Targeted Molecular Therapies for Treatment of Advanced Prostate Cancer - Scott Tagawa
March 30, 2020
Scott T. Tagawa, MD, Associate Professor of Clinical Medicine, Clinical Urology, Medical Director, Genitourinary Oncology Research Program, Weill Cornell Medicine, New York, NY
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.
Alicia Morgans: Hi. I'm delighted to have here with me today, Dr. Scott Tagawa, who's an Associate Professor of Medicine at Weill Cornell. Thank you so much for talking to me today.
Scott Tagawa: Pleasure to be here.
Alicia Morgans: Wonderful. So, Scott, you have really been an innovator in the radiopharmaceutical field, and I'd love to hear your thoughts on some of your early phase clinical trials, and some of the work that you're doing regarding radiopharmaceuticals and prostate cancer.
Scott Tagawa: Sure. One of the nice things about prostate cancer is it's a radio-sensitive disease. So as long as we have enough radiation to all of the areas, we can cure prostate cancer, as we do with clinically localized disease. Another nice thing about prostate cancer is there are cell surface targets which are there much of the time, such as PSMA, which roughly speaking, we'd say about 90% of the time, it's going to be cell surface target in advanced disease.
And we have a number of what I would call targeting agents, really too many to list. But in broad buckets, they're small molecules, and large antibodies, and there are different properties with each different type of targeting agent, which we can use to essentially exploit, depending on what we want to do in combination with two general types of radionuclides, or what I tell the patients, small radioactive particles, the beta emitters, which are a little bit weaker but can travel a longer distance, and the alpha emitters, which are more powerful but travel a very short distance.
Alicia Morgans: Great. Can you tell us about any particular agents that you are currently working on in some of these early-phase trials to bring these into clinical care?
Scott Tagawa: Sure. So we continue to work on lutetium PSMA-617. Lutetium PSMA-617 is an agent that has completed a randomized Phase II and a randomized Phase III, and hopefully, that's going to be approved and available for our patients. We are still using it in earlier phase clinical trials to optimize the dose and schedule, as well as look at combinations, and I think that's quite exciting. We are also looking for combinations in randomize settings to move forward and/or to help other drugs work. For instance, the NCI is supporting a trial that's in frontline metastatic castration-sensitive disease, in combination with ADT plus a potent AR antagonist.
That will be a randomized trial with and without looking at RPFS and OS as co-primer endpoints. And fortunately, it got information recently of funding for a trial that's looking to add a radionuclide against PSMA to improve the response rate to immunotherapy with pembrolizumab. So examples of ways that we can use these to make other drugs and other situations even better.
Alicia Morgans: So one of the things that I think is so fascinating is that, if we're thinking about external beam radiation, for example, in androgen deprivation therapy kind of settings, it seems to be amplified. So low testosterone levels or this androgen deprivation state can amplify the effects of radiation. So I think in the setting of the study that you mentioned, which I think is an Alliance trial that's moving forward across the cooperative groups, it'll be very exciting to see how really intense androgen depletion could potentially be really augmented even by lutetium, which then is going to be this kind of targeted radiopharmaceutical force. So that's exciting.
Scott Tagawa: Absolutely. We're hoping that besides the drugs working independently, we hope that the AR targeted therapy is going to do two things. One and two upregulate the target, PSMA, as well as to add to radiosensitization.
Alicia Morgans: Absolutely. And then to think about using checkpoints or immunotherapies in combination with these as well, as they may be damaging DNA, causing more neoantigen presentation, perhaps these IO approaches could be made even more powerful as well. So very exciting.
Scott Tagawa: Absolutely. We're quite hopeful that rather than a single point of SBRT to generate an abscopal scope response, we're able to deliver radiation to most sites of disease. So the abscopal response would just have to be in those single cells or tumors that happen to be PSMA negative.
Alicia Morgans: Absolutely. So there are definitely some novel agents on the horizon. I've been hearing whispers about seeing some early data. I think your group is working with some of them. Can you tell us a little bit about actinium or thorium or any of the others, the other molecules that you are working with right now?
Scott Tagawa: Yeah, we're very excited with targeted alpha particles, so it's mentioned before, they are much more powerful than the beta emitters, but they travel a very short distance, so they have to actually get into the tumors if the main mechanism of action is actually the radiation and not generating an immune response. One of the downsides to targeted PSMA is the areas of expression that are outside of the tumor. Generally speaking, that is the salivary and lacrimal glands, the small bowel and the proximal renal tubules.
We haven't seen devastating toxicity so far with the beta emitters, likely because they are weaker, but there is the danger with the alpha emitters that getting them into the wrong areas can lead to more toxicity, especially longer-term toxicity. In the anecdotal reports we've seen of targeting PSMA with the small molecules and small molecules, unlike the antibodies can get into these other areas of PSMA expression, can lead to severe toxicity such as xerostomia, which is when talking to a patient, if I'm going to die of prostate cancer and I'm going to have a dry mouth, no big deal. But occasionally these can really be devastating with the loss of taste, loss of teeth, inability to eat, so a major effect on the quality of life. We haven't yet seen any significant renal toxicity, but we also do not have any significant longterm followup.
We, as well as Bayer, have gone forward with Phase II studies using antibody targeting of PSMA. What we know based on physical properties, as well as when we've done immuno-PET, so using the antibody usually with thorium, we have prior studies looking at planar gamma emission as well, that we don't see any significant uptake in the salivary glands, the small bowel or the kidney, as would be predicted based on the physical properties.
Alicia Morgans: Wonderful. So for patients who are thinking about trying to get access to these therapies, are there clinical trials that are ongoing right now, looking at actinium or thorium, or any of these novel agents? And certainly, we know lutetium has been out and its large Phase III is now close to enrollment, but there may be lutetium trials out there as well. What would you recommend to patients?
Scott Tagawa: Number one, my suggestion is they act as their own advocates or their family acts as their advocate, as they're talking to their individual oncologist or urologist, to look around. Some of the time, so we're in New York right now, it's fairly easy to go to a number of different centers that are very close to each other. Some centers will have the same trials open, but some of the time, there'll be different trials, and some of the time it's worth some travel.
We know that that people from the United States that have means have gone to Germany for instance, for treatment outside of clinical trials. Why not do some travel in a more limited scope, within the United States for some of these trials, some of these treatments that are provided as part of clinical trials? So there are a number of earlier phase clinical trials using lutetium, whether it's with a small molecule or an antibody, as well as at least two trials using targeted alphas. So one is ours with the J591 antibody, developed my Neil Bander. And the other is Bayer's antibody, which they licensed from Progenics®, which has been started outside of the United States, but that Phase I will continue in the United States as well, as we're looking for different doses. Our particular trial has finished the dose escalation, so we've moved forward with an expansion, as we're opening additional repetitive dose trials, as well as combination trials.
Alicia Morgans: Absolutely. So going on clinicaltrials.gov, I think can be a really good place to start. Certainly, if you have any interest in traveling to New York, Dr. Tagawa is doing multiple studies and that's important. Hopefully, these studies will open up in more places. I know Dr. Sartor is in process of opening some and my hope is that we'll have some at multiple institutions across the country, to really give people access to these exciting therapies.
As you think about this whole landscape and think about what patients and clinicians should understand, what is your main overarching message regarding these radiopharmaceuticals and where this aspect of the field of treatment of prostate cancer is going?
Scott Tagawa: I think initially if we think ahead for a potential FDA label, I think it's going to be for late-stage disease. But what I anticipate is a nice combination in terms of an improvement in overall survival, or at least radiographic progression-free survival, as well as an improvement in symptomatic disease. So I think that'll be a nice combination because what we've seen to date is a lack of major toxicity. So that's the hypothesis and that'll be very nice for our patients to have hopefully in the near future.
What I'm looking forward to a little bit later is moving forward in terms of lines of therapy and for combinations. If we look at the target as a diagnostic type of a target, so PSMA PET for example, where we have someone that has primary therapy surgery or radiation, has a rising PSA. We know that we see sometimes, unfortunately, multiple sites of disease. So local salvage therapy is unlikely to lead to a cure. However, in that situation, whether it's alone or in combination with other therapy like hormone therapy as was mentioned, maybe PSMA targeted radionuclide therapy would then move into a salvage setting, where the goal is not just prolongation of life and improvement in the quality of life, it's actually a cure.
Alicia Morgans: Absolutely. So increasing the chances of cure, giving access to patients with very late-stage disease, and trying to do all of this in a way that is tolerable for patients so that they can live longer and feel well at the same time is a wonderful message and hope for the future. And I look forward to continuing conversations with you, as we see how this all unfolds. Thank you so much for your time.
Scott Tagawa: Thank you.