Understanding PSMA Targeting in Prostate Cancer Treatment: An Interview With Scott Tagawa, MD

Scott T. Tagawa, MD, Professor of Medicine and Urology at Weill Cornell Medicine, and Attending Physician at New York-Presbyterian – Weill Cornell Medical Center, explains the benefits and roadblocks of prostate-specific membrane antigen (PSMA)-targeting in prostate cancer treatment.

This is the second part in a conversation with Dr. Tagawa. Read part one here.

GU Oncology Now: PSMA has emerged as a target of interest for prostate cancer. Can you discuss PSMA as a target and your thoughts on its potential to expand treatment options?

Scott Tagawa, MD: PSMA is nice in that it is almost always there in the setting of prostate cancer, and there to a greater extent in the setting of prostate cancer with high grades, metastases, and hormonal therapy. Especially in the metastatic, or recurrent population, and especially in the treated population, it’s a target of interest. I would say it’s a clinically validated target because PSMA imaging agent was approved actually more than two decades ago. What has happened is that improvements in technology, I think, are leaning towards soon approval of at least one, if not multiple, diagnostic imaging agents. PSMA PET agents, I think, are coming soon, and in parallel with that are PSMA-targeted therapeutic agents.

I would put those into three general classes. There are drugs like antibody drug conjugates, or small molecule toxin conjugates; that’s one class that we’re looking to improve upon. There are immune ways of targeting, whether that’s a CAR T cell, or bispecific, those are in development, generally speaking in phase I. The early data shows that there’s toxicity, as expected, but they look to be a subset that can have a deep response, and we’re waiting to see how durable that can be. The furthest along, and that was partly because, based upon what technology was available a couple of decades ago when we first started in the clinic, is targeted radionuclide therapy. Using PSMA as a self-service target, having some sort of a targeting agent, generally speaking either a small molecule or an antibody, and attaching a radioactive particle, most commonly a beta emitter such as lutetium-177. Also, different alpha emitters have been used, either as part of “standard of care,” in countries that have laws that say anyone that doesn’t have anything else can get one of these, or as part of clinical trials, and clinical trials are quite young for the alphas, but now maturing for the betas.

Early this year at ASCO we saw the initial results of a randomized phase II trial that compared lutetium PSMA-617, which is a beta radiolabeled small molecule that has gone through several different companies, currently resides with AAA Novartis, head-to-head against cabazitaxel. The selected patients based on PSMA and FDG PET imaging, so to qualify it wasn’t all comers, more PSA declines of at least 50%, with the radioligand therapy as compared to chemotherapy. Offsetting toxicity is generally more for chemotherapy, but different toxicities. On the heels of that is a phase III trial we refer to as VISION, which completed enrollment last fall. So, we suspect that we’ll have some data in early 2021, that could lead to the approval of this type of an agent.

This is on the heels of a similar type of a construct for neuroendocrine GI cancers and pancreatic cancers with lutetium and radiolabeled somatostatin analogues. This would be the first radiolabeled therapeutic agent for prostate cancer. Many of us suspect that that is going to be a positive trial and can lead to the first approval of a PSMA-targeted agent. We have radium, and we’ve had other bone-targeting beta emitters, but radium, the key with that is it’s an alpha and it has an overall survival advantage, but it’s not directly tumor targeting, it’s bone targeting, hydroxyapatite, whereas PSMA is tumor targeting, as well as the other areas in the body that express PSMA, such as the salivary and lacrimal glands, the small intestine, and part of the kidney.

What do you see as downsides or potential roadblocks to targeting PSMA?

So one, and I guess this is not unique to PSMA, but anytime we have a very specific target, including PSMA, it’s not always there. So, there are some tumors that are PSMA negative. Generally speaking PSMA has a link to the AR, androgen receptor, pathway, so in the tumor types that we might call neuroendocrine small cell, or there’s various names for that, but have loss of AR, those are the most likely to lose PSMA, as well. So, an entire tumor burden patient might be PSMA-negative or low. There’s also some heterogeneity. So, most of the time when we do an image we see all the tumors light up fairly brightly, but we know from studies that have looked at tissue that not every single cell within a tumor might have PSMA on it, and that there are different levels of PSMA.

One way around that is combinations. Another way around that is kind of the crossfire effect with the beta emitters that have a longer path length. That is a downside to any PSMA-targeted therapy, as well as any therapy, I think, that’s a single agent is that the targets might be there only partly, or not at all, depending on the patient. One of the nicer things about, let’s call it the theranostic platform, meaning having some sort of imaging of the target, followed by treatment of the target, some people are strict enough to say that agent has to be the same agent, but let’s say, loosely, some sort of PSMA imaging with PSMA-targeted therapy, at least we’ll get an idea of those who are completely negative. Then, may also have an idea, based upon level of uptake, some hint at heterogeneity that is there.

I think that will be a nice pair, and I think that, hopefully, is a nice problem to have once we have the available drugs, and figure out do we not use this therapy at all, or do we pair it with another drug that’s either going to alter the targets i.e., make more PSMA expression, and/or amplify the results, such as an agent that would lead to radiosensitization, if we’re using it with a radioactive particle.