The Future of PSMA-Targeted Therapies in APC: Part 1

Michael Morris, MD, Prostate Cancer Section Head, GU Oncology, Memorial Sloan Kettering Cancer Center, was interviewed by Akhil Saji, MD, urology resident at New York Medical College/Westchester Medical Center on the future of PSMA-targeted therapies in APC.

This is the first in a two-part conversation with Dr. Morris. Watch part two of this discussion to learn more about PSMA-targeted therapies.

Akhil Saji, MD: Thank you for joining. So first question will be, could you very briefly describe what PSMA is and what its clinical utility is?

Michael Morris, MD: Sure. PSMA stands for prostate-specific membrane antigen, and it is a protein that sits on the prostate cancer cell. It’s also a normal prostate tissue as well, and it’s also expressed on the neovasculature of nearly every solid tumor. The main advantage of PSMA is that it’s minimally expressed in normal tissue. So expression is generally restricted to some isolated, normal tissues like cup for cells, the proximal renal tubule, salivary glands, specific portions of the gut, but otherwise it really isn’t present in normal tissue. And it provides an ideal target really across all the clinical states of prostate cancer from early disease through the most advanced and heavily pretreated disease. And it generally expressed across sites of disease as well. So it’s in the primary, it’s in nodal disease, it’s in bone metastases and it’s in visceral and soft tissue disease.

Akhil Saji, MD: Okay, great. And could you describe the utility of PSMA in the diagnosis of prostate cancer, both in localized as well as advanced disease?

Michael Morris, MD: It’s really one of the emerging and potentially transformative areas of diagnostics and prostate cancer. So it’s the basis of a PET imaging that really is the first opportunity that we’ve had to directly image prostate cancer in particular extra glandular disease, very early in the disease course and/or very early in relative to relapse from where we used to be able to image. Remember that standard anatomic imaging is dependent on size. So lymph node is designated as suspicious when it’s one and a half centimeters in its longest dimension, visceral disease equally has resist criteria for documenting a suspicious visceral metastasis at one centimeter. And bone disease, you have to wait for the surrounding bone to transform in order to see it on a standard bone scan, a relatively insensitive medium for imaging.

So all of those really impair the ability to detect disease before a certain amount of growth and impact on surrounding tissue has been made, whereas PSMA PET imaging, has the ability to image tumor directly and much earlier than you would see it on standard cross-sectional imaging or on or bone scintigraphy. So you can detect disease both at the point of diagnosis that may have left the prostate itself and make treatment planning much more accurately based on the truer distribution of disease. And also for the biochemically relapsed patient, you can detect where their disease is, whether it’s local, local regional, or distant much earlier than you could with standard CT, MRI or bone scans.

Akhil Saji, MD: Okay. Very, very nice. So this kind of goes into my third question for you, but in a standard high risk prostate cancer patient, let’s say according to NCCN risk grouping, do you foresee PSMA PET adopting some kind of role in staging these patients?

Michael Morris, MD: I do because it allows us to understand where the patient’s disease actually is not where the probability of it being. Right now we use nomograms and predictive models to understand who’s likely to have nodal disease and who’s likely to have distant disease, but now we can actually see where patients have disease with much greater accuracy than we could. And so we’re basing our treatment paradigms or developing those treatment paradigms on a much more accurate representation of their distribution of disease. We of course have a long way to go in terms of understanding, how do you treat best a patient who otherwise would’ve been designated just as high risk, but now whom we can actually see that there is disease that previously would just be hypothetically or probabilistically determined, but now we can act actually demonstrate disease.

So how do we treat the patient who has an isolated bone metastasis that otherwise would’ve been detected? Or how do we alter a lymph node dissection or radiation portal in reaction to patients who have a disease that otherwise wouldn’t have been detected in the pelvic nodes? But you can’t develop those paradigms and you can’t test newer ways of treating those patients unless you actually know where the disease is and now we do.
So I think it will become not just part of clinical trials, but as those clinical trials result, part of standard treatment based on PET imaging. PSMA PET imaging that is.

Akhil Saji, MD: And for a patient, let’s say prebiopsy, or they’ve had a biopsy. So there’s a potential to, let’s say you’re wondering if there is any disease and they haven’t been diagnosed yet and you end up getting a multiparametric MRI of the prostate. Do you foresee any situations where that patient may also benefit from getting a PSMA PET scan?

Michael Morris, MD: Sure. But what we don’t want to do is develop more imaging modalities to diagnose disease that’s clinically irrelevant. We don’t need PET imaging to diagnose Gleason 6 disease.
We need PET imaging to diagnose Gleason 8, 9, and 10 disease and perhaps 4 + 3 disease. So I think we have to be careful in the screening population, right. You’re talking about prebiopsy.

So we need to ensure that PSMA PET can selectively identify those patients who require a biopsy or in lieu of a biopsy, I suppose, ideally, right.

You’d be able to just via a PET, be able to appreciate high grade disease or clinically significant disease. But what we don’t need is a lot of low risk patients being identified by PSMA, where we would otherwise not treat those patients or follow them with active surveillance. So we just have to be careful in treating PSMA as a screening tool, not to fall into the trap of overdiagnosis. You need to selectively diagnose.