cell and it doesn't leave the cell.

Dr. Manish Shah: And it's a different protein entirely. So, it just happens to be either secreted by the prostate, so PSA, or bound to the prostate cell, PSMA.

Dr. Scott Tagawa: Correct.

Dr. Manish Shah: And you were amongst the first to actually develop PSMA both, I think, as a diagnostic tool and as a therapeutic tool. Is that right? You want to tell us about that story?

Dr. Scott Tagawa: It starts before me, but it really is a New York story. So, the gene was discovered in New York. And the first, essentially four antibodies or proteins that were able to identify and bind viable prostate cancer cells is also a New York story. So, the gene was discovered by Skip Heston at Memorial Sloan Kettering, and Neil Bander, who is a urologist at Weill Cornell, now emeritus, invented the first drug, if you will, that is able to bind to viable prostate cancer cells.

And that has been developed mostly as a therapeutic, but really led the way for the diagnostic studies as well. So, diagnostic could be we have a biopsy, we’re not sure what it is, and helping the pathologist say, “Oh, it looks like it actually is prostate or prostate cancer.” That’s one thing.

But in the real-world, for the average patient, the more important, utility-driving test is the scan, which we started with antibodies, but for scans, it’s a little bit more cumbersome to use the antibody scan where we do the injection today and we scan several days later. So, the next generation of technology was developing what we call small molecules. And they’re called small molecules because they are literally smaller than these antibodies, where we do the injection and then about an hour later we do the scan. And that has, as I mentioned before, really revolutionized the management of prostate cancer, and frankly, interpretation of all the other data we have for therapy.

Dr. Manish Shah: This development program from the discovery of the antigen and then the application, that's spanned over 20 years or so, if I recall correctly.

Dr. Scott Tagawa: Thirty years plus in terms of discovery. In the clinic, really, it's been 25.

Dr. Manish Shah: Let's talk about prostate cancer now and its treatment. It's an uncontrolled growth, and it can become aggressive and it can require treatment. We mentioned some treatments already, surgery or radiation for localized disease. But then, there are other treatments like androgen deprivation therapy, chemotherapy, and we're going to get to PSMA-directed therapy. Do you want to start us off with how that started?

Dr. Scott Tagawa: So, one reason that PSMA imaging has revolutionized things is because it really has helped us in telling patients, we think it's all in the prostate or not, because we have a much more sensitive scan. So, it's helped both radiation and surgery as well.

As medical oncologists, what we primarily do in terms of treatment or drugs, led to the Nobel Prize many decades ago was, at the time, castration. So initially in mice, surgically removing the testicles, and then using estrogens and then subsequent therapies that essentially block the production of the male hormone testosterone. We use drugs to do that now, both injectable or oral. Combined, we call that androgen deprivation therapy or ‘ADT’.

It comes in the bucket of what I would term hormonal therapy. And when I say that, usually when I say that for the first-time to a patient, I usually say, "Well, we call it hormonal therapy. It really is anti-hormonal therapy".

Overall, we either block the production of the male hormone called testosterone, or we block the binding of that to the main problem inside the cell called the androgen receptor. You can just think of that as the hormone receptor. There's something that circulates in the blood that can stimulate the cancer to grow, and then something within the cancer that can cause the cancer to grow and spread. And that is what we call a driver of almost all prostate cancers, especially the ones that haven't yet been treated.

And we've learned to block that with different drugs. And that is very successful in terms of cancer response, where almost a hundred percent that start off untreated, we give this type of a treatment, this androgen deprivation or hormonal therapy, and the PSA drops a lot.

I don't want to get into the complexities of blocking the pathway versus actually killing the cell. It's a little bit of both. But it is successful in that manner almost all the time, that we've now moved on to the next generation of hormone therapy that we call ARPIs or ‘RPs’ for short. It's just a different way of doing the same thing, either lowering the production of testosterone or blocking this androgen receptor pathway.

And nowadays, most often these are combined, so someone that walks in the door with prostate cancer that has spread, it's usually going to be both of those types of agents together. That has been, in the last small number of years, traditional backbone of therapy where sometimes we will also add a third drug and sometimes not.

Dr. Manish Shah: So, the prostate is a male gland. It's only in males. And so, it kind of makes sense that endogenous androgens or testosterone, for example, but others as well, are important for the growth of the prostate gland. So, a cancer that starts in the prostate would be driven by this pathway, the androgens. And so, blocking this pathway by doing an orchiectomy or by blocking the androgen production or by an ARPI, that will inhibit any cancer that's driven by this pathway. So, I think that's really quite fundamental. And that actually helps a lot of people. But at some point, the cancers become independent of that pathway. Is that right?

Dr. Scott Tagawa: They might be. So, independence of the pathway happens in a fraction of patients/tumors where they can actually even lose the androgen receptor that is there. Most often, they become resistant to the pathway, where the pathway is there, but the cancer learns to activate the pathway in different mechanisms. So, there still is the AR pathway, there still is PSA, that's the blood test, production. But despite the ADT and the ARPI -- these abbreviations that we have for the main hormonal drugs -- the cancer learns to grow.

That's a distinction to totally losing the AR pathway where it can turn into something we call small cell or neuroendocrine or aggressive variant. There's different terminologies that are there. Most often if that happens, there is very little, at least relatively, PSA, that blood production. And as it turns out, when we get to the PSMA-targeted therapy, if there is a tumor, which is maybe 10-20% of the tumors that are PSMA low, if that happens, they typically are also this hormonal therapy-resistant, or AR low as well.

Dr. Manish Shah: And so, what do we do? I'm sure it's chemotherapy and other things. But walk us through that.

Dr. Scott Tagawa: I mentioned the word small cell. And one of the reasons we call it small cell is because the cells look small under the microscope, and they're blue with certain stains. The most common small cell comes in the lung, small-cell lung cancer. And we've developed certain drugs, typically we call platinum drugs that work in that, and those types of drugs have kind of been extrapolated to all the small cell cancers of other sites. That is part of the backbone. But overall, chemotherapy as the general rule is what we will use. And often, it'll be with a platinum drug.

So, the typical chemotherapy drugs for prostate cancer are what're called taxanes. So, docetaxel and cabazitaxel are the two FDA-approved drugs. Sometimes we'll add a platinum drug to that, or sometimes we'll do a kind of a traditional small-cell regimen: cisplatin-etoposide or carboplatin-etoposide.

You're right in terms of chemotherapy. We have interesting data from Cornell actually, that say the taxane chemotherapies can also work with the androgen receptor pathway, but especially when we add these platinum drugs.

The genes that are associated with AR-independent or neuroendocrine small-cell are sometimes a little bit different. So, sometimes we'll take other therapies based upon the genes. But they also may have different proteins that are there. And for instance, there's a protein that's called DLL3. That happens to be a protein that is almost always present on small-cell lung cancer. And there is a DLL3 treatment. It's an immune type of therapy where there's a drug that half of it recognizes this DLL3. So, it binds to the small-cell lung cancer cell and also activates, or at least influences, a T-cell with CD3 that's part of it. And that target, DLL3, actually through some Cornell data in this neuroendocrine type of prostate cancer, rather than being there maybe 20% of the time in a low level, with the average metastatic prostate cancer, in this neuroendocrine type, it may be more like 75-80% of the time there, and more to high levels. So, that is a target of interest in this disease state.

There's other ones that you may be interested in as a GI oncologist. So CEACAM5 is an area of interest for GI cancers that are typically not there in regular prostate cancer, but then emerge. So, it's an area of what we call unmet need, because this unfortunately growing fraction of patients, that may be one in five or more, will lose the typical receptors or targets to hormonal things, PSMA. And we’re looking to develop, whether they’re targeted chemo agents, whether they’re targeted immune agents, whether they’re targeted particles of radiation, in this subset.

Dr. Manish Shah: I wanted to take a step back and conceptually think about how do we treat cancer in general, and using prostate cancer as a framework. So, we began by saying that the prostate cancer cells are very dependent on this androgen pathway. So by blocking that pathway by different means, you can treat cancer that way. That’s the first thing.

But then, Dr. Tagawa explained that this pathway, even though it may be present, the cancer cells have learned a way to no longer depend on the pathway. So, you need to use different ways to treat the cancer cells.

One way is chemotherapy. And what that does is it disrupts the intracellular workings of key functions. So, we mentioned docetaxel or cabazitaxel. These are agents that bind to microtubules and stop the function of microtubules within the cell. But, other chemotherapies might be agents that actually target and damage DNA. And DNA is important for cancer cells because you need the DNA to replicate to develop daughter cancer cells. So, chemotherapy is another way to target cancer.

And then, the third way, which we just mentioned very briefly, but we should spend more time on, is radiation, which is high energy particles or beams that actually damage DNA directly. And people have heard of radiation, what we call external beam radiation where radiation is provided from an external source. And then, it's directed into the body. That's how you treat, for example, localized prostate cancer.

But one of the exciting things about PSMA is that we're able to now use that target as a way to deliver radiation. And in fact, that's one of the most recent therapies that got approved. First, correct any of this that I got wrong, and then maybe expand on that.

Dr. Scott Tagawa: You are, not surprisingly, correct. Because while you specialize in GI cancer, you have general knowledge as an oncologist. So overall, correct. There is a type of therapy broadly called targeted radionuclide therapy. So, targeted means it's in some way targeted. It could be pushed to a certain area or kind of like a smart bomb where it circulates and finds certain things.

It's therapeutic, designed to harm cancer cells. And then, radionuclide just means it's a radioactive particle, so a small particle that emits radiation. And loosely speaking, there's beta emitters, alpha emitters, and now zeta emitters, I don't think we have to go into that so much, but there's weaker ones that can travel through tissues and stronger ones that can't really travel through so many tissues.

To just get one thing out of the way, the one target is to put it in beads that we can infuse into a certain area, and that's one way of targeting. Ignoring that, what most of the field is doing now, really coming from eight decades ago, from thyroid cancer, learning that there may be something that is more unique to cancer cells and maybe an organ, such as the thyroid itself. And something we can put into the body, into the blood and it circulates around and lands in the cells that we really want it to. And in the case of radioactive iodine, that's thyroid cancer, just because it naturally takes up iodine. That is the prototypical thing in the field of what we call theranostics, which means that we find a target that we can take a picture of with a scan, and then use something similar to treat it.

So, just to kind of get some terminology out of the way, but PSMA, and there's other targets that are out there with prostate cancer and other cancers, is something we already talked about, is relatively selected on prostate tissue and prostate cancer tissue, wherever it is in the body.

We've already talked about that we can inject something that circulates around and only lands in the tumor to light it up in terms of scans. Well, we can attach a therapeutic radionuclide, and the approved one is called Lutetium‑177 or 177-Lu, which is one of these beta emitters that's relatively weaker, but we get a bunch together and that can penetrate across cells. And we essentially do the same thing as we do with a scan, except that attached to it is not primarily designed to light up and look at, but it is designed to go and kill tumors. So, it's a radiation smart bomb that has these tiny radioactive particles that circulate in the body for some number of hours and wind up in this PSMA-positive prostate cancer.

And it doesn't mean there's no side effects, just because it's targeted. But predominantly, the radiation goes into these tumors. And the reason it's FDA-approved is because in the first study that came out in 2021, leading to a 2022 approval, patients that had cancers that grew despite the typical drugs, such as a minimum of hormone therapy and chemotherapy, but others too, the patients live longer. And that led to the initial approval of what we call a overall survival benefit.

Dr. Manish Shah: So, the other analogy is almost like a Trojan horse. So you're using the binding of the antibody to the target, in this case, PSMA. And then, delivering the lethal blow, which is in this case lutetium or the beta emitter. But that actually brings up another point, because I think this will come up in the next several years, the difference between beta emitters and alpha emitters.

Dr. Scott Tagawa: I would say that their size is the difference, but the important thing is the properties. One is how potent or powerful. We call that linear energy transfer or ‘LET’, but that's really just how powerful are they, and when they land, how far away can they do damage.

So, the beta emitters, the approved ones are iodine first and Yttrium-90. But in terms of the main ones that we target for cancers that happen to be prostate cancer and mostly GI neuroendocrine tumors is Lutetium‑177, which is predominantly a beta emitter. So, relatively weak energy. And when I say relative, this is relative to the alphas that I'm going to talk about, but can travel millimeters to centimeters, meaning that not necessarily the particle, but the effect can go through several cells. So, there's what we call a bystander effect. So, where it lands, it could affect that cell, but also cells around it, which can be good if the cells around it are cancer, even if they don't have the target there. So, a cell that has PSMA can bring that in. The neighboring cell that doesn't have PSMA can be affected so that can be the good part, but also, can affect normal organs. And that could be some of the side effects.

The beta versus alpha, the beta, relatively weaker energy, but can travel through; and alpha, depending which one, is thousand to several thousand-fold more potent, this energy amount, but typically can only travel through a couple of cells, so not a millimeter, much less than that. And that's on a high level, the major differences. As of today, there's one alpha that's approved. It happens to be in prostate cancer. It's called radium-223, which lands in bone.

Dr. Manish Shah: The current approval of the PSMA-directed therapy is with the beta emitter, but there's research with alpha emitters. And if I understand correctly, the idea is that you might be able to deliver very potent therapy more focally, but it may not be as broad. So, is it possible that an alpha emitter might be better for a smaller volume disease or something like that?

Dr. Scott Tagawa: There's physical properties. In all types of radiation, we work with physicists. And they look at models. And if you have one cell and you put in, literally you can inject, an alpha or you can inject the beta, the alpha has a good chance of killing the cell. The beta, because of two things, number one is it’s the lower energy, but number two is the energy is actually going pretty far outside the cell. So for those two things, I would say, yes, what we call micrometastatic disease, things that are just millimeter or less type of things that we can’t see on scans, based upon those properties, less likely to be cured with a beta emitter, more likely to be cured with an alpha emitter, assuming that we can target the cells.

Dr. Manish Shah: So from a drug development standpoint, it may have implications because you might think of adjuvant treatment, more in the realm of an alpha emitter. From a patient and a caregiver standpoint, understanding these differences gives us a high-level understanding.

But what about safety? You’re injecting essentially particles that have radioactivity. Do patients need to worry about their loved ones if they're in the same house, if they're using the same bathroom? What about those implications?

Dr. Scott Tagawa: So, you asked “should they worry”. I would never tell someone to worry or not, but there can be some risks that are there, that as far as I know, have never translated to actually any real harm.

So, the beta and alpha that we're talking about is the part that we are interested in as oncologists in terms of killing the cells. However, even the long-range betas like Yttrium-90, there's shielding, it's inside the body, it's not really going to be harmful to others. There's something we call gamma and people have heard about gamma rays, that's what we see on scans. So to see it in a scan, if someone thinks about it, we do an injection. And then, the scanner is inches to feet away. So, those can travel. So, particles or radionuclides such as Lutetium‑177 also have gamma. And we utilize that to be able see where it landed. We can do scans, but that's the part that could cause harm or damage to other people or other living things. I know some people worry about their pets.

So yes, in terms of radiation safety, this common dogma is time and distance. So, the closer someone is or something is, and the longer it's close, the higher the risk. There's two instructions that we'll give. One has to do with the time and distance. So depending on the dose and other things, we'd say loosely, especially for the first couple of days, not within a foot for more than an hour, that's kind of a loose type of a thing-- giving someone a hug, no problem. Even giving a baby a hug, no problem. But not spending so much time, especially within the first couple of days of treatment. The time part is these all decay. So, the amount of radiation today versus tomorrow is different, and it depends on what drug we're talking about. But lutetium is a week, so half of it's gone in a week. So, we know that several days out, there's a lot less that is there.

The other part is, at least these small molecules, the way they leave the body is through the urine. And even though the urine will have much less radiation than what's actually in the body, there's nothing shielding it. So, we really worry about the urine that comes out, especially the first couple of voids. So that same day, we make sure that people have flushed the toilet, et cetera. And if there's any incontinence, we make sure that the linens or the diapers, or whatever else are taken care of a little bit separately. So, that is something that's a little bit different.

All of our drugs that we have can be harmful to the patient and others if they happen to get exposed. But this is something that can be passive exposure. It's not someone taking their cancer pill by accident or on purpose, it is just being near someone for a long time. So, it is something that we discuss and counsel with this type of therapy.

Dr. Manish Shah: That's so helpful. And it makes so much sense, the way you explained it. We've covered a lot of ground. I wanted to make sure we got in the key things. As both of us are in drug development, you led a pivotal phase III trial, and it was presented at one of the international meetings last year. I just wanted to make sure that you had a chance to talk about that and how does that play a role with what we talked about today.

Dr. Scott Tagawa: The first drug that was approved in terms of PSMA happened to be this drug that we call Lutetium-PSMA-617. It's branded as Pluvicto. It was first FDA-approved in patients with metastatic or spread cancer that was beyond hormonal therapy and chemotherapy, that was 2022. And then, another trial again in patients that had treatment resistance, this one to only hormonal therapy, called PSMA-4. So once someone had what we now call APMR or androgen pathway modulator resistant therapy. We used to call this castration resistance. But castration has a negative connotation and it is not patient friendly. So, we've eliminated that term from the jargon.

But anyway, in this hormonal or APM-resistant patient population, there's benefit and FDA approval. What we did-- we, literally us-- because it started in the cooperative groups and then, it was taken over by a drug company, said, "Well, what about upfront?" And there's multiple scientific reasons why this should work. It should pair well with hormonal therapy. Hormonal therapy can make more PSMA, some more target. It can what we call radiosensitize. So, there's multiple scientific reasons for this.

But we simply ask the question, okay, we have the standard of care that is these two hormonal drugs when someone walks in there with metastatic disease. What if we also add in this lutetium PSMA at the very beginning? This is called the PSMAddition study. What we call the primary endpoint, or the first main readout, of how well this worked called efficacy, what’s called radiographic progression-free survival. So basically, how long was it until cancer grew on scans or the patient died? That combination. And it turned out to be a positive study presented in Germany, as you mentioned, at ESMO. The early addition of Lutetium PSMA‑617 to initial therapy with that hormone therapy doublet was better. It led to a longer time until scans get worse or someone died if we added this Lutetium PSMA‑617 early. It was already standard to do later. And in fact in the trial, if a patient entered and was assigned or randomized only the two drugs, when the scans get worse, they were offered the lutetium.

Dr. Manish Shah: The same treatment. It was the crossover. So, congratulations. It's no small feat to do that study. And it's an important point. If you think of targeted therapy, if you have a target and you're able to attack that target, we've learned through many different trials and many different cancers, the earlier you hit the target, the more successful you're going to be.

And I'll just talk about BRAF, which is a very important target in colon cancer. The first drugs that got approved were approved in the second line setting. There was a modest benefit in survival. When we applied it in the first-line setting, patients lived much longer and the survival benefit was much more.

And in some respects, this trial that Dr. Tagawa led is exactly the same way. The PSMA lutetium targets PSMA. We have a target. It is expressed on prostate cancer cells. And if you apply that early, so before progression on the standard therapies, he showed that the rate of progression on scans was much longer with the use of the lutetium PSMA treatment.

So, it is a common theme. And I think it's an important thing, and I think it maybe even addresses the way that drug development is going to go where instead of developing these targeted therapies in the metastatic setting, their application may be most before the cancer has spread, where in earlier stage or in what we call neoadjuvant treatments. What are your thoughts on that?

Dr. Scott Tagawa: I totally agree. There's some implications in terms of the betas in adjuvant or neoadjuvant. So, talking about drugs versus, let's say the knife, with surgery. The knife is pretty good for everything that's within that part. But we want to take care of everything that's outside of that part, or we call micrometastatic disease.

So, some of these things can work really well. Like most of our drugs, even chemotherapy, just poisons that preferentially harm the cancer cell, they work and improve cure rates. And most of the time, the difference between cure versus just getting a few more years, it's a much different type of endpoint. So, there is a caveat with these radionuclides that maybe some of them will be suboptimal in that particular setting.

But in terms of earlier, yes, most effective therapies, rather than measuring outcome in months, we're measuring the outcome in years because they're just more effective. Generally speaking, I think the cancer cells are more sensitive or less likely to be resistant when we move them in earlier.

Dr. Manish Shah: So, I think this has been terrific. And I wanted to thank you very much, Dr. Tagawa. We covered a lot. We covered what prostate cancer is, the dependence on the androgen pathway, the treatments from hormonal treatment to chemotherapy and radiation, different types of radiation, the Trojan Horse of lutetium and PSMA versus PSA. It's really quite amazing.

I'll ask you one final question. What's the most exciting thing about the future in terms of treatment?

Dr. Scott Tagawa: Well, to stick with a theme, is that we have, number one, identified these targets, which are much more on cancer cells than the normal body, and now, with technology, have paired those with therapeutics and/or diagnostics that can target them. And those could be targeted chemotherapy, we call them antibody drug conjugates. And that has made huge changes, really huge paradigm shifting things where now we have actually gone to increase the cure rate in bladder cancer. And we're working on some of those drugs in prostate cancer. We can attach a radionuclide, and that really changed the way we diagnose and stage, as well as treat patients with prostate cancer. And there’s new agents that are about to be FDA-approved in terms of imaging with kidney cancer, as well. So, it's great that we have those, essentially now, 2026, 2025. And now, we can leverage that, because we have identified additional targets that are there. And the pathway, now that we know how to do it, should be much quicker to develop these agents against all these different types of tumors, and not just in GU, but across the board in a more selective fashion.

Dr. Manish Shah: Absolutely. And it's an exciting time. I think that you're absolutely right, we are identifying more targets. We're identifying therapies that can target those proteins or targets, biomarkers, and we're learning how to use them in better ways.

I'd like to thank you very much for your time. You can download, subscribe, rate and review CancerCast on Apple Podcasts, Spotify, YouTube or online at weillcornell.org. We also encourage you to write us at CancerCast at med.cornell.edu with questions, comments, and topics you'd like to hear us cover in the future.

That's it for CancerCast, conversations about new developments in medicine, cancer care, and research. I'm Dr. Manish Shah. Thanks for listening.

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Opinions expressed in this podcast are those of the speaker and do not represent the perspectives of Weill Cornell Medicine as an institution.