A session at the 31st Annual Prostate Cancer Foundation (PCF) Scientific Retreat touched on current progress with prostate-specific membrane antigen (PSMA) and the possibilities with next-generation theranostics.

Following these proceedings, featured expert Neha Vapiwala, MD, FACR, FASTRO, FASCO, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Vapiwala’s clinical perspectives on this topic are presented here.

As discussed at the 31st Annual PCF Scientific Retreat, this is an exciting time in the world of PSMA theranostics. On the diagnostic side, PSMA positron emission tomography (PET) imaging has revolutionized the staging of patients with more advanced prostate cancer and is increasingly being employed in the evaluation of those with newly diagnosed unfavorable or high-risk disease. No tool is perfect, but PSMA tracers improve upon the sensitivity and specificity of conventional imaging for detecting metastases.

Having said this, we are still seeking to understand the implications of PET-based imaging on staging and treatment, in both the newly diagnosed and the post-treatment settings. I do think that it is important to manage patients’ expectations and explain up front that PET imaging is one tool in our toolbox, and all tools have limitations. For example, PSMA PET still has relatively limited sensitivity in certain clinical settings; not all prostate cancers express PSMA, and the clinical significance of uptake of varying degrees is not fully understood. So, I tell my patients, “If the PET helps to guide us, fantastic. But if it does not reveal any new or clear findings, we will still rely on other available tools and the other clinical and pathologic information at hand.”

Open and active questions for the field are myriad. PSMA PET represents a relatively recently adopted technology, while clinical trials and treatment recommendations have historically all been based on conventional imaging. These questions include how best to integrate PSMA PET in staging when the findings are discordant with the findings of conventional imaging or when PSMA PET detects low-volume disease earlier than conventional imaging would have identified it. There can be real-world implications on patients and the treatments they are offered or denied as a result of stage migration and increased sensitivity. Thus, it is important that we try to answer questions regarding the optimal integration of new technology through well-designed clinical trials.

On the treatment side, ¹⁷⁷Lu-PSMA-617, in particular, is very exciting, and targeted radioligand therapy (RLT) for metastatic castration-resistant prostate cancer was a topic of discussion at the 31st Annual PCF Scientific Retreat in a talk by Louise Emmett, MD, MBBS, during a session on next-generation theranostics. Given the limitations of conventional ADT approaches in this population, RLT offers an attractive therapeutic mechanism. There is great potential for increasing clinical benefit with the different types of RLTs that are actively in development, and I think that future treatment paradigms will involve understanding the current limitations; identifying new, possibly nonoverlapping targets; and investigating RLT in conjunction with other systemic therapies and external beam radiation therapy.

Our Australian colleagues are global leaders in this area, and we are grateful to them and to the patients they enrolled in clinical trials and treated for the incredibly useful data that has guided our use of these agents. As noted during Dr Emmett’s presentation, one important area of inquiry is how to apply ¹⁷⁷Lu-PSMA-617 to earlier-stage treatment settings. Ongoing studies are also trying to determine how to use ¹⁷⁷Lu-PSMA-617 in combination with other systemic therapies to ensure optimal sequencing for patients.

Here and abroad, there is tremendous excitement about research on additional options for targeted RLT. One of the original radiopharmaceuticals in this space, radium-223, is an alpha emitter, and we are now considering the use of new generations of alpha emitters that are known for favorable features such as high mass and high linear energy transfer. Together with their characteristic short range, alpha emitters have the appeal of limiting off-target effects while delivering effective and efficient cell killing to the cancer.

How might dosimetry evolve throughout this era of targeted RLT? It will likely be a function of many different things, including the degree to which the patient and the tumor express the target molecule, the tumor burden, and probably additional variables that we have yet to fully understand. This is one of the areas in which there is a great need for multidisciplinary collaboration and continued research.

I think that radiation oncologists will continue to play a key role as novel radiopharmaceuticals emerge for a number of reasons, including the relevance and strength of their specialized training. Whether one thinks of external beam radiation therapy, brachytherapy, or other forms of radiotherapy, a crucial part of that training involves understanding how the treatment plan delivers the dose both to the intended/targeted volumes and to the healthy tissues. From the Hounsfield units and beam angles to the normal tissue tolerance of the surrounding organs—all of that modeling, and the basis of radiation therapy planning, are very well developed and well understood by radiation oncologists.