Beyond PSMA - New Targets in Prostate Cancer - Tanya Dorff

May 24, 2022

Tanya Dorff joins Alicia Morgans to discuss the highlights from her presentation at the 2022 GU ASCO Annual meeting focusing on new targets in prostate cancer beyond prostate-specific membrane antigen (PSMA). She highlights potential new targets including prostate stem cell antigen (PSCA), JNJ-75229414 is a KLK2 CAR T, and STEAP-1. Drs. Morgans and Dorff also discuss tumor heterogeneity and neuroendocrine disease.


Tanya B. Dorff, MD., is an associate clinical professor in the Department of Medical Oncology & Therapeutics Research and serves as head of the genitourinary cancers program at City of Hope. She is an internationally recognized leader in prostate cancer and is renowned for her work in other genitourinary tumor types, including kidney, bladder, and penile cancer. City of Hope Comprehensive Cancer Center, Duarte, CA

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute. I'm so excited to talk today with a good friend and colleague, Dr. Tanya Dorff, who is the Section Chief of The GU Disease Program and an Associate Professor of the Department of Medical Oncology and Therapeutics Research at City of Hope in California. Thank you so much for being here with me today, Dr. Dorff.

Tanya Dorff: Hi, thanks for having me.

Alicia Morgans: Of course, we are always excited to have you. And really, one of the more exciting things of GU ASCO 2022 was actually your talk on the way that we, as clinicians, need to start thinking not just about PSMA targeted treatments, but really thinking about next steps, thinking beyond PSMA. I'd love to hear some of the highlights from that talk, really starting with why targeting PSMA may not be the "be-all and end-all" that we hope that it will be if we are only targeting PSMA. What are you thinking about in terms of that?

Tanya Dorff: Yeah, so it was a really interesting session that the organizing committee put together. The abstract that was presented showed that on a PSMA PET scan, the intensity of uptake, and the amount of uptake could predict response. We've also seen some data in the past, that the amount of disease might correlate inversely with on-target, off-tumor toxicity. So there is a lot, even within PSMA, that we still have to learn about who will benefit, what's enough expression, what's the best way to identify the expression? Is it with a PET scan, or should we be looking at circulating tumor cells, or RNA, to really try to understand whose cancer can be adequately targeted with this?

But then there was also a talk on resistance and how that develops, and of course, one mechanism is that cancer can stop expressing PSMA. So you see that in these discordant PET results when you get the PSMA PET looking better, but the FDG PET shows that there is still active and progressing disease. So PSMA targeted treatment is great, we can't wait to have it in the clinic for our patients, but there are just going to be some who do not benefit, like the 10% to 15% who couldn't get into VISION because their PET scan was negative. And then, it won't work forever if cancer outsmarts us by down-regulating expression.

Alicia Morgans: I think those are great points. And like you said, we are really, really excited to have PSMA targeted treatment with PSMA Lutetium hopefully coming down the line in the very near future. But what's also important is, that we always think about, how we can continue to outsmart these cancer cells. From what I understand, and what you presented, there are other approaches to targeted therapy that are already making their way into clinical trials and may make their way into our clinics at some point in the relatively near future. Can you tell us about them?

Tanya Dorff: Yeah, so I think there are a lot of promising targets that have been identified, and it's very exciting to see therapeutics already in early-phase testing and showing responses. For instance, at the City of Hope, we've been working with prostate stem cell antigen, PSCA, which was discovered at UCLA, and it is very strongly expressed on adenocarcinoma of the prostate, kind of similar to PSMA. It's regulated by androgen receptors and yet over-expressed in castration-resistant disease.

We have a CAR-T targeting PSCA that has shown some ability to induce significant responses, which is super exciting for such an early phase of development. We have seen on-target, off-tumor toxicity of cystitis because of PSCA expression there. And that is kind of the story across these antigen targets, is that the toxicity profile is not only about the construct, like with an antibody-drug conjugate, what the payload is, of course, impacts toxicity, but it is also about the antigen.

So some other targets are nice and clean, and it will be interesting to see how that plays out in terms of toxicity. There is a BiTE antibody from Amgen, targeting STEAP1, which is pretty clearly expressed. It will be interesting to see how the toxicity of that BiTE differs from their BiTE which targets PSMA, the AMG160, where you do see some of the salivary gland toxicity because of PSMA expression there. And some of the other side effect profile, I think, is probably due to PSMA expression as well.

And then there's KLK2, which is a very, very clean profile, very little normal tissue expression. And there is both a radio-pharmaceutical in phase one testing that's labeled with actinium-225 and then also a CAR-T that's been developed targeting KLK2. So just so much for us to learn about both the different strategies, as well as the different targets.

Alicia Morgans: Well, and I think that gives us such an opportunity, too, because one of the things that you touched upon in your talk, is the fact that there is tumor heterogeneity and that combination approaches may ultimately be what we need to see. Because of course, things change in prostate cancer cells across the spectrum of disease. And these cancer cells evolve in terms of their expression, in terms of proteins, and in terms of how we might best target them over time, as they are adenocarcinomas, or even are pushed through our therapeutic advances into something that's closer to a neuroendocrine or dedifferentiated state.

So, tell me a little bit about your thoughts on heterogeneity, and how we can best address it.

Tanya Dorff: Yeah. So I really had the opportunity to witness it firsthand. Some of our on-study biopsies, well, at least one of them, showed that there was already some neuroendocrine disease, although there was also still adenocarcinoma staining for PSCA because we're doing immunohistochemistry prior to study entry. So how are we going to eradicate all the disease if we're only targeting the adeno component, right? So his PSA went down after CAR-T, but then his lymph nodes grew, and the post-study biopsy was just pure neuroendocrine.

So, one of the great things about CAR-T cells is they are such a flexible platform that can allow for innovation. So you can do dual targeting by various means. And so that is one thing that we are working on together with UCLA in SPORE, is dual targeting to try to target the neuroendocrine component. And we are looking at CEACAM5, which is one of the antigens expressed on that type of prostate cancer, as well as PSCA.

Another antigen that's very much up-regulated in neuroendocrine prostate cancer is DLL3, and there are some therapeutics, there's an antibody-drug conjugate with an MMAE payload that was tested, and there is also a BiTE. So, but again, will you need to do that in combination with something to control the adeno component? That will really remain to be seen.

Alicia Morgans: Well, that's great. And you know, some of the treatments that you have mentioned, of course, we've talked about, and have for a couple of years, these radiopharmaceutical approaches. But things like antibody-drug conjugates and immunotherapies, including some of the cellular therapies, are relatively newer for the prostate cancer landscape. Can you tell us a little bit about how you think about these approaches, and where their strengths might lie versus maybe some of the weaker parts of these agent approaches?

Tanya Dorff: I had a little audience response question in my talk, and I thought it was really interesting to see where people's enthusiasm lies, right? Because there are so many different approaches and I think radio-pharmaceuticals are so comfortable. They are relatively well-tolerated, they are dosed infrequently, once every six weeks is one typical dosing schedule. And so that is going to be really appealing to patients.

On the other hand, immunotherapies are much more intensive. The BiTE antibodies are infused every week or every two weeks. There can be a lot of cytokine release syndrome, so patients have to put in a lot upfront, although over time those side effects do wane, and I guess the trade-off there would be if you're able to get a more durable remission, because we see that with the radio-pharmaceutical, at least targeting PSMA, we tend to get resistance by about six months.

And patients, of course, are hoping for therapeutics that will give them longer remissions. So we will be looking at the BiTE antibody data to see how long the remissions are lasting, and then CAR-T, I think, of course, holds significant promise along those lines. So because the CAR-T will continue to proliferate and expand, it's as if the treatment is ongoing. And I think that can explain part of why, in the hematologic malignancies, you get these really, really durable remissions. And that's what we are hoping we will see as we continue to study our CAR-T in prostate cancer.

Alicia Morgans: Well, that's great. So if you had to sum up your talk and the message that you were trying to give to the audience and the community for prostate cancer, what would that be?

Tanya Dorff: I guess, PSMA is a very good target and we have a pharmaceutical that will be in the clinic soon, but that doesn't mean we are all done and we don't need more research, right? Because every prostate cancer patient is not the same, cancer evolves in different ways. So some of these antigen targets might lead to better responses, they might lead to different toxicity profiles, and they might encompass a different set of patients based on their tumor expression profiles. So just to keep one's mind open to additional avenues of exploration, and continue to think about clinical trials as part of the treatment lineup for your patients.

Alicia Morgans: I think that's a perfect message. And one that really highlights the hope that we have for some of these agents that are very, very close, I think, to make it into our clinical practices, and the promise of the newer agents that I think will be coming, down the road. So thank you so much for your time and your expertise today.

Tanya Dorff: Thanks, Alicia.