Ulka Vaishampayan, MD

 There are other ways of engaging PSMA [prostate-specific membrane antigen]. Some of those are the T-cell or cellular therapies. For instance, there is the Regeneron compound, REGN 5678, which is a bispecific antibody, or a T-cell engager that binds to PSMA and CD28 on the T-cells and creates this activation of the immune system directed exactly at the PSMA-expressing cells—the prostate cancer cells.

That has reported some preliminary positive results, but most of these are at a much earlier phase compared with the radioligands that we discussed. But the imaging part is there to first find these patients who have the predominant PSMA-expressing tumors and then treat them with some of these novel immunotherapies.	

The other is a PSMA bispecific T-cell engager called pasotuxizumab, which is also in early development. So far, the maximum-tolerated dose is being determined in an early phase 1 trial, but it’s showing preliminary promise of efficacy against metastatic CRPC [castration-resistant prostate cancer].

Amgen has a compound, AMG 160, which is also a bispecific T-cell engager, or BiTE, that binds on PSMA and CD3 on the T cells to activate the T cells. The advantage of AMG 160 seems to be that it’s relatively longer acting and has an extended half-life. We’ll have to stay tuned and wait and see if any of these make it to the approval setting and prove better and better efficacy in the long term.

Clearly, the immunotherapy could be then combined with radiation and sequenced after the radioligand therapies. There are lots of combinations to look forward to in the future.

 Ulka, I wonder if you could mention a little about the toxicities. That has been a concern, particularly at this point, about the inpatient obligation for this type of therapy. 

 I agree. CAR [chimeric antigen receptor] T cells and a lot of these BiTEs were first developed in the lymphoma malignant hematology tumors. We’re now seeing that applying those kinds of techniques to older adults with comorbid conditions and the prostate cancer population is going to be somewhat challenging. The toxicity has to be taken into account. Patients have to be monitored very closely. There is the potential for the cytokine storm. Close monitoring using pressors and using a lot of immunosuppressant agents afterward because of the immune-related adverse events is key. If they do give remarkable response rates in efficacy, it may well be worthwhile. We probably will have to carefully select patients who can tolerate those kinds of toxicities with these treatments.

Going forward, the other modality is the CAR T cells. CAR T cells have shown remarkable 80% or 90% response rates in lymphomas, etc. The same technology is being utilized and evaluated in solid tumors like prostate cancer using PSMA as a target. These are very early data with phase 1 dose escalation studies ongoing, but so far it looks like patients are able to tolerate it without a lot of toxicity. Stay tuned for more PSMA-directed techniques, both immunotherapy, radioligands, etc, and there is the potential for more to expand on what we’re seeing so far.

Oliver, do you have any last remarks or any more things to comment on?

 It’s a remarkable time in prostate cancer drug development. We’re moving forward fast in a lot of ways. PSMA is probably the most-studied target in clinical trials today, whether it’s immunotherapy or a variety of radiopharmaceuticals. In addition, we have the imaging implications of being able to use PSMA PET [positron emission tomography].

This is going to be dominating the conversation over the next 5 to 10 years. Maybe 10 years is a bit too far, but over the next 5 years, I see many manuscripts and studies with these compounds entering clinical practice in a very pragmatic way. Patients are going to be better for that intervention. They’re going to be better off because of the PSMA-targeted therapies and the PSMA imaging. That’s what we really want to do: improve patient care in the first place.

 Absolutely. That’s a perfect note to end on: looking at patient care and improving outcomes for our patients. This has been an extremely informative discussion. Thank you, Dr Sartor, for this insightful discussion. A huge thanks to our audience for watching this Targeted Oncology™ presentation on precision medicine. We hope you found this discussion to be useful and educational. Thank you.

Videos

A look toward the future development of bispecific T-cell engages (BiTEs) and CAR T-cell therapy for metastatic castration-resistant prostate cancer (mCRPC). 

Future Directions of BiTE and CAR T for mCRPC

 What about other PSMA [prostate-specific membrane antigen]-targeted radioligands? Can you comment on those?

 Sure. This is a very rapidly burgeoning area. First, let me mention PSMA617 lutetium-177, which I have mentioned several times. That is going to be moving up in the treatment paradigm. There are trial designs in the pre-taxane setting. That can be in the post–abiraterone-enzalutamide setting, similar to the PROfound trial design but without the taxanes. Then there are trials bringing it all the way up front that NRG [Oncology], Alliance [Oncology], and Novartis are working together on to be able to look at metastatic castrate-sensitive prostate cancer. 

We talk about PSMA617 lutetium-177 and those coming up, but there are also other small molecules. There’s 1 called PSMA(int) [intracellular domain of PSMA] that is being developed by a little company called POINT Biopharma. They’re also going to be looking at phase 3 trials, and they’ll be looking at these concepts in the pre-taxane metastatic CRPC [castration-resistant prostate cancer] setting, again with selecting some patients. Then we have novel things like some of the copper isotopes, copper-67 being developed by some small companies that are trying to move those forward. Also very early in clinical development are some of the small PSMA molecules that are going to be binding to albumin to be able to prolong the half-life of the PSMA617 and diminish the renal excretion. 

I didn’t mention: 1 of the fears we have is that there will be renal toxicity because of the renal excretion. Albumin-targeted molecules manage to diminish that renal excretion and may improve the therapeutic ratio between tumor and kidney.

Those are the small molecules. We also have big molecules. These are antibodies. There’s 1 called J591 that is in development in multiple settings. There is another that doesn’t have a name but was developed to bind PSMA as a dimer. It’s a very good antibody. That’s not being developed with lutetium but rather thorium-227.

Let me back up just a second. I mainly mentioned these lutetium-177s, but there are also iodine-based molecules. There’s a small molecule called 1095 with iodine-131 attached that’s a beta emitter. In addition, I mentioned the copper-67 as an alternative isotope. Lutetium has a different beta. Then we have the alphas. Alphas are 2 protons, 2 neutrons like radium, but radium is really difficult to chelate. We have actinium-225 and thorium-227 that are moving forward and maybe even radium-212.

There’s a lot of activity in these areas. There are multiple small molecules, multiple big molecules, and multiple isotopes. It’s a very active area of investigation.

 That is exciting, especially with the wave of new radioligand therapies under investigation. If you think about it, it does make sense to move these therapies earlier. As you get into the later stages of disease, prostate cancer does tend to get undifferentiated neuroendocrine features, so it typically won’t express PSMA. That may be the concern if you wait until the more advanced stages.

 I agree, Ulka. It’s interesting. Drug development favors the late-stage patient because you get the end point sooner. On the other hand, it may not be optimal to wait until the end of the line. It may be better to treat these patients up front. Of course, there’s so much more to learn, not only about tumor heterogeneity but also the underlying genetics. Some alterations like BRCA may actually be radiosensitizers. Of course, we may have radioresistance for others.

We have a lot more to learn about the influence of genotypic biomarkers with the phenotypic biomarkers, the outcomes, and the therapeutic landscape. Of course, everything is always evolving. No matter what you think, it’s going to be different tomorrow.

 Every treatment brings its own resistance with it. That’s true.

 But it’s fun. That’s what keeps us going.

This transcript has been edited for clarity.

A review of the PSMA-targeted radioligand therapies that are currently in development.

Other PSMA-Targeted Radioligands in Development

 How do you think these phenotypic biomarkers are going to impact personalized medicine for patients with prostate cancer in the future?

That will depend on the clinical trials. I wonder if I should go ahead and discuss 1 of the most promising clinical trials called TheraP. TheraP was put together by Michael Hofman and colleagues in Australia, particularly at the Peter MacCallum Cancer Centre. They did a great job of leading this trial. Very simply, they used PSMA [prostate-specific membrane antigen] as a biomarker to select patients for PSMA lutetium-based therapy. 

Let me give a little background because there is more to the story. The use of PSMA with lutetium-177 has developed in part because of the efforts of a variety of German centers, particularly those in Heidelberg, that demonstrated activity, particularly in retrospective settings. The patients were treated and then analyzed, as opposed to setting up protocols going forward. 

When we look at the retrospective data, it was unequivocal that they were active. But then the investigators at Peter MacCallum Cancer Centre, and Michael Hofman in particular, were able to design prospective trials. They used a double-selection criteria, not just PSMA positivity but also FDG [fluorodeoxyglucose] PET [positron emission tomography] discordance. Let me explain that for a brief moment. When you’re selecting patients, you can look for PSMA positivity, and that’s a good thing. But what happens if you run an FDG PET and you find that there are lesions that are not PSMA positive? In that case, you have a PSMA-negative lesion and FDG-positive 1. That patient is not going to respond, so you probably don’t want that patient on the trial.

In TheraP, which is a prospective trial, they screened 291 patients but enrolled only 200. They excluded 91 patients because either the PSMA uptake wasn’t sufficient or there was discordance between the PSMA PET scan and the FDG PET scan. These discordant patients were tossed out. We don’t actually know a great deal about those patients who were thrown out, but it was a priori decided that these patients would not be treated. 

Now we have 200 patients. TheraP is a randomized phase 2 trial. The 2 treatments are the PSMA617 lutetium-177, and the comparative arm is cabazitaxel. The patient population included metastatic CRPC [castration-resistant prostate cancer], and they had to be previously treated with a novel hormone and a taxane. The use of cabazitaxel here is a very good control group. In fact, I’m going to say it’s a tough control group to beat. We already know from the CARD trials, for instance, that cabazitaxel is unequivocally active in this space. 

They found out that the number of PSA [prostate-specific antigen] responses were better with the PSMA lutetium-177. The number of radiographic responses were better with the lutetium-177 treatment. They found that the time to progression-free survival was better with the PSMA lutetium-based treatment. They found that the time to PSA progression was better in the PSMA-targeted treatment. It was a clean sweep pretty much every way they looked at it. They also looked at pain relief, and that was better.

The TheraP trial had a whole variety of end points that were positive for the PSMA617 lutetium-177, and that was in comparison with cabazitaxel, which is a known active agent. This has been published in The Lancet’s brand-new February 2021 publication. It was also presented at ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium] this year, so you can read about it as well as the article in The Lancet, which was led by Michael Hofman. Survival was too immature to evaluate. There were very few deaths, so it’s not sufficient to assess overall survival yet.

If you don’t mind, I’m going to talk briefly about the VISION trial, because that needs to be covered. VISION is a prospective randomized trial also in that post–abiraterone-enzalutamide, post-docetaxel setting, metastatic CRPC, selected on PSMA biomarkers. You had to be positive on PSMA to get into the trial. You were then randomized between the best standard of care and the best standard of care plus the PSMA617 lutetium-177. It was best standard of care without chemotherapy, so no cabazitaxel. The end point is actually 2 end points. There’s an rPFS [radiographic progression-free survival] and then there’s an OS [overall survival].

Everybody is aware of what happened with COVID-19 and the whole disaster we’ve all been living through. I’m a little concerned about radiographic images being obtained in a timely manner, so we may or may not get great rPFS data because they’re dependent on bone scans, CT scans, etc. On the other hand, the overall survival data will be pretty strong. We’re going to get a look at that in 2021. That important trial is going to report this year, but we don’t know exactly when. That could be pivotal for FDA approval.

Yes. A lot of people are looking to get access to the PSMA lutetium treatments. The results of the VISION trial will be critical in determining if we can apply this therapy to the next patient we see with metastatic CRPC.

Clearly, the VISION trial had many more pretreated patients. Up to 2 prior chemotherapy regimens were allowed compared with TheraP, but TheraP is a smaller study. It doesn’t quite have the power to show overall survival benefit, unlike VISION, which was a large global trial in which overall survival was 1 of the main end points. I’m looking forward to getting those results.

 I should mention that VISION enrolled over 800 patients and is appropriately powered for survival end point. It will be the first real shot on goal for a regulatory approvable trial. TheraP is a great trial, but it will not sway the regulators.

 Do you also want to comment on the toxicities of PSMA lutetium?

 I do. I should have mentioned that in the TheraP trial and others. It appears as though the toxicity is quite low. Initially the concern with radiopharmaceuticals of course is you would suppress the bone marrow and have a cytopenia: thrombocytopenia, neutropenia, and the like. It turns out that those are actually quite rare. The cytopenias are basically nonexistent for the PSMA lutetium-177, which is great, but there is an off-target toxicity that can be in the salivary glands and also the lacrimal glands.

It turns out that these small molecules will bind to the salivary and the lacrimal glands, and you can get dry eyes and dry mouth. That is a relatively unusual adverse effect. Usually it’s not too bad, but in some cases, it can be quite bothersome. I have a couple of patients in my practice who constantly complain of dry mouth and are using dry candies and mints and things like that to try to lubricate the mouth. It can be bothersome in some patients. The other adverse effects, like the cytopenias, etc, are pretty minimal.

 I agree. It’s a very well-tolerated regimen in general.

Oliver Sartor, MD, reviews clinical data from the TheraP trial looking at the activity of 177Lu-PSMA617 in patients with metastatic castration-resistant prostate cancer.

PSMA as an Actionable Target in mCRPC

 What is PSMA [prostate-specific membrane antigen], and how can a PSMA PET [positron emission tomography] or CT identify phenotypic biomarkers? Do you want to comment on this? 

Sure. Let’s talk about what PSMA physically is. It’s a transmembrane protein. By the way, it is interesting that the target of PSMA has been in the clinic for a long time. There was a molecule called ProstaScint that targeted an internal epitope of the PSMA molecule. Then we used it for imaging, and it wasn’t very good, but it was better than anything else we had. It was the first molecular imaging in prostate cancer.

We have evolved much further. PSMA is actually a folate hydrolase. It’s transmembranous. The majority of the molecule is on the extracellular side and only at minimal amount on the intracellular side. The wonderful thing about PSMA is that we’ve learned how to image it well. We were initially working with some antibodies, which are not optimal in these agents, and then discovered small molecules that would bind tightly to the folate hydrolase and then could be tagged with things like the F-18 [fluoroethyltyrsine] or gallium-68 to be able to use PET imaging. That’s where the precision really occurred.

In my opinion, this approach is about to transform prostate cancer because of the tremendous number of patients who can benefit from PSMA imaging, both in the early stage disease pretherapy and in the recurrent setting. There are also some predictive biomarkers. 

This is a big area. We’re going to find out a lot more about PSMA over the next decade, but I’m anticipating PSMA PET to be FDA approved for the gallium-68 and the F-18–based molecules later this year.

It also has the advantage that imaging is noninvasive. It’s fairly easy to do for the patients. You get a very rapid turnaround time for the readings, compared with sending genomic markers that you have to wait a long time for. If the patients need a biopsy, there is the invasive nature of the biopsy, which is sometimes another hurdle for some patients. 

The proPSMA studies showed us that, compared with conventional CT bone scan imaging, which we knew was extremely limited utility, especially in patients with low PSA in prostate cancer, PSMA PET scan remarkably improved sensitivity and specificity of detection of the cancer. Of course, at lower and lower PSA levels, you can still be able to detect oligometastatic disease. 

 It’s interesting and a bit of a sea change that we’re about to see, hopefully not only in the diagnostics but in the therapeutics. The therapeutics are what have people very excited because we hope the opportunity to treat PSMA-positive prostate cancer is around the corner. We already have some preliminary data that is quite provocative.

Key opinion leaders expand on the broad clinical utility of prostate-specific membrane antigen (PSMA) for patients with advanced prostate cancer.

The Clinical Utility of PSMA in Advanced Prostate Cancer

 I’d like you to comment a little more about PSMA [prostate-specific membrane antigen], not just in late-disease setting as a predictive biomarker for PSMA therapy but also the imaging in early stage disease and the ability to alter therapy as a consequence of finding metastatic disease when a CT scan and bone scan are probably going to be negative. Would you be able to comment on that and on the recurrent disease setting, when the PSMA may be rising after radical prostatectomy and radiation?

This is definitely a great noninvasive way for early detection of metastases. What that allows us to do is detect minimal amounts of metastases with very high sensitivity and specificity with the gallium-68 PSMA PET [positron emission tomography] scan. That has opened new avenues of therapy where you can do local therapy, such as stereotactic body radiation therapy [SBRT], to those specific areas. Oligometastatic disease especially has evolved as a condition with 3 or fewer sites of metastases, where you can do just radiation or local therapy to those lesions and continue to monitor the patients. 

The big advantage of this may be down the road. Because this is a relatively newer condition, we don’t have years and years of follow-up to tell us if this is the right approach and if this improves life expectancy of the patients. It does allow us to delay the systemic therapies, such as androgen deprivation therapy [ADT], which has the possibility of immediate adverse effects like hot flashes and fatigue but also long-term bone loss, increased risk of dementia, cardiac issues, and things like that. This makes it much easier to avoid or at least delay androgen deprivation therapy. 

 I wonder if you might want to briefly mention the ORIOLE trial as a specific example of clinical benefit in the treatment of oligometastatic disease. Not everybody is aware of ORIOLE, but it’s really interesting, so maybe you could give a brief landscape of the trial.

Both ORIOLE and STOMP trials have randomized patients to do early detection of metastatic disease using novel imaging techniques, such as the PSMA PET scans. Outpatients who were randomized are then selected to receive either standard androgen deprivation therapy, stereotactic body radiation therapy, or local modalities of therapy. So far, there appears to be a clinical benefit, but follow-up is ongoing in both trials. Oliver, do you have anything to add?

We have a lot more to learn when it comes to the utility of these metastasis-directed therapies. The STOMP and ORIOLE trials were conducted in castrate-sensitive oligometastatic disease. We have a whole world of castrate-resistant metastatic diseases that needs to be evaluated. We also need longer-term follow-up. We need to better understand the combination therapies with maybe combining things like abiraterone, enzalutamide, ADT, plus the SBRT and what’s an optimal approach.

We’re in the infancy of these studies, and we’re going to be seeing these studies evolve in rapid-fire fashion over the next 5 to 10 years. This is going to be a growth area because of the better imaging we have, particularly with PSMA PET.

Oliver Sartor, MD, and Ulka Vaishampayan, MD, discuss noninvasive imaging with PSMA PET/CT for patients with advanced prostate cancer.

PSMA-Imaging as a Noninvasive Detection of Metastasis

We need to move on to talk about some phenotypic markers as opposed to genetic markers. This is a bit of a new concept, but biomarkers really help us understand a couple of things. Biomarkers can be prognostic or they can be predictive. When they’re predictive, they’re used in terms of selecting therapies and have a differential effect.

We have phenotypic biomarkers, particularly image-based biomarkers, that help us choose therapies and hopefully be able to find patients who will respond. I’ll give an obvious and old example of this: a bone scan. A bone scan is actually a phenotypic marker. If you have a bone scan that is positive, you may have a patient who would be a candidate for radium because you have a bone-targeted therapy. 

Now we have new and interesting things like PSMA [prostate-specific membrane antigen]. Now that we are developing PSMA-targeted therapies, it makes a lot of sense to think about PSMA image in terms of selecting those patients. If they don’t have PSMA positivity, you probably want to treat with a PSMA-targeted molecule, so this is going to reverberate not only through the radiopharmaceuticals but also in potentially some of the newer BiTE [bispecific T-cell engager] molecules, the immunotherapy, instead of targeting PSMA.

The idea of a phenotypic biomarker is something you’re going to hear much more about in the coming months and years. It’s pretty simple. It just means what you detect on the cell, nongenomic, will help us predict either prognosis or the responsiveness to therapy. We’re going to have a whole bunch more other than PSMA. We’re going to have a whole series of image-based biomarkers that are novel, based on the entire remarkable nuclear medicine conferences that are ongoing where all these new data and biomarkers are being presented. It’s quite interesting.

Why do you think PSMA is such a useful phenotypic marker?

There are a couple of reasons why. No. 1 is that it’s highly overexpressed in aggressive cancer, probably even more upregulated in the context of cancers that have been hormonally treated. Maybe even enzalutamide will cause a little more upregulation. It’s present in the majority of patients, so it’s not like a rare patient. You can actually visualize the PSMA with the PET [positron emission tomography] imaging, either with PSMA-11 gallium-68 or maybe the DCFPyL with a F-18 [fluoroethyltyrsine] marker. We have the ability to image with it. We can treat with it. That image-treated approach is called a theranostic approach, which is going to be very valuable. 

PSMA, because it’s been linked to the imaging as well as the treatment, has an inherent advantage because we can immediately translate what we see into what we treat. A couple of advantages to PSMA: the natural overexpression in aggressive disease, so the majority of patients expressing it, and the targetability of this particular protein on the cell surface.

 I agree. The 80% of our patients with prostate cancer expressed are likely to have PSMA expression. You can benefit much more compared with genomic biomarkers, where you are selecting 5% to 20% of the patients, depending on which genomic marker you use. It makes the treatment widely applicable.

Oliver Sartor, MD, discusses the use of phenotypic biomarkers such as prostate-specific membrane antigen (PSMA), and how these biomarkers can be utilized for prediction of prognosis as well as responsiveness to therapy.

Ulka Vaishampayan, MD | Authors

Articles

Future Directions of BiTE and CAR T for mCRPC

Other PSMA-Targeted Radioligands in Development

PSMA as an Actionable Target in mCRPC

The Clinical Utility of PSMA in Advanced Prostate Cancer

PSMA-Imaging as a Noninvasive Detection of Metastasis

What is a Phenotypic Biomarker?