Dr. Evan Yu on PSMA-PET imaging in prostate cancer

PSMA-PET imaging has emerged as a new frontier in prostate cancer diagnosis and treatment. In this interview, Evan Y. Yu, MD, discusses the background of PSMA-PET; the first FDA-approved PSMA agent, gallium 68 PSMA-11 (Ga 68 PSMA-11); the emerging PSMA PET imaging agent 18F-DCFPyL; the theranostic 177Lu-PSMA-617; and more. Yu is a professor in the Department of Medicine, Division of Oncology, University of Washington and Fred Hutchinson Cancer Research Center.

Please discuss the background of PSMA PET imaging.

PSMA PET imaging has been available and used outside of the United States for quite some time. This includes much work that was done in Germany, and it’s use in Australia is widespread. So it's not completely new, it's just newer to the United States. And as you know, in the United States, regulatory approvals for things like drugs/therapeutics are probably easier than in other places, such as Europe; however, regulatory approval for imaging agents, seems to require a higher bar. That being said, next-generation PET imaging, whether it's fluciclovine (fluciclovine F 18 [Axumin]) or PSMA-PET imaging, has really now arrived in the United States.

What is the advantage of PSMA imaging over standard imaging?

I think the key advantage to PSMA-PET imaging is the fact that it’s a lot more sensitive than standard imaging. It picks up lymph nodes, visceral metastases, bone metastases, and does it at a very low PSA level; we're talking levels that are even less than 0.5 ng/mL and down to the 0.2 ng/mL range, so it's much more sensitive for detection of prostate cancer.

There can be challenges at late stages of disease where sometimes PSMA expression is lost because PSMA expression is directly tied to the androgen receptor and there can be patients with prostate cancer variants, or let's say neuroendocrine development of prostate cancer, where PSMA-PET imaging may not be as useful.This may occur in 10-15% of patients when the patient's prostate cancer is undergoing some sort of transformation biology.

Please discuss gallium 68 PSMA-11 (Ga 68 PSMA-11), the first FDA-approved PSMA-targeted PET imaging agent for men with prostate cancer.

UCLA and UCSF did outstanding work in this area using gallium 68 PSMA PET imaging.Ga 68 PSMA-11 is a radiotracer attached to a small molecule that binds to PSMA. And, as you know, PSMA is a membrane-bound protein that's highly expressed in 90% of prostate cancer. UCLA performed a really nice study where they took patients who had a PSA between 0.2 ng/mL and 2 ng/mL and they compared Ga 68 PSMA-11 to fluciclovine PET, which is also FDA approved for recurrent prostate cancer with a rising PSA. Fluciclovine is a synthetic amino acid that is uptaken in prostate cancer.

The researchers at UCLA did the comparative study in patients with a PSA of 0.2 ng/mL to 2 ng/mL, and I believe the prespecified statistic measure for success was to demonstrate at least a 20% to 22% absolute improvement in detection rates.What they found is at 26% detection rate for fluciclovine, whereas the detection rate was 56% for Ga 68 PSMA-11. As per their prespecified statistical analysis, that was a positive study. That study was published and it was likely a big component of their submission package that led to Ga 68 PSMA-11 receiving FDA approval for use at those centers.

What are the risks with using Ga 68 PSMA-11?

There is radiation that's delivered but it's a low dose of radiation. It's not a therapeutic where you would see more significant safety issues. Of course, patients worry about long-term risk of radiation through CT scans, through PET scans, etc. But that risk is very, very low. And it's a cumulative dose over time that leads to problems with radiation, like secondary malignancies. The risk/benefit ratio is certainly in favor of doing the imaging versus that tiny bit of radiation.

Is Ga 68 PSMA-11 now being used in the field regularly?

I wouldn't say regularly in the United States, again, in Germany and Australia and other countries, it is being used much more regularly. But in the United States, it was recently approved. And the approval is still limited, for instance, UCLA and UCSF can do it. But very few centers, at this time, can do gallium PSMA-PET imaging. This is going to require that people file their own paperwork to the regulatory agencies that attach to their approval at UCLA and UCSF. I can’t speak to all the details, but you can draw an analogy to when Choline PET imaging was approved and it was available at the Mayo Clinic. It's not like anybody can set up a shop and start doing Ga 68 PSMA-PET imaging, at least not yet.

Another emerging PSMA PET imaging agent is 18F-DCFPyL, which uses fluorine-18. Please compare fluorine-18 with gallium-68, which is used with Ga 68 PSMA-11.

When you think 18F for PET imaging in cancer, you’re usually thinking about 18F-FDG, which images glucose metabolism. So, fluorine 18, or 18F, is a radiotracer that has a long half-life. The data that I've seen for initial staging and for biochemically recurrent prostate cancer with 18F-DCFPyL looks really quite similar to the data we’ve seen with Ga 68 PSMA-11. I don't think that there are huge differences in regard to sensitivity, specificity, accuracy, and ability to detect the cancer, between these 2 agents. Personally, I like them both. I think they're both outstanding. I think the 1 advantage that 18F-DCFPyL might have is that since it has a longer half-life, it’s probably easier to just ship to centers. And since Ga 68 PSMA-11 has a shorter half-life, you have to be able to have a generator, if not at your center, somewhere in town, or reasonably close. So it has to be generated, and then administered in a reasonably short period of time. That’s 1 advantage that PyL might have down the road.

One of the pivotal studies of 18F-DCFPyL is the phase 3 CONDOR trial. Please discuss this study.

The CONDOR trial is a trial in the biochemical recurrence setting, so that’s somebody who had local therapy to their prostate, like surgery or radiation, and then the PSA comes back up. The purpose of the imaging to try to detect the cancer. The brief summary of the CONDOR trial is that in about two-thirds of the patients that they looked at who had PSA recurrence, they visualized the prostate cancer. One key thing that they looked at in that trial was not just whether can you find the cancer or not with the imaging, it's whether the findings are impactful enough to alter treatment management? About two-thirds of the patients in that study had their clinicians change the therapy that was originally planned due to the findings on the PyL PET imaging study. So that has greater impact than just saying, “Great, we see the cancer.” The fact that people change treatment, that makes a much greater difference.

Now, that being said and done, I want to add a caveat that what matters even more than, “Do they change treatment or not?” is were those changes intelligent changes? Meaning, did they lead to better outcomes for the patient? So, let's say you were going to just observe the patient, but now you see something in 1 spot, and you go in and ablate it with radiation, does that patient live longer, do better, and have better outcomes because you did that? That's still yet unknown, and there are prospective trials being developed through many of the NCTN cooperative groups. But those will take a decade to read out. So at this point in time, I think the imaging is here with fluciclovine, here with Ga 68 PSMA-11 at specialized centers of excellence, and soon likely to be here with PyL. It'll start getting used just like it's getting used in Australia—regularly for many patients. But that being said, the real questions that are going to be of greatest significance are, “Are those changes that we make based on the PSMA-PET findings intelligent and do they really affect patient outcomes?” We just don't know that yet and won’t know for quite some time.

What was shown in the OSPREY trial, which is the other pivotal trial of 18F-DCFPyL?

The OSPREY trial was a presurgical staging trial. It's an interesting study and I've talked to some of my urology colleagues about it. I think the key point from the OSPREY trial is that nodal disease in the pelvis, that could change a surgical or radiation field, around 27% of the time.You know, I'm not a surgeon, I'm a medical oncologist, but after I saw that data I reached out to some of my surgical colleagues and they said, “Yeah, that's a game changer, because if it changes my surgical approach 20-plus percent of the time, that really means something.”

Another PSMA product is the theranostic ¹⁷⁷Lu-PSMA-617. Please discuss this product.

A nice advantage of PSMA is the fact that while it can be a target for imaging, it can also be a target for therapies. So for instance, ¹⁷⁷Lu-PSMA-617 is a compound that is a small molecule fused to a beta emitting radiopharmaceutical. And the whole idea is that you can image the patient beforehand with PSMA-PET, find the metastases, and when you give your radioligand therapy, it should go to that area and deposit that radiation right there in the spot that you want it to treat.

I can tell you that it's not FDA approved yet, but ¹⁷⁷Lu-PSMA-617 is being used in other countries, for instance, Germany being one. But in the United States, we are waiting for the VISION trial results. The VISION trial is a large, randomized phase 3 trial in the post-docetaxel setting for patients with metastatic castration-resistant prostate cancer (mCRPC), and it’s examining ¹⁷⁷Lu-PSMA-617 versus standard of care treatments. Those results will probably read out in the next year/year-and-a-half or so, and I think most people anticipate the results will be good.

The reason they anticipate those results will be good is that ANZUP, the Australian and New Zealand Urogenital and Prostate Cancer Trials Group, did a great study where they randomized patients with mCRPC and prior docetaxel to ¹⁷⁷Lu-PSMA-617 versus cabazitaxel (Jevtana), which is a standard of care in that setting. The preliminary results of that trial have shown significant improvements in PSA declines, significant improvements in objective response rate for those who have soft tissue disease that's measurable, as well as improved progression-free survival and disease-free survival, that is in favor of ¹⁷⁷Lu-PSMA-617 over cabazitaxel. That's quite good because cabazitaxel has recently been shown in the CARD trial to be superior to abiraterone acetate (Zytiga) and enzalutamide (Xtandi) in patients with mCRPC with prior docetaxel who had disease progression on a one of the prior novel hormonal therapy agents.

They also showed that ¹⁷⁷Lu-PSMA-617 had fewer grade 3/4 adverse events versus cabazitaxel. A statistically significant benefit has not yet been shown with ¹⁷⁷Lu-PSMA-617 in terms of overall survival; however, that was only a secondary end point. Overall, early hints are showing for just about every efficacy endpoint, that ¹⁷⁷Lu-PSMA-617 may be superior to cabazitaxel in this setting. So, we eagerly await the VISION results because that's what would lead to FDA approval in the United States, and I think the bar for success in that trial is even lower, since the comparator arm in VISION is not mandating use of an agent with as much efficacy as cabazitaxel.

Are there other emerging PSMA PET products?

The nice thing about PSMA is the fact that it's a great target for a lot of different therapies. So, it's not just 177Lu-PSMA-617, there are other radioligand therapies being developed. An alpha-emitting radiopharmaceutical, like actinium, can also be fused to a small molecule and might have greater tumor cell kill; of course, it also has potential greater side effects, too. PSMA is also expressed in the salivary glands and can lead to xerostomia that can be uncomfortable, and it may be greater with the alpha-emitting radiopharmaceutical. So, we might have to consider how small the molecule is and use larger antibodies, which might not penetrate so well into the salivary gland or renal tubules. Of course, when you do that, that has flip sides of hanging out in the circulation longer with a longer half-life, which could lead to more myelosuppression. The alpha-emitting radiopharmaceuticals are potentially exciting, but still early in development.

There are other radiopharmaceuticals being attached to small molecules to PSMA. I-131 is something we use in thyroid cancer and that's also being studied. I-131-1095 is an early compound that's being studied in a randomized phase 2 setting in the prechemotherapy space for patients who have progressed on abiraterone, and they’ll be randomized to enzalutamide versus enzalutamide plus I-131-1095 in a 2:1 ratio in favor of the I-131-1095. So, again, there are many newer radioligand therapies targeting PSMA.

And finally, the immunotherapies. PSMA is a great target for immunotherapy! There are bispecific antibodies that are being developed with the whole idea that you can bind CD3 on a T cell and bring it to PSMA in the tumor microenvironment. There are many companies that are developing these bispecific antibodies. We have started to see response rates in the 30% range, and some agents will be going soon into the randomized phase 3 setting.

And, of course, I'm at Fred Hutchinson Cancer Research Center, and the hematologic malignancy physicians at our center did a lot for the development CAR-T cells. Now CAR-T cells are coming so solid tumors and PSMA is one good target. There are CAR-T cells where the T cells are being re-engineered to have costimulatory molecules, to bring cytokines or immunokines, to the tumor. The imaging is critical, because it's not just for detection, but down the road, it will be for treatment response. We will be doing serial PSMA-PET imaging as a pharmacodynamic measurement to determine, “Are we really hitting our target?” And so I think that it's really an exciting time right now.

Where do you see the field in terms of PSMA PET/CT imaging, say 10 years or so from now?

With new technology, there comes new growing pains. And one of the things that we'll have to grow to accept is the fact that PSMA-PET imaging is going to be here to stay, just like it is in other countries, such as Australia. But what do we do with those PSMA results? We haven't had imaging studies that are this sensitive. What do you do when you see changes in PET scans? Right now, for metastatic disease, castration-resistant disease, we have Prostate Cancer Working Group (PCWG) criteria—we’re at PCWG3, but soon we'll have PCWG4, I'm sure. But these criteria help delineate when patients progress using standard bone scans in clinical trials. Recognizing that bone scans aren't quantitative, and they're more qualitative, you have to have multiple, at least 2 or more new lesions on a bone scan with confirmation to really consider that progression. Now when you have something like PSMA-PET, PET is quantitative, it gives you an SUV which is a numerical value—the intensity gets greater, gets lesser, etc. What does that mean? And that's something we're going to have to learn because I think PSMA-PET imaging is here to stay. Eventually, it'll replace bone scans and every patient for staging of prostate cancer, and for treatment response, 5 to 10 years down the road, will be getting PSMA PET/CT imaging. Patients will receive one imaging study together, with CT scan and PSMA-PET imaging, and the field will have to learn how to deal with what we find. But it's a good problem to have, and we'll learn to adapt to it. I look forward to that.