Dr. Tagawa: 30,000 people roughly die of prostate cancer per year.
Erin: Dr. Scott Tagawa is a medical oncologist at NewYork-Presbyterian, and director of the Genitourinary Oncology Program at Weill Cornell Medicine.
Dr. Tagawa: That's more or less how many are newly diagnosed with metastatic disease.
Erin: About five to ten percent of prostate cancer cases are metastatic, and despite incredible leaps in recent years in terms of treating a variety of other metastatic cancer types, metastatic prostate cancer remains incurable.
Dr. Tagawa: Some of the other cancers have been really revolutionized by immunotherapy, leading to either cures or durable long-term survival, even off therapy, and that has been missing in prostate cancer.
Erin: To bridge that gap, Dr. Tagawa and his team are harnessing the power of precision medicine to find new biomarkers and targeted therapies to identify those who could benefit from earlier intervention, slow the cancer's progression, and potentially redefine the standard of care for patients with metastatic prostate cancer.
Dr. Tagawa: Identifying those that are destined to have prostate cancer, that's going to affect their lives, whether it affects the quality of their life and/or their quantity, both are equally important.
Erin: I'm Erin Welsh, and this is Advances in Care. Today, I'll speak with Dr. Scott Tagawa about his recent Phase III clinical trial that led to the groundbreaking discovery of a new targeted radionuclide therapy, or TRT. This novel approach aims to create a pathway to extend both quantity and quality of life for patients with hormone-sensitive metastatic prostate cancer.
Dr. Tagawa, it's great to meet you. Thank you so much for joining me today.
Dr. Tagawa: Happy to be here.
Erin: So, you have this foot in the world of clinical care and this foot in the world of drug development. I'm curious how you became interested in genitourinary oncology in the first place, and what drew you to this intersection?
Dr. Tagawa: During medical school, I had the opportunity to work with a couple of leaders in medical oncology, as well as a urologist, world-renowned, excellent clinicians, excellent researchers. So it was essentially at the beginning of my fellowship that I really developed an interest and started some projects in, in terms of GU cancers, in terms of research. I find taking care of the, the patients that have the GU cancers, um, some that we cure almost all the time, some that we rarely can cure, but we can, you know, keep patients with a relatively good quality of life and a length of life that may sometimes exceed decades now. I, I really like that, that mix of both diseases, as well as the ability to participate in, in clinical research at a very early time point.
Erin: Right. And that research is, is really critical because prostate cancer remains one of the most common cancers in men, and it's the second leading cause of cancer death overall. And I was wondering if you could share why you think this cancer remains such a major challenge in oncology today?
Dr. Tagawa: So, one of the issues from prostate cancer, until relatively recently, is deficiencies in imaging. You used to see maybe just the very tip of the iceberg, where we would miss a huge percentage of the tumors that are out there. Now, the other that's different in terms of, of prostate cancer, as a general rule, is that the standard immune drugs that we have for many other cancers rarely work in prostate cancer. Some of the other cancers have been really revolutionized by immunotherapy, leading to either cures or durable long-term survival, even off therapy, and that has been missing in prostate cancer. So prostate cancer, uh, I think is harder to cure, in part because it's a slower-growing cancer. So traditionally, when we give chemotherapy, we need tumors that replicate faster, so we can get rid of them. And the other is that the main effective way that we treat is with hormonal therapy. That kills some cells but really slows them down more, and we get years rather than months, but most often have a lot left over, and then we have deficiencies in what we've discovered in terms of research.
Erin: Right. So, the biological component is tricky, and it's one of the more stigmatized cancers. So, I imagine getting patient buy-in to participate in research, that might be a bit more difficult.
Dr. Tagawa: Yeah. So those for, I think, decades in the past, have led to, you know, us in the prostate cancer field being behind-- we always compare ourselves to breast cancer. Now, now it's, you know, much more widespread. The ability to offer research and patients participating in research is much more common than it used to be, but we're still looking to catch up.
Erin: Right. And when you talk about catching up, what have some of the major advances in prostate cancer detection looked like?
Dr. Tagawa: I mentioned, uh, screening, and, you know, in the older days, there was no such thing as PSA, and then PSA was introduced. You know, became available in the '80s, but more widespread in the '90s, and initially, it was used for, for patients with prostate cancer to monitor, but then came in as a screening tool.
Erin: Got it. And building on that, I know that the discovery of PSMA more recently was another step forward in being able to identify more advanced or more aggressive cancer, and that, that discovery actually happened at Weill Cornell Medicine. Can you briefly take me through the discovery of PSMA and what that finding meant for its potential as a therapeutic target?
Dr. Tagawa: I don't want to exclude some prior researchers, but I look at it as a kind of New York-centric-... where the gene was discovered in New York, and then the first agent that's able to target, this is all preclinically, able to hit PSMA-positive live cells is also in New York. That happened to be at, um, NYP Weill Cornell with Neil Bander, developing several different antibodies, one of which is called GF-101, which went into humans, that, you know, really set the stage as, wow, we can actually see tumors that we couldn't see before? You know, at our shop in, um, Weill Cornell NewYork-Presbyterian, it's been really three decades going from the preclinical development to the first in-human therapeutic trials, which really started twenty-five years ago. It has really set the stage for what we have today.
Erin: I was wondering if you could tell me about the PSMA PET scan and, you know, h- why it's been such a transformative advancement in prostate cancer care.
Dr. Tagawa: So most prostate cancer cells, and particularly untreated prostate cancer cells, virtually all will have PSMA that, that is there, and all cancers will have cells that are out there that we can't see. Doesn't matter if it's a CT bone scan, first or second generation PET scan, we can't see it most of the time. But because of a combination of how much PSMA expression that is there, plus the development of the agents that are able to sometimes see things that are a few millimeters that we couldn't see before, you look at a screen, and we see this bright thing that's out there. It's just so obvious that a three-millimeter lymph node that has prostate cancer in it, we might pick up on a PET scan. A radiologist scrolling through the same section on the CT or MRI is just gonna bypass it. So i- it's the ability to exploit the target that's relatively selective, and then the technology to be able to develop the agents, administer the agents, and have the scanners to detect them, all that has come together really over the last decade.
Erin: Okay, so, so you're able to look at the images from that PSMA PET scan and then decide if the patient is a good candidate for PSMA-targeted therapy. Can you explain how PSMA targeted radioligand therapy works in particular?
Dr. Tagawa: So the world of TRT or targeted radionuclide therapy, we have a target. We have a radionuclide that is therapeutic, so that's the R and the T. So a radioactive particle that's delivered to a target, that is able to selectively kill those target cells, utilizing radiation that is able to damage DNA. For targeted radioligand therapy, the carrier or targeted agent happens to be a small molecule ligand, that's radioligand therapy.
Erin: Got it. So for targeted radioligand therapy, the target is the PSMA cells, and the radiation is delivered directly to the tumor using a small molecule ligand as the delivery mechanism. And so it's a more targeted, less damaging way to treat cancer cells.
Dr. Tagawa: Yeah. Yeah.
Erin: And is this approach being used in treatment today?
Dr. Tagawa: So there's only one approved therapy. So it's lutetium psma-617. So it just, it takes lutetium-177, which is a relatively weak energy particle, but it can travel millimeters. It can, it can affect both PSMA-positive and PSMA-negative or low cells in the areas, and that's how we are able to treat or eradicate those tumors, because a lot will go to that, that area, just like what happens on the PET scan, except these have the energy that not just is visible, but also can damage the DNA. So it's-- radiation is the mechanism. The main way that the radiation is able to kill the tumor cells is because of damaging DNA.
Erin: And so I, I understand that until recently, PSMA TRT was often a sort of last-line therapy, but you recently led the PSMA addition Phase III trial, which evaluates this therapy earlier in hormone-sensitive metastatic prostate cancer. So could you take me through the rationale of testing this therapy earlier in the disease course, rather than reserving it for late-line treatment?
Dr. Tagawa: I would say that scientifically, there were three reasons to do this trial. One is the target. So PSMA, when it's lost, it's most often lost in tumors that are more resistant. So one of the pathways or the mechanisms of, of resistance to hormonal therapy is losing the andro receptor, and PSMA is loosely tied to the andro receptor. So those that have PSMA-low disease much more often have five-plus lines of therapy or at least a couple lines of therapy. PSMA positivity is, is more universal at the beginning, is one reason. Another reason is that the mechanism is radiation, and as a tumor becomes more resistant to whatever therapy, they often develop changes, genomic changes and other changes, that make them radiation resistant. And then PSMA addition, the addition is adding it to the back of hormonal therapy, and then there's that potential synergism with hormonal therapy. So hormonal therapy will often modulate PSMA, so any cell that has survived hormonal therapy generally has more PSMA. Those are the main reasons that we said, "Okay, let's move this up front." It's not just early; it's at the very beginning. So some patients, it is recurrent disease, but for many patients, it's walking in the door at diagnosis. This is the patient population that we're looking at with the initial treatment.
Erin: Okay, got it. So what were some of your key findings from this trial?
Dr. Tagawa: In terms of results, the, the primary endpoint that we wanted to hit was prolonging-... radiographic progression-free survival, so prolonging time until scans getting worse or the patient dying, um, and that primary endpoint was met with a 28% improvement. Many of the other secondary endpoints also favored the early addition of the lutetium PSMA-617, such as overall survival.
Erin: I mean, that is, that's very exciting. And it also strikes me how NewYork-Presbyterian and Weill Cornell Medicine have always been so deeply involved in the evolution of prostate cancer research. What do you think has made this institution able to, you know, advance standards of care globally in this arena?
Dr. Tagawa: So one is, it's clearly people. You know, I think there's many institutions that will have the, the bench science know-how to, to have discoveries, but then have the available team infrastructure to be able to actually, at the same place, put it into humans. So multidisciplinary on the research side first, and then multidisciplinary in the clinic to be able to administer this type of, of therapy. Relatively unique, and, but that is something that they were able to do and that we have been able to do. We've been able to, um, build upon the existing infrastructure that started, really, I credit Neil Bander for starting that. Um, and then we've kind of moved on to the next generation. So, Neil kind of passed that on to me, and then now we're training the next generation to kind of take over from us in terms of the newer trials. And now we're actually-- we're looking to leverage the infrastructure that was created to hopefully come up with, you know, additional agents against, uh, additional targets.
Erin: Wow! I mean, that-- it's so encouraging to think about where this research might go in the future, and it must be so incredible to take part in the entire process of medical innovation. You know, being able to see a drug development through from its origins all the way to its end in a clinical setting, I mean, that must be so fulfilling.
Dr. Tagawa: It is. I really do my best, and I take pride in that essentially every patient walking through the door, I will mention or offer the ability to them to participate in research. And I think that's the, the main way that we can, you know, it- do our best to eliminate or lower our prejudices against participation. You know, we've developed a program where we have something to offer virtually every single patient walking in the door. One of the reasons I like the ability to do that is because I see it as helping the patient that's sitting in front of me, hopefully also their family members, as well as, regardless of the outcome, you know, taking one cell or one tumor from one patient might lead into a discovery that helps millions down the line.
Erin: Well, I am really excited to see where this research goes, and I appreciate you taking the time to chat with me today.
Dr. Tagawa: Thank you very much for the invitation. It was a pleasure.
Erin: Thanks so much to Dr. Scott Tagawa for speaking with me today about these incredible advancements in prostate cancer care. I'm Erin Welsh. Advances in Care is a production of NewYork-Presbyterian Hospital. As a reminder, the views shared on this podcast solely reflect the expertise and experience of our guests. To listen to more episodes of Advances in Care, be sure to follow and subscribe on Apple Podcasts, Spotify, or wherever you get your podcasts. And to learn more about the latest medical innovations from the pioneering physicians at NewYork-Presbyterian, go to nyp.org/advances.
