How PSMA PET will change the treatment of prostate cancer

In a recent interview, Neil H. Bander, MD, emphasizes some of the specific innovations that are on the horizon for PSMA.

Prostate-specific membrane antigen (PSMA) advancements have been improving the diagnosis and treatment methods for patients with prostate cancer over the past several years.

In a recent interview, Neil H. Bander, MD, emphasizes some of the specific innovations that are on the horizon for PSMA. He dives into PSMA PET imaging, lutetium-177, actinium 225, and how all of these developments will benefit patients in the future. Bander is the Bernard & Josephine Chaus Professor of Urologic Oncology at Weill Cornell Medicine, New York City, New York.

At the recent Prostate Cancer Foundation Scientific Retreat, you gave a presentation titled, “Insights and Future Predictions from 25 years of PSMA Research.”1 Could you provide a brief summary of this presentation? How has PSMA changed the detection and treatment of prostate cancer?

In my presentation, I tried to focus on the fact that what we're seeing evolve right now, with the recent approval of PSMA PET imaging and the anticipated approval of the PSMA-617 Lutetium therapeutic on the basis of the New England Journal-reported VISION trial,2 [is] just the tip of the iceberg. What I was asked to do was to focus on where I thought the field would be going ; I tried to focus on things that people haven't anticipated yet. So, 1 thing I mentioned was that it's very clear that PSMA PET imaging is having, I guess you could call it, almost a transformative impact on our ability to image metastatic disease, in that it is much more sensitive than we've had for the last 50 plus years—and also, 98% specific.

I do think 1 of the areas with respect to imaging that we haven't seen a lot of activity in, but which I anticipate we will, is in the ability to image localized disease within the prostate. Part of what I anticipate is going to happen is that we'll start seeing PSMA PET imaging being applied to patients from the time they first enter the urologist’s office with a potential diagnosis of prostate cancer; that is, even before a biopsy is done. I think that because there is already some data in our center and we're starting to see some indications from other centers, you can image the site of disease within the prostate gland. Also, because we know that the PSMA level correlates very well with Gleason score, there's even the potential that we would be able to, in effect, non-invasively determine the Gleason score of the lesion or lesions we identify on the image. That will help identify which patients merit a biopsy so we can eliminate the large proportion of unnecessary biopsies or negative biopsies that are done today, which obviously would be a significant benefit for patients [and] a significant economic benefit for the health care system to not have to pay for those unnecessary biopsies. Beyond that, in the patients who merit a biopsy, it will direct where the biopsy should sample. In that sense, it can be co-registered, if you will, with an MRI. So, we'll really get a good sense as to where the lesion is, and instead of doing multiple needle sticks in an effort to find a tumor, we'll be able to directly biopsy the site of suspicion—maybe reduce the number of needle passes that are necessary and that will, in turn, decrease the morbidity of the procedure.

Another imaging area that is coming is—it's already been demonstrated by our work and others—that you can also put an optical dye on these targeting agents. And so, the potential is that at the time of prostatectomy, you will actually be able to, in essence, visualize the tumor at the time of surgery. You'll be able to see whether the margin is involved. And you'll also be able to, with a reasonably high degree of accuracy, identify whether the lymph nodes are positive and which lymph nodes need to be removed. So, again, I think that's an area that we haven't heard much about yet, but I can see that it's developing.

On the therapy side, I think an interesting area is the ability to move from beta particles to alpha particles. The difference for those in the audience who aren't familiar with this is that alpha particles are 1000-fold more potent than beta particles. Lutetium 177 is a beta particle. In addition to alpha particles being much more potent than beta particles, they are also much more precise. The range is much narrower, so you only deliver the therapeutic effect within the tumor and not around the tumor. And so, the toxicity can be less with an alpha particle than a beta particle. There have been some demonstrations, clinically, that a PSMA-targeted alpha particle can have an enormous benefit to patients. There were cases published from Heidelberg, Germany,3 that showed patients at the end of life, who had exhausted every known treatment option, who had very bulky disease. In 1 case, the PSA was 300 ng/mL. In the other case, the PSA was about 3000 ng/mL. In those 2 cases, albeit anecdotally reported cases, those patients had complete responses to the PSMA-targeted alpha particle even after they failed PSMA 617-177Lu. The shortcoming, if you will, of that approach is that those small molecule ligands also target the salivary glands and the lacrimal glands and the toxicity delivered to those sites is substantial, and basically intolerable for a significant proportion of patients.

What we have seen is that when we target PSMA using an antibody instead of a small molecule ligand, for a variety of reasons we don't target the salivary glands or the lacrimal glands. We've already reported at GU ASCO and at ASCO that targeting an alpha particle by way of the antibody can result in substantial anti-tumor effect without the side effects in the salivary glands and the lacrimal glands. So, I foresee significant utility of a PSMA antibody-targeted alpha particle. It actually goes beyond that. It turns out that if you consider tumor targeting by a PSMA-targeted antibody or a PSMA-targeted small molecule ligand, they both do a very effective job of targeting the tumor. But interestingly, their normal tissue bio-distributions are, for all intents and purposes, mutually exclusive. So, the small molecule agents target the salivary glands and the lacrimal glands and get excreted by the kidneys. The kidney gets a significant dose, although it hasn't been dose-limiting at this point. With antibody targeting, you don't get detectable targeting of the salivary glands or the lacrimal glands, and they don't get excreted by the kidney because the antibody is too large to be filtered through the glomerulus. As a result, the side effect profile of these 2 different targeting classes (small molecule ligands and antibodies) are also mutually exclusive so that when you combine PSMA antibodies and small molecule ligands, they both converge on the tumor, giving you an additive dose to the tumor. But the side effect profile is not additive, so you benefit by the additive dose to the tumor without increasing the side effects. Our as yet unpublished pre-clinical data shows that the antibody actually improves the uptake and retention of the small molecule ligand. So, you actually get a synergistic dose to the tumor when you use a combination targeting approach.

Last but not least, is that, again, because of the difference in the physical properties of alpha particles vs beta particles, you widen the range of curability size of lesions. Beta particles, because of their longer range of penetration actually do a better job of treating larger volume lesions, but they don't do as good a job at treating small volume lesions—micro-metastatic lesions. If you look at the publications of trials that have been done with the small molecule- lutetium-177 agents, they typically point out that when progression occurs, it occurs in the development of what they refer to as "new” lesions, which are, in fact, pre-existing lesions that were too small to be seen on pre-treatment PSMA PET imaging. They're lesions of 5-6 mm and smaller. That turns out to be the sweet spot for actinium-225, the alpha particle. When you combine targeting of the antibody-alpha plus the small molecule ligand-beta, you get the synergy on 1 hand in the dosing, and you get the complementary nature of the of the 2 radiopharmaceuticals. Again, our preclinical therapy models all show us that the combination of the 2 agents is substantially superior to either agent alone. We already have a phase 1 trial underway at Weill Cornell, in collaboration with Point Biopharma, where we are combining our antibody targeted alpha particle plus Point’s PSMA I&T-lutetium-177 (NCT04886986).

What innovations in PSMA do you expect to emerge in the future?

I've talked about it from the perspective of radiopharmaceuticals, which are under active development, but I think the advances are even more fundamental and broad. I mentioned this during my Prostate Cancer Foundation talk—that the ability to target PSMA on prostate cancer cells is not limited to the imaging space or the radiopharmaceutical space. There are PSMA-targeted antibody-drug conjugates in development. There are PSMA-targeted CAR-T cells in development. There are PSMA-targeted bi-specific T-cell engagers under development. And so, I think we will see, just like anti-androgen therapy has been a cornerstone of the treatment of advanced prostate cancer for 80 years now, the ability to target PSMA is as fundamentally valuable as the ability to target the androgen receptor. Over the next 20-plus years, I think we're going to see the development of a variety of diagnostics, imaging agents, and therapeutics, all of which will target prostate cancer by virtue of the ability to target PSMA. I believe the ability to target PSMA will fundamentally change everything about how we approach a prostate cancer patient, from the day they first walk into the office and thereafter. So, it will be as transformational as Charles Huggins[,MD]'s initial development of hormonal therapy in the 1940s. There'll be a lot of interesting developments to follow and all of which will be to the great benefit of prostate cancer patients.

I'll add 1 more thought here. When we use these modalities today, as demonstrated in the VISION trial, we're really not able to cure those patients. They have far advanced, typically bulky disease. They've been treated by numerous previous modalities which have made them more resistant to treatment. However, the setting of prostate cancer, in my mind, is very receptive to potential therapeutic cures because we can identify very early on who are the patients at high risk of having aggressive prostate cancer. We can identify those patients at the time of radical prostatectomy, and we can certainly identify those patients who relapse after definitive local treatment, whether it's surgery or radiation therapy. We can identify them when they have a really minimal burden of disease, often even before they're able to be imaged, even with PSMA PET imaging. But we know those patients, particularly the ones that have a rapid PSA doubling time, are destined to have a problem. So, we can treat those patients when they have very small burdens of disease, which you can't really do with other cancer types unless you're talking about treating them in an adjuvant setting, which is in a sense what I’m talking about here. But we can be more precise because we can identify with certainty who are the patients who need treatment. I believe we are moving toward an era where we will be able to cure a significant subset of patients who we are not able to cure today. It’s going to be a very exciting era.

Disclosure: Dr. Bander is an inventor on patents that are assigned to Cornell University for a PSMA targeting technology.

References

1. Bander NH. Insights and Future Predictions from 25 years of PSMA Research. Lecture presented at: 2021 Prostate Cancer Foundation Scientific Retreat; October 28-29 and November 4-5, 2021; Virtual

2. Sartor O, de Bono J, B CH, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103. doi:10.1056/NEJMoa2107322.

3. Kratochwil C, Haberkorn U, Giesel FL. 225Ac-PSMA-617 for therapy of prostate cancer. Semin Nucl Med. 2020;50(2):133-140. doi:10.1053/j.semnuclmed.2020.02.004

4. National Institutes of Health US National Library of Medicine ClinicalTrials.gov. 225Ac-J591 plus 177Lu-PSMA-i$T for mCRPC. Updated August 18, 2021. Accessed November 18, 2021. https://clinicaltrials.gov/ct2/show/NCT04886986