EP. 2B: New Horizons in Nuclear Medicine for Prostate Cancer

Positron emission tomography (PET) imaging agents are used to discern PSMA-positive lesions in men given a diagnosis of prostate cancer. These agents build upon the success of genomic tests discussed in “The role of imaging and genomic testing in prostate cancer therapy.” That article, first presented in the New Precision Medicine Approaches in Advanced Prostate Cancer series of Targeted Oncology™, highlights the importance of genomic testing for the initial diagnosis, staging, and treatment of prostate cancer.

Recent advances allow providers to also target phenotypic expression, which offers new precision medicine approaches for prostate cancer treatment. Use of tracers that target PSMA, a new biomarker, with PET/CT and PET/MRI shows particular promise for detecting and characterizing metastatic disease.

This area of nuclear imaging is developing rapidly. Until recently, the United States Food and Drug Administration (FDA) had cleared only 3 PET tracers (choline C 11 choline, sodium fluoride F 18, and fluoride F 18 fluciclovine) for use in men with prostate cancer. Since December 2020, the FDA has approved 2 more PET agents that target PSMA, gallium Ga 68 PSMA 11 and fluorine F 18 DCFPyL. The success of the VISION trial, as announced in June, made lutetium Lu 177 PSMA-617 (LuPSMA) a candidate for the first PSMA targeted therapy in prostate cancer.

The success noted during the VISION trial created another exciting possibility—that theranostics such as focusing onPSMA might not only detect, but also treat, prostate cancer. Although investigators studied the drug in a specific population of patients with late stage, highly pretreated prostate cancer, clinicians and researchers who have reviewed the trial’s results have become excited about the possibility of using theranostics to treat men given a diagnosis of this disease at earlier disease states such as the hormone sensitive setting.

In the second interview of the series, Phillip Koo, MD, chief of Diagnostic Imaging and physician executive at Banner MD Anderson Cancer Center, discusses both the role of novel PSMA tracers in prostate cancer imaging and the promise that theranostics like LuPSMA holds for prostate cancer therapy.

TARGETED ONCOLOGY™: Nuclear imaging is a rapidly developing field. What factors do you consider when using tracers—and especially these new PSMA tracers—to track prostate cancer?

KOO: When we’re thinking about what radiotracer should be used with imaging, whether it’s PET/CT or PET/MRI—[with] PET/MRI [being] much more limited in terms of access—you really want to answer 2 questions: … [W]hat disease state are you in? And what is the question you’re trying to answer?

So, for me, when it comes to these next-generation PET imaging agents in prostate cancer, there are really 2 main areas where we’re seeing the greatest impact. [The] first—[and] primary—area is in patients with biochemical recurrence. In that space, currently, there are two FDA-approved, PSMA-targeted PET agents: gallium Ga 68 PSMA 11 and fluorine F 18 DCFPyL. Those two agents have labels that approve the use in patients with biochemical recurrence.

And then the other disease state, or other bucket that we like to think about is patients at initial diagnosis. So these are patients [who present] before prostatectomy or radiation therapy, where you’re looking to detect metastatic disease. And those 2 radiotracers also have FDA approval in that initial workup space.

TARGETED ONCOLOGY™: What challenges do these PSMA tracers present?

KOO: There are currently several challenges with regards to these PSMA-targeted agents. The first is access. What do you actually have access to? Right now, all of the PSMA-targeted agents are being rolled out rapidly. We’re hoping that in 6 months, they will be available in every facility across the country.

Gallium Ga 68 PSMA 11, which was first approved in December of 2020, was only used at the University of California, Los Angeles, and the University of California, San Francisco. Access was limited. However, there’s a new cold kit-based gallium Ga 68 PSMA 11 product. We hope that this can be readily distributed to any site in the country that has access to PET/CT. The fluorine F 18 DCFPyL compound, called Pylarify, is a fluorine F 18 -based agent, so that could be more easily commercialized and distributed across the country.

The various PSMA-targeted PET products have chemical differences, but, functionally and from an output perspective, I would treat them all the same. If you want to get a PSMA-targeted PET image, it really doesn’t matter which one you’re getting, as long as you’re getting one of the FDA-approved agents.

TARGETED ONCOLOGY™: How will increased use and study of PSMA agents in the coming years change our understanding and treatment of prostate cancer?

KOO: We’re at a very nascent stage with regards to PSMA imaging. We’ve read and heard about this imaging, and it has been used widely across the globe over the past few years. But in the United States, this will be new, and we’ll have much wider access for the entire population. I think this is just the beginning. Once we start having access to this, we’re going to learn more, and it’s really going to impact how we treat patients. But more importantly, hopefully, it’ll impact the clinical outcomes of our patients.

PSMA PET has been more widely studied in patients with biochemical recurrence, and it’s been shown to detect disease even at PSA levels of less than 0.5 [ng/mL]. The idea of detecting and treating metastatic disease for those patients has led to increased investigation of metastasis-directed therapy (MDT). It has also given excitement to this idea of improving oligometastatic disease outcomes, whether radiographic progression-free survival (PFS) or, potentially, overall survival (OS).

Several studies have given strong signals that treating these metastases in patients with oligometastatic disease does have a clinical benefit. One of the first studies came from Dr Piet Ost from University Hospital in Ghent [Belgium], who examined the use of choline C 11 PET scans in metastasis-directed therapy. His team found that you could delay the initiation of hormonal therapy in patients whose metastases were detected by choline C 11 PET and treated with radiation or surgery. Then we see other studies, like ORIOLE and SABR-COMET. The results of the ORIOLE trial suggested that if you treat all of the metastases that are detected on conventional imaging and PSMA PET, patients do better in terms of PFS than those patients whose metastases were not detected through conventional imaging and thus leaving untreated lesions. Results of these studies suggested that we can harness PSMA PET diagnostic imaging tools for better clinical outcomes.

We’re also seeing the use of PSMA PET at initial diagnosis before curative therapies. The hope here is to detect metastatic disease early and to choose a therapy that will lead to a durable clinical outcome. This area is a little earlier in its development. But over the next few years, we hope to have more studies that can address the clinical benefit of PSMA PET in this patient population.

One point I’d like to highlight is that although PSMA PET-CT is much, much better than the imaging agents we’ve had in the past, it is not perfect. You’ll see anecdotes and you’ll read literature about the sensitivity of PSMA PET at initial diagnosis only being in the 40% to 50% range. And you’ll also find that what is seen on PSMA PET is often just the tip of the iceberg. So if you correlate the PSMA PET findings with the lymph node–dissection findings, you’ll see that at surgery, oftentimes more lymph nodes are detected than what was seen on a PSMA PET. And this isn’t surprising, because PSMA PET is still based on an imaging tool, which does not replace a microscope. Pathology remains the gold standard with regards to the detection of micrometastatic disease.

TARGETED ONCOLOGY™: Do you see these advances in imaging leading to different therapeutic advances?

KOO: PSMA PET has 2 major uses. The first is diagnosis, answering this binary question of, ‘Is there metastatic disease or not?’ This is what we talked about earlier. The second is picking and choosing certain therapies and trying to maximize their clinical benefit.

And what we’re seeing is this transition, or this growth, of an area called phenotypic precision medicine. Phenotypic precision medicine is really the combination of genotypes with environmental factors that might lead to a specific phenotypic expression of a certain genotype. It is very interesting, because PSMA PET is noninvasive. It’s not invasive, and it’s also whole-body imaging, so you can get a global picture of how a disease is presenting itself in a specific patient with a single imaging test. There’s no question about the importance and power of genotypes. And the genetic information that we get from biopsies, we’ve seen that can be the driver of how we select therapies in patients. But the phenotypic expression can also be very powerful. And with PSMA PET, it’s this approach of being able to confirm that the patient is expressing a certain target, and it’s also able to see how the patient’s whole body is expressing that target. And then from there, you could actually choose a therapy that will focus onthat specific target.

PSMA is exciting, because we have the diagnostic tool of PSMA PET, and now we have a therapeutic tool that targets the PSMA. The one that we’re awaiting FDA approval for is the Lu177 PSMA. So we could use the imaging to help predict and pick the right patients that will benefit from that therapy; you really have the best of both worlds. And this is why there’s a great deal of excitement around this new area called theranostics. And theranostics is really the idea of being able to see and treat simultaneously. That see part, the visualization part, comes from the PSMA PET and the treat part comes from the Lu177 PSMA. We’re just really scratching the surface of the phenotypic expression of disease, and there will be more to come when it comes to phenotypic precision medicine.

TARGETED ONCOLOGY™: You mentioned LuPSMA. Results from the VISION trial may lead to FDA approval of this theranostic agent. What would that approval mean for the treatment of advanced prostate cancer?

KOO: The release of the VISION trial data created a lot of excitement in the prostate cancer field. This is really just the beginning of radiopharmaceutical- and PSMA-targeted therapies in prostate cancer. The drug in the VISION trial treated patients who were post chemotherapy, post novel hormonal therapy—patients with cancer at a later stage. And these patients had significantly improved OS and PFS when compared with patients given standard care. We’re going to see continued investigation regarding how best to use this therapy. We’ll see trials that investigate LuPSMA use in patients who are castration-resistant before receiving chemotherapy. There’s a trial that’s investigating LuPSMA use in patients who are castration-sensitive and have metastases before receiving chemotherapy, as well. We’ll see this therapy investigated earlier and earlier in the disease course.

We’ll also start exploring how best to select patients to actually undergo the therapy. Some researchers question whether imaging is necessary before you undergo PSMA-targeted therapy. Personally, I think it is. But we need to prove that more convincingly so that there is no question with regards to the benefit of PET imaging for patient selection. And then the more interesting question is, ‘How do you determine the level of expression at which patients get a better response?’ Maybe we can use LuPSMA more effectively in a certain group of patients.

We’re also seeing a lot of development in other types of radiopharmaceutical therapies. For instance, α-particle therapies are being investigated actively. Lutetium Lu 177 is a β emitter. It gives off an energy that can kill cancerous cells. However, β energy can travel further from the site of decay, which can lead to more nontargeted radiation and cause some adverse effects. Thankfully, the adverse effect profile in the VISION trial was relatively good. But the idea of α-particle therapies is very exciting. These α particles have greater linear energy transfer—a greater punch, greater power—and actually travel a shorter distance, so the nontarget radiation delivery is a lot shorter. Theoretically, an α-particle therapy might have fewer adverse effects. We saw this with radium Ra 223 dichloride. This is another part of this radiopharmaceutical journey that is just starting. There’s a lot of excitement and potential for the future.

TARGETED ONCOLOGY™: In the end, how should we think about the role of these novel PSMA-targeted agents in prostate cancer therapy?

KOO: The development of these PSMA-targeted imaging agents and therapeutic options really expands and also complicates how care should and can be delivered for patients with prostate cancer. It’s exciting from my perspective, because it really engages another specialty to be part of that multidisciplinary team at a higher level. And nuclear medicine, nuclear medicine radiology, in my eyes, is becoming that fourth pillar of any [genitourinary] (GU) oncology program that is focusing on prostate cancer. So in that team-based approach to cancer, nuclear medicine is serving a critical role with regard to being able to diagnose disease better, and now offering treatment options. We’ve had radium Ra 223 dichloride in the past. Now we’ll have PSMA-targeted radiopharmaceuticals, as well. My advice is to really find ways to engage all members of that team, because that will lead to better communication, better integration, and better care for our patients.