PSMA-PET leads imaging breakthroughs in prostate cancer paradigm

In this interview, Daniel Spratt, MD, highlights the evolving paradigm of PET-based imaging agents in prostate cancer, with a focus on the impact of PSMA-PET imaging. He also touches on the importance of implementing a multidisciplinary approach when using these next-generation imaging agents in clinical practice. Spratt is the chairman and professor of radiation oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University in Cleveland, Ohio.

Daniel Spratt, MD

What imaging products are currently approved in the prostate cancer setting?

There are many new available imaging modalities in prostate cancer that range from MRI imaging that has evolved over the years to PET-based imaging, which now has really taken over with PSMA-PET CT imaging, for which there's a multitude of FDA approved tracers in the United States and multiple others in development.

How do PSMA-PET agents currently fit into the prostate cancer treatment paradigm?

Right now, imaging plays a vital importance to the spectrum of management of prostate cancer. In early-stage disease now, even before diagnosis, we're using MRI imaging to help us pre-select patients that are at higher risk of prostate cancer using the PI-RADS system, as well as to guide fusion or targeted biopsies to give us the highest yield to detect the most accurate foci of prostate cancer. In addition, MRI imaging is helping both for pre-surgical planning to understand the risks of things such as it invading the neurovascular bundle–so, the ability for the surgeon to preserve the nerves prior to prostatectomy–or with radiation therapy planning, where we now have level 1 evidence to boost or give targeted doses of radiation to those dominant areas above and beyond what we typically treat the whole prostate to.

PSMA-PET imaging, especially for men with unfavorable intermediate risk prostate cancer or higher grade, as well as high-risk prostate cancer, is now the standard of care imaging to help stage patients. Studies have shown that somewhere between 10% to 20% of men will actually have disease that appears in the lymph nodes or sometimes even metastatic sites. This helps us personalize treatment. After patients receive definitive therapy with surgery or radiation in the biochemically recurrent space, PET imaging is now the standard of care to assess patterns of failure to where disease is and how best to optimally manage these patients.

What is on the horizon in terms of new products?

Most of the advancements that are coming relate to PET-based imaging. Some would call this metabolic imaging or immuno-targeting in that you can identify receptors or antigens on cells and image them. There's a variety of tracers that are in the pipeline that image various metabolic aspects of cancer, as well as things that may be enriched in patients with prostate cancer. These are often paired with therapies such as radionuclide therapy. We call this combination together theranostics. There's work with hK2, which is based on a kallikreins or KLK2. PSA is a kallikrein; it's called KLK3, but KLK2 or hK2 is the protein. Now there's an imaging modality to help image these tumors, but also there's a theranostic or a partner radionuclide that is in trials right now to help target those cancer cells, especially in advanced prostate cancer. This is the same concept with PSMA-PET imaging, as well as lutetium PSMA, which is the FDA-approved partner theranostic or radionuclide to treat advanced prostate cancer. There are other tracers right now undergoing testing that target various endocrine or metabolic features of tumors. It'll be interesting to see where ultimately these end up in the landscape of treatment for prostate cancer.

What are some current or future applications for these agents in the urology clinic?

One of the things that people around the world have been running trials to evaluate is, are we able to either number 1, minimize or even avoid doing prostate biopsies, and can imaging be accurate enough–whether that's by MRI alone, PSMA-PET alone, or the combination–to give high enough confidence that there is clinically significant prostate cancer. These trials are in the early phases, but [it does] appear that PSMA-PET imaging adds value to identify clinically significant prostate cancer as well as MRI does. The best results seem to be both together. Ultimately, whether this something that will be adopted as standard of care pre-biopsy is unclear, simply because it is resource-intensive, but it's definitely of great interest.

Additionally, imaging will continue to change the landscape of how we manage intact and recurrent prostate cancer. What we're finding is a major stage migration in that if you look at men with high-risk prostate cancer that were treated with radiation or with surgery, there was always at least 10%, some series 20% or higher, of them develop metastatic disease long-term. With this imaging, we're finding about 10% to 20% of men at baseline actually have disease that we can visibly see outside of the prostate. We're starting to see early data of trials that have staged patients or pre-selected them before treatment by PET and excluded the men who already have disease that have spread. The outcomes are looking phenomenal from receiving definitive therapy. What does that mean in terms of treatment intensification, or really, de-escalation, and what are the outcomes? How aggressive is modern day high-risk prostate cancer in the setting of MRI and PSMA-PET imaging? Lots to come on this.

Could you touch on the importance of a multidisciplinary approach to PSMA-PET?

With any new treatment technology, and imaging falls right into that category, there's a big learning curve, both for the radiologist or nuclear medicine physicians to interpret and read and understand that imaging, but often, it requires a multidisciplinary approach with the clinicians, with the surgeons or radiation oncologists or medical oncologists, because there are some unique false positives with this PSMA PET imaging. One of the most common that we discuss a lot in our clinics is there can be subtle uptake in ribs. It's been pretty well established that most of these appear to be false positives. That low SUV uptake does not translate into these actually being metastatic sites. But if you call these as metastases, you would be giving potentially doublet or maybe, depending on other features, triplet systemic therapy, vs maybe just offering local therapy to the patient. I think that having the clinical context such as the PSA, the Gleason score, the other features that assess the aggressiveness of the disease can help with some of these subtle findings that can be found on PET imaging.

Is there anything else that you’d like to add?

Anytime there are technological advances, it opens our eyes to things that we couldn't see before. It's very exciting that we can now better prognosticate or risk stratify patients before we even treat them, thanks to improved imaging. But with every new advancement, there are many questions that come with it. We have a lot of questions now because we have decades of clinical trials where we didn't have this imaging. How do we apply our previously done clinical trials in the setting of patients that have metastatic disease only by this advanced imaging technology, or even [in] patients [who] now with advanced imaging technology, do not have metastatic disease [and] seem to have more indolent disease? This is an opportunity as well as something that we often discuss in our tumor boards and require this multidisciplinary opinion because there is a gray zone now in how best to optimally manage these patients. Sometimes there's really not one right answer, because we don't have those answers now because of this new imaging.