A Study Evaluating Optimal Use of Radioactive Drugs for Prostate Cancer Therapy - Misha Beltran

August 2, 2019

Misha Beltran shares details on the Department of Defense grant, a collaboration with Scott Tagawa and Neil Bander at Weill Cornell, and now a continuing effort at the Dana-Farber Cancer Institute.  This grant is providing funding to really hone in on the therapeutic side of who are the patients most likely to benefit from PSMA scanning. Focusing on better treatment options for these patients and who are those patients that are going to achieve the maximum benefit from these drugs. An additional focus of the work being supported by this grant is understanding the heterogeneity of PSMA and on molecular features of cancer, as well as liquid biomarkers, and it’s the relationship with imaging and response. There is preliminary data that suggests that potentially the DNA repair altered tumors are more sensitive, so studying resistance, and figuring out if it is related to the target PSMA or is it related to radio-resistance is a focus of this group.  This supports research into an experimental therapy that combines a radioactive atom with a molecule that seeks and destroys cancer cells. This technique, called targeted radionuclide therapy, delivers radiation directly to the cancer cells to destroy them.  The therapy targets a protein that is present in 85 to 90 percent of prostate cancers, called prostate-specific membrane antigen (PSMA). The goal is that cancer cells containing PSMA take up the radionuclide and are destroyed by the radiation. PSMA radionuclide therapy is mostly being studied as a treatment for prostate cancer that has spread and not responded to hormonal therapy. Overall this approach will lead to a greater understanding the tumor biology and application as a predictive biomarker.    Dr. Morgans ask if there are trails that patients today can participate in related to this research.  Dr. Beltran discusses the VISION Trial that is actively recruiting and is an international, prospective, open-label, multicenter, randomized phase 3 study of 177Lu-PSMA-617 in the treatment of patients with progressive PSMA-positive metastatic castration-resistant prostate cancer (mCRPC).  The novel therapeutic drug 177Lu-PSMA-617 is a prostate specific membrane antigen (PSMA) targeting agent to deliver radionuclide therapy for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).  The primary objective of this study is to compare the 2 alternative endpoints of rPFS & OS in patients with progressive PSMA-positive mCRPC who receive 177Lu-PSMA-617 in addition to best supportive/standard of care vs pts treated with best supportive/best standard of care alone. 


Himisha Beltran, MD, Medical Oncologist, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States

Alicia Morgans, MD, MPH, Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois, United States
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Alicia Morgans: Hi. I'm thrilled to have here with me today, Dr. Himisha Beltran, who is a medical oncologist at Dana-Farber Cancer Institute. Thanks so much for being here today.

Himisha Beltran: Thanks for having me.

Alicia Morgans: Wonderful. Well, I wanted to talk with you about a really exciting Department of Defense grant that you and some colleagues were just awarded, to really look into PSMA scanning and understand, or even treatment perhaps. You'll have to tell us all about it. But to understand, who are the patients who are really potentially going to benefit from scanning or treatment with PSMA targeted advances. So, can you share a little bit about that?

Himisha Beltran: Sure. Yeah. I think it's a very exciting advance in prostate cancer in general. The opportunity to use PSMA as both diagnostics in the imaging space, as well as the therapeutic in the more advance disease space. So, PSMA is a cell surface protein that's highly sensitive and specific for prostate cancer, and I think has a great opportunity in sort of the localized and recurrent setting, as far as imaging and for diagnostics. In the more advanced disease setting, because it's cell surface, it lends many opportunities for targeting. There are radio targeted therapies that are in development. There's a phase three clinical trial, the Vision Trial. A number of other approaches to try to target PSMA, either using radiation, using CAR T and other immune approaches that are in various stages of development.

So, our DOD award, which is a collaboration with Scott Tagawa and Neil Bander at Weill Cornell, and now I'm continuing the work at Dana-Farber as well, is to really hone in on the therapeutic side on who are the patients most likely to benefit. We know from reports from various set clinic studies now that response rates tend to be quite high. In the phase two trial, led by the Peter Mac Group, the response rate was I think 57%, even in patients that were heavily pre-treated, CRPC patients. Some people are achieving exceptional responses. I'm really curious as to why a patient might have high levels of PSMA expression and not respond, and who are those patients that are going to achieve the maximum benefit from these drugs.

And so, we're really trying to hone in on molecular features of the cancer, as well as liquid biomarkers, and correlate that with imaging and response. We have some preliminary data that suggests that potentially the DNA repair altered tumors are more sensitive, which makes sense. We also, I'm very interested in resistance, like is it going to be related to the target PSMA? Or is it related to radioresistance? I think there's a lot of opportunities on the therapeutic side, as well as understanding heterogeneity of PSMA on the imaging side as well.

Alicia Morgans: Absolutely. I think we're all really interested in those questions, but we haven't even gotten that far, so I-

Himisha Beltran: Yeah.

Alicia Morgans: Commend your group for thinking in advance. How are these patients going to develop resistance, and which are the patients who will benefit most?

Himisha Beltran: Mm-hmm (affirmative).

Alicia Morgans: One of the things I love about your collaboration is certainly your clinical experience and expertise, but you also have a lab where you are looking at all of these things in such a detailed way, using these molecular techniques. So, what are some of the pathways that you're investing in the lab, and how are you actually making this happen? Are you getting samples from patients or how are you going to actually do this work?

Himisha Beltran: Yeah, that's a good question. I think that there's a number of questions that we're trying to answer. There's the therapeutic question which is mainly in the context of clinical trials. There are a number of clinical trials that we're looking at. We're looking at a small molecule, the PSMA 617, looking at antibody approaches with J591, which is a PSMA antibody. Looking at combination approaches. Actinium, which is an alpha emitter, in combination with an antibody. Looking at all these different clinical trials and trying to systematically collect specimens from patients in the trials.

I think for me, from a laboratory, from a biologic standpoint, I'm really excited about the opportunity to use noninvasive imaging to understand evolution and heterogeneity and resistance. I think PSMA is a great example of how we're not just looking at a target, we're actually looking at a biologic molecule in prostate cancer that's doing something, and it's regulated by the antigen receptor. So, we know that basically all prostate cancers express PSMA at diagnosis. After ADT, PSMA goes down. Goes up with castration-resistance. Can be further modulated with AR targeted drugs. Then in later stages, some tumors develop loose PSMA or develop heterogeneous PSMA expression. Why that occurs and who that occurs in and are these because they lose the antigen receptor.

A lot my interest has in been AR independent and neuroendocrine, and how do we kind of use imaging to noninvasively understand tumor evolution and resistance patterns. I think that's going to be important, not just for biologic insights, but as we start thinking about moving these types of drugs earlier into the disease, as well as combining them. I think we really have a lot to learn as to what regulates PSMA and how we can use these tools that are now here to stay, even though we sometimes don't know what to do with them, and how we can use that to really understand this better. I think it's like two questions in my mind really. Tumor biology as well as predictive biomarkers.

Alicia Morgans: I agree. I think it'll be really fascinating to use PSMA to understand actually tumor biology and tumor evolution. Not necessarily just in the setting of targeting PSMA.

Himisha Beltran: Right.

Alicia Morgans: But you can understand sort of the biology of what's happening when you're using these other therapies.

Himisha Beltran: Mm-hmm (affirmative).

Alicia Morgans: And driving things like AR independence, which you have done so much work in. So really, it all just dovetails beautifully. So for patients who are interested, are there ways to participate? Can they get into studies at Weill Cornell? Are there ways that they can actually participate or is this mostly focused only on patients who are currently enrolled in trials that are ongoing?

Himisha Beltran: My role has really been on the correlative and the biologic side, but there are clinical trials that are available, especially the VISION trial which is a phase three clinical trial. That's an international trial, so I think that's really opening access for patients to get onto some of these new drugs. I think that it's a great example of how it's really multidisciplinary care. This is using imaging and using radiation and having the medical oncologist, so I think establishing teams is really changing. Getting nuclear medicine into our team is something that's very new, but I think it's now going to be very important. As far as imaging, the US has been a little bit slow to uptake PSMA imaging, but this is something that's being used a lot in other countries. Just like any technology, sometimes you don't really know what to do with the information and it's creating new clinical challenges.

I think that it's kind of our job to really still, in lieu of all this new information, design studies that are clinically meaningful so that way ... We don't know if acting early sometimes is really the best thing to do, and making sure we have those endpoints and making sure we have quality of life endpoints as well and things like that that are very important, as you start treating earlier based on more sensitive imaging. But I think just like with genomics, when we got all the sequencing data and no one knew what to do with it, it takes a lot of time to really understand the data and how it can help us, but I'm very encouraged by this as a really great avenue.

Alicia Morgans: Wonderful. Well, thank you for helping us shorten that timeline, because I think your work is really going to help answer a lot of these questions.

Himisha Beltran: Thank you.

Alicia Morgans: Make a difference for patients and the clinicians that are trying to take best care of them. So I really appreciate your efforts. Congratulations on your award and thank you for sharing your time today.

Himisha Beltran: Great, thanks for having me.