Dr. Pienta on the evolving paradigm of PSMA-PET imaging

In this interview, Kenneth J. Pienta, MD, discusses the impact of PSMA-PET imaging in prostate cancer and future directions for advancement. Pienta is the director of research at the James Buchanan Brady Urological Institute and a professor of urology and oncology at Johns Hopkins School of Medicine in Baltimore, Maryland.

Kenneth J. Pienta, MD

Piflufolastat F 18 (Pylarify) was approved in 2021. Could you touch on the significance of the FDA approval and where we are now with this agent?

I certainly was very pleased to be part of the clinical trials and the initial work to demonstrate the ability of piflufolastat F 18 to detect prostate cancer, especially metastatic prostate cancer in the lymph nodes and bones. The approval of piflufolastat F 18 has allowed us to do some amazing work in understanding how prostate cancer spreads over time, helping us identify men at high-risk for having locally advanced prostate cancer, prostate cancer in the lymph nodes, at the time of primary treatment. That is something we want to know so that we can either do a better surgery or refer the patients to radiation for primary therapy because their disease has escaped the gland. And then, as has been demonstrated in the recurrent setting, biochemical recurrence happens in too many men. Previously, before piflufolastat F 18, we had to treat those patients empirically, not knowing where their disease was, or we had to wait until their disease manifested sometimes years after their PSA started to go up. Piflufolastat F 18 has allowed us to identify where that cancer is in those men with biochemical recurrence much sooner. That has allowed us to direct therapy appropriately, whether that's salvage radiation, hormonal therapy, or specific stereotactic radiation to say a lymph node or a bone metastasis.

How has PSMA-PET imaging impacted the diagnosis and management of prostate cancer in clinical practice?

PSMA imaging is impacting therapy in 3 types of patients. Number 1, the patient who, at the time of biopsy has high-grade prostate cancer, and we want to do PSMA imaging to understand who has cancer that has already escaped the gland, and we need to modify their curative therapy with either better surgery or potentially changed radiation fields. The second place that PSMA imaging has impacted the field is in the setting of biochemical recurrence, where we can direct therapy appropriately once we see where the disease is. We can do that much sooner now, maybe months to years before regular imaging would ever detect that cancer. The third place that PSMA imaging is impacting the field is to identify patients who are eligible for treatment with drugs like 177Lu-PSMA-617 (Pluvicto), the radioligand-directed therapy. You have to have a positive PSMA scan to be able to get that therapy appropriately.

Can you discuss any ongoing research with F-18 targeted theranostics?

There are multiple agents in development for the therapeutic application of PSMA conjugated radioligands. Once you have a positive scan and metastatic disease, the question is, what happens to patients after 177Lu-PSMA-617? In the castrate-resistant setting, what else can they do? Well, there are multiple trials moving 177Lu-PSMA-617 up as a therapy. Should we be treating patients in the castrate-sensitive setting? Should we be treating patients who have oligometastatic disease with systemic 177Lu-PSMA-617 therapy? Those trials are ongoing, and then there are multiple new agents that continue to be investigated [in comparison with] 177Lu-PSMA-617. Many of the alpha particles will continue to be looked at. For example, lead and thorium. We're going to have to see what the [adverse] effects of those newer agents are compared to say actinium vs lutetium. We know that the beta particles like lutetium have less [adverse] effects, but are probably less efficacious. There's a balancing act with decreasing systemic toxicity around the alpha particles. There are also trials ongoing to try and mitigate the [adverse] effects of, for example, salivary gland dryness or renal damage, by using various protective agents. Those trials are ongoing also.

Could you discuss the significance of using a multidisciplinary approach with PSMA-PET imaging?

The advance of PSMA imaging has put an emphasis on multidisciplinary care. We now have a new imaging agent that identifies cancer that has spread outside of the prostate or is now oligometastatic. Now we are seeing, for example, therapy that requires surgery to take out the primary prostate, but potentially radiation also with it for an oligometastatic disease patient. Then you have to put into the mix, "Well, how do you do hormonal therapy and chemotherapy in that setting?" So, all of a sudden, we're seeing the use of nuclear medicine and radiology driving decision-making that involves urologists, radiation oncologists, and medical oncologists.

Where do see the PSMA-PET imaging paradigm in prostate cancer advancing to in the next 5 to 10 years?

I think what we're going to see over the next 5 to 10 years with PSMA imaging is to understand if identifying the cancer earlier changes outcomes. Or is it just an example of lead time bias in that we've identified the cancer earlier and we have to treat it, and by treating it earlier, did we cure more people, or did we simply treat them longer and they're all now cured and living the same amount of time? That's going to be the great question over the next 5 to 10 years and what most academic folks who think about PSMA imaging and its impact on the field are wondering about.