Phillip J. Koo, MD, discusses the clinical use of PSMA PET imaging in patients with prostate cancer.

Dr Koo on the Clinical Utility of PSMA PET in Prostate Cancer

Phillip J. Koo, MD, chief, Diagnostic Imaging, Banner MD Anderson Cancer Center, discusses the clinical use of prostate-specific membrane antigen (PSMA) PET imaging in patients with prostate cancer, highlighting ongoing research that is further investigating the use of this imaging.

Numerous clinical trials are now integrating PSMA PET into their protocols, marking a significant advancement in the treatment of patients with prostate cancer, Koo begins. The wealth of data being accumulated in this field promises to shed light on the impact of PSMA PET and its role in guiding treatment decisions, Koo adds. In the context of biochemical recurrence, pivotal studies, such as the phase 2 ORIOLE (NCT02680587), SABR-COMET (NCT01446744), and STOMP (NCT01558427) trials, have provided valuable insights into optimizing the use of PSMA PET to inform the application of metastasis-directed therapy (MDT), he reports. However, debate persists as to whether the available data warrant the widespread adoption of MDT in these cases, and varying perspectives prevail, he notes.

The phase 3 EMBARK trial (NCT02319837), which enrolled its first patient inapproximately 2015, holds significance as well, Koo continues. EMBARK stratified patients based on whether they had a high risk or low risk of biochemical recurrence, which was particularly meaningful, as those with high-risk profiles likely exhibit more aggressive biological behavior, he adds. Consequently, tailoring disease management strategies based on risk stratification is imperative, Koo elucidates, saying that although PSMA PET was not used in EMBARK, incorporating this imaging strategy introduces complexities in patient treatment.

The absence of definitive answers regarding the optimal role of PSMA PET in prostate cancer underscores the necessity for multidisciplinary discussions to dissect these findings, he continues. Moreover, ongoing efforts to design trials integrating PSMA PET seek to address lingering questions and ascertain the most appropriate treatment approach for patients, Koo adds. This collective endeavor reflects the evolution of clinical practice, driven by a commitment to optimizing patient care through informed decision-making and collaborative exploration of emerging technologies and data, he concludes.

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Dr Koo on PSMA PET Imaging in Prostate Cancer 

Phillip J. Koo, MD, is the Chief of Diagnostic Imaging at the Banner MD Anderson Cancer Center in Phoenix, Arizona, discusses the use of prostate–specific membrane antigen (PSMA) PET imaging in prostate cancer, including its potential use for patient selection for radiopharmaceuticals.

Koo stresses the need for a nuanced approach to utilizing PSMA PET imaging, cautioning against its indiscriminate application across all clinical scenarios for patients with prostate cancer, including treatment response assessment. Although PSMA PET imaging is a valuable diagnostic modality, Koo advocates for judicious utilization, emphasizing the necessity of aligning its deployment with scenarios where it offers maximal clinical benefit. He cautions against over-reliance on PSMA PET, noting the importance of adhering to established appropriate use criteria set forth by various medical societies.

Additionally, Koo highlights a common pitfall in the adoption of novel technologies—namely, the tendency to overuse them due to perceived superiority. Advocating for balance, Koo explains the need for evidence-based approaches, urging clinicians to exercise prudence in incorporating PSMA PET scans into routine clinical practice.

Furthermore, Koo discusses the evolving landscape of radioligand therapy in prostate cancer, noting a shift in clinical trials investigating their use earlier into treatment regimens, including pre-chemotherapy and potentially in hormone-sensitive settings.

Ongoing trials are underway to explore the utility of PSMA PET imaging to better select patients for these therapies, Koo explains. These trials encompass prospective, retrospective, and real-world evidence investigations, aiming to optimize patient selection strategies and maximize the clinical impact of PSMA PET technology, Koo concludes.

Phillip J. Koo, MD, discusses the use of PSMA PET imaging in prostate cancer.

Phillip J. Koo, MD, division chief of Diagnostic Imaging, Northwest Region Oncology physician executive, the Banner MD Anderson Cancer Center in Phoenix, Arizona, discusses ongoing areas of technological and therapeutic advancements within the prostate cancer landscape.

Current data on the use of PSMA-PET scans show support for its use as a highly effective and predictive tool in prostate cancer, Koo begins. Ongoing and developing trials in prostate cancer continue to incorporate PSMA-PET into their study protocols, he says. Accordingly, PSMA-PETscans may become the new standard technique for localizing prostate cancer recurrence, Koo explains.

Moreover, the role of radiopharmaceuticals is an additional area of interest in prostate cancer research, Koo continues. The phase 3 PSMAfore (NCT04689828) trial of Lutetium 177 (177Lu) PSMA-617 (177Lu-PSMA-617) evaluated the role of this targeted radioligand in earlier stages of metastatic castration-resistant prostate cancer (mCRPC). Evaluable will be treated with 177Lu-PSMA-617 vs changing AR-directed therapy.

Evaluable patients will have mCRPC or metastatic hormone-sensitive prostate cancer (mHSPC), had prior exposure to an alternate AR inhibitor, and were not exposed to a taxane-containing regimen. The trial was reported as positive in a recent press release, and initial data are forthcoming, Koo notes. Results from this trial may support the continued inclusion of radioligand therapies into standard treatment strategies, Koo says.

Several other trials are being designed to investigate the utility of radiopharmaceuticals across disease states, Koo adds. This includes the phase 3 PSMAddition trial (NCT04720157) 177Lu-PSMA-617 in combination with SOC androgen deprivation therapy (ADT) plus an AR inhibitor in patients with mHSPC.

Although PSMA-PET imaging and radioligand therapies continue to improve the treatment landscape in prostate cancer, future investigations are still needed to identify patient subsets who would most benefit from these approaches, Koo concludes.

Phillip J. Koo, MD, discusses ongoing areas of technological and therapeutic advancements within the prostate cancer landscape.

Dr. Koo on Novel Technological and Therapeutic Advancements in Prostate Cancer

Let’s talk a little about the data that led to the 18-fluoride DCFPyL PSMA [prostate-specific membrane antigen] PET [positron emission tomography] agent. This was tested in several trials, both with bird-type names. Birds must have very good eyesight, perhaps that’s why. Scott, I’d love to hear you talk through this with us a little bit. The OSPREY trial was started a few years ago and was presented about a year ago in patients with high-risk prostate cancer, some maybe with locally recurrent metastatic disease. Can you tell us a little about the OSPREY trial and the 2 cohorts that were enrolled?

Yes. Let me speak a little more broadly. Both of the FDA-approved tracers were tested in similar ways in terms of grouping patients, in terms of the label, suspected metastatic disease, or basically higher-risk disease prior to primary treatments. For both of the trials, their major readout in that situation was compared to histology and pathology. Then in post-primary treatment, biochemical relapse disease, there were additional data sets.

There are 3 different uses for PSMA PET that are essentially in prime time today. One is deciding on initial treatments, especially it’s helpful to know if there’s something we see outside the prostate or not. Whether that changes things, we don’t know, but it’s still useful information. With biochemical relapse, the major question is, where’s my PSA [prostate-specific antigen] coming from? When there’s surgery and then radiation, the PSA goes up. Localization can be quite helpful. And then, not that we have an approved agent yet, but it can be helpful in treatment selection, or at least optimization for metastatic disease with PSMA-targeted radionuclide therapy.

The 2 data sets, in terms of the preoperative settings, were almost identical. I agree with Phil that there are clear differences in radiochemistry. But for an end user, I don’t think they really matter. It’s probably not addressing the question today comparing both head to head—and there are several more coming—vs figuring out the best use for them and getting long-term data. That’s more important. But it showed basically the same thing, that when compared with the microscope, each one was only about 40%. But when we look at the larger results, in terms of true positivity, then we’re looking at 95% to 98%.

With OSPREY being published relatively recently in the 

, and the Gallium-68 PSMA-11 from UCSF [University of California, San Francisco] and UCLA [University of California, Los Angeles] in press in the 

, we have to put things into perspective, in that the sensitivity of imaging is not going to be down to the single-cell level, like a microscope, especially with a microscope plus immunohistochemistry. But on a practical basis, it especially would expand this and go to something like proPSMA compared with CT and bone scan, then there’s really no comparison. CT, bone scan, and MRI led to some major advances, but not near the sensitivity of PSMA PET. It doesn’t approach the sensitivity of the microscope, but these are some major advances in prime time now.

I completely agree. Certainly, we’re not here to suggest that the Gallium agent is better or worse than the fluoride agent. From my perspective, any PSMA PET imaging that you can undergo is great, and there’s no evidence that either is better than the other. But it’s important to recognize and tell our patients that this will only identify PSMA-positive disease. That can be a challenge sometimes for patients who think, “Any of my disease should be identified.” But that’s not always the case, and we saw that in the TheraP trial. We’ll probably talk about that later. Some disease can sometimes be FDG [fluorodeoxyglucose]-avid, but not PSMA-avid, so it’s important to recognize this is only going to pick up the PSMA-positive disease. Phil, do you have any comments on that?

 That’s a great point. Something that we should re-emphasize is PSMA PET-CT is not perfect. As Scott mentioned, it doesn’t replace a microscope. For some reason, a lot of times I see PSMA PET equated to identifying micrometastatic disease, and that’s not true. It cannot identify micrometastatic disease. By definition, these are things that we’re detecting with microscope, pathology, and tissue. That’s important because it sheds light on the limitations of the imaging modality. Clearly, we’ve seen a lot of the trials that use PSMA PET to identify patients who will be treated and how they’ll be treated, like those oligometastases types of trials. What we see is those patients still recur. That’s because even though we might see 1, 2, or 3 lesions on a PSMA PET, in reality, there are maybe additional nodes that have micrometastatic disease that we’re not seeing with PSMA PET. It’s because we need a certain threshold of cells that are expressing the PSMA receptor in order to detect it on the PET-CT technology, on the hardware.

Great. Thank you for clarifying that. Although it’s a great way for us to identify low volumes of disease, it will not be able to replace a microscope.

An interpretation of the OSPREY study of 18F-DCFPyL injection in patients with high-risk prostate cancer and implications of its use.

PSMA-Targeted 18F-DCFPyL PET/CT in High-Risk Prostate Cancer

Let’s move on and ask Phil a question, because Phil’s a nuclear medicine physician, a true expert in our field in prostate cancer, and has collaborated with us over the years to try to help us understand some of the biomarkers that we find in imaging, particularly with PET [positron emission tomography] imaging. Phil, can you tell us a little about radiotracers in prostate cancer? What are your thoughts on some of the different agents that exist?

 Sure. Thanks, Alicia. Radiotracers in nuclear medicine are the backbone of our specialty. We specialize in the use of these unsealed sources of radiation to diagnose and treat tumors. And in prostate cancer, they’re not new. We’ve been using various radiopharmaceuticals to diagnose and treat disease in the past. What we’re seeing in prostate cancer is this elevation and huge step forward with the validation and FDA approval of PSMA [prostate-specific membrane antigen]-targeted diagnostic agents. To me, this is shepherding a new era in precision medicine that’s focusing on the phenotypic precision medicine, which looks at the expression of a specific biomarker in patients with prostate cancer to help us guide treatment decisions.

When we talk about precision medicine, we focus so much on the genotype, which is obviously very important. But the phenotype in PSMA is now opening up a whole new world of opportunities. To me, this is extremely exciting, and we’re only scratching the surface. A lot of times, the focus has been on detecting disease. But now, the idea of using imaging to select patients for treatment is real. It’s with us today, and we’ll talk about that later. The idea of using imaging to help us understand prognosis is another area where we’re just scratching the surface.

All of this is really exciting. Clearly, a lot of the people at this table have done groundbreaking work to help us answer a lot of these questions. One other point I’d like to add is the fact that imaging has always shed light on heterogeneity. We talked a little about this earlier, but heterogeneity is something we’ve seen so often on imaging, but we couldn’t explain it. In the past, we used FDG [fluorodeoxyglucose] glucose analogues to image, and we’ve seen various tumors have more glucose expression vs less glucose expression. Even with sodium fluoride, there were some tumors that would be really bright, and some that would be less bright. It was telling us something. It’s incumbent on us to search more, because heterogeneity is going to be a big driver of how our patients respond to these various therapies in the future.

Absolutely. And in a later conversation, we’ll get to the way that we can use several different PET tracers, FDG and PSMA perhaps, to find a bit of a different phenotype of the disease in the same patient, with different areas of metastatic spread. It’s really important and interesting. Sandy, how commonly do we see PSMA expression? We’re really interested, as one of the newer technologies is PSMA-directed PET technology. How commonly do we see that protein expressed in our patients?

 It depends on the type of patients you see. In my practice, for patients with more advanced disease, we’ll talk a little more about the VISION trial. But in the VISION trial, all patients ended up having a positive PSMA as an inclusion. It turned out that close to 85% of patients with advanced disease do have a positive PSMA expression. We know this from earlier studies showing us that PSMA is prognostic. As you get more treatment, perhaps with AR [androgen receptor]-directed therapy, there’s increased expression of PSMA. You can even see in patients with localized disease, those with more aggressive disease have a higher PSMA expression. It’s going to be interesting to see how we utilize this imaging, and in which patient population it is going to add the most value. It’s remarkable that it’s prognostic, and now we’re able to target it both therapeutically and diagnostically.

I agree. I heard a talk once that compared our ability to target PSMA with imaging as a light bulb, and our ability to target it with theragnostics as a little bomb, and to think about PSMA being utilized in both ways, allowing us to image our patients potentially more sensitively or accurately, as well as potentially to treat our patients. It’s really interesting, because both of those characteristics are there. But we should be very careful and also explain that there are different ways for us, at least in imaging, to target PSMA. There are also multiple ways to target it therapeutically. Phil, I’d love to hear from your perspective a characterization of some of the different agents that we can use to target PSMA with imaging. Let us know how those approvals—because they’re approved at this point—have panned out.

 Sure. As of today, speaking for the diagnostic perspective, there are 2 approved PSMA-targeted diagnostic agents. Gallium 68 PSMA-11 was approved at UCSF [University of California, San Francisco] and UCLA [University of California, Los Angeles] in December of 2020. Then we have the F18 [fluorine-18]-based PyL compound that was approved in May of 2021. Both of these agents, for all intents and purposes, are the same. There are subtleties in image quality, biodistribution, and dosimetry. But for all the users out there, the end product is pretty much the same, and the output will be pretty much the same.

What we’re seeing right now, especially in the United States, is a relatively rapid rollout of these agents. With the Gallium 68 PSMA limited to UCSF and UCLA, there was clearly a limitation in access. Patients would only be able to get access at those 2 sites. Now, we’re seeing nationwide commercialization of the PyL compound because of the isotope, which allows it to be distributed across the United States pretty easily. This is going to really change what we see in terms of access. Then we have other compounds, such as the Gallium 68 PSMA-11 kit, which will also help us increase the access for patients across the United States. But again, the performance is pretty much all the same. So if we say PSMA-targeted PET or PSMA PET, they’re all going to be roughly the same.

Great, thanks. That’s so helpful. It’s also helpful to understand that these are different compounds between the gallium and the fluoride, and that the gallium agent at this point, also a very good agent, is only available at 2 sites in the United States, so we were very excited when it was approved. It’s showing a shift in our paradigm and opportunities to potentially identify patients for these therapeutic agents that we’ll discuss later. But it wasn’t necessarily something that we could see at all sites, and so that’s a bit of a challenge for some of our patients who do not live near those particular sites.

A discussion regarding the use of PSMA PET imaging to detect phenotypic biomarkers that may simplify approaches to precision medicine in advanced prostate cancer.

Phenotypic Biomarkers in Advanced Prostate Cancer

Phillip J. Koo, MD, division chief of Diagnostic Imaging at Banner MD Anderson Cancer Center, discusses the need for next-generation imaging in prostate cancer.

Next-generation imaging has been sorely needed in the field of prostate cancer, explains Koo. Conventional imaging tools, which have been limited to bone scan and computed tomography (CT), can miss a lot of lesions. However, it’s critical to be able to identify these lesions, so the spread of disease and the type of treatment patients need can be accurately assessed.

Currently, 18F-fluciclovine (Axumin), which is a next-generation diagnostic agent, is widely used in the United States. However, the future of next-generation imaging is going to be focused on prostate-specific membrane antigen (PSMA)—based imaging agents, says Koo. Currently, the use of these agents varies across the globe. In the United States, there are no FDA-approved PSMA PET agents. However, several sites in the United States are offering these agents under new drug applications or clinical trials. The United States will see widespread use of generic 

Ga-PSMA-11 PSMA or commercialized versions of PSMA once they receive regulatory approval, concludes Koo.

Phillip J. Koo, MD, discusses the need for next-generation imaging in prostate cancer.

Dr. Koo on the Need for Next-Generation Imaging in Prostate Cancer

Phillip J. Koo, MD, division chief of Diagnostic Imaging at Banner MD Anderson Cancer Center, discusses the actionability of next-generation imaging results in prostate cancer.

The results of next-generation imaging tests should be actionable in order to be valuable, says Koo. As such, prior to ordering a test, it should be known how the information could influence treatment decisions.

According to a trial that enrolled a SPARTAN-like population, 55% of patients with nonmetastatic castration-resistant prostate cancer (CRPC) had N1 disease when they were scanned with prostate-specific membrane antigen. Notably, those patients were included in the phase III SPARTAN trial based on conventional imaging with a bone scan and CT and still derived a 2-year improvement in metastasis-free survival.

Although next-generation imaging modalities have higher sensitivity compared with conventional imaging, it’s important to adhere to the data and use next-generation imaging where appropriate, says Koo.

Patients with CRPC have aggressive disease. Prostate-specific antigen (PSA) is an important biomarker, but patients can progress without a rise in PSA. According to data from the PREVAIL trial, 25% of patients have radiographic progression without a rise in PSA; these patients may be candidates for monitoring with next-generation imaging, concludes Koo.

Phillip J. Koo, MD, division chief of Diagnostic Imaging, Banner MD Anderson Cancer Center, discusses the actionability of next-generation imaging results in prostate cancer.

Dr. Koo on the Actionability of Next-Generation Imaging Results in Prostate Cancer

Phillip J. Koo, MD, division chief of Diagnostic Imaging, Banner MD Anderson Cancer Center, discusses the use of metastasis-directed therapy in prostate cancer.

Next-generation imaging modalities are better equipped to detect oligometastatic disease compared with conventional imaging tools, says Koo. For example, if a patient presents with biochemical recurrence and a low prostate-specific antigen of 0.5 ng/mL or 1 ng/mL, a bone scan or CT scan will likely be negative. However, if next-generation imaging is employed, there's a greater chance of detecting locally recurrent disease, local metastatic disease, or oligometastatic disease outside the pelvis, says Koo.

According to surveys and consensus meetings, such as the Advanced Prostate Cancer Consensus Conference, patients who are found to have oligometastatic disease should be treated with metastasis-directed therapy. The data supporting the impact of this approach is growing, adds Koo. For example, a study from The University of Ghent demonstrated that the time to initiation of androgen deprivation therapy was prolonged in patients who had a C11-choline PET/CT and then received radiation or surgery on identified lesions, concludes Koo.

Dr. Koo on Metastasis-Directed Therapy in Prostate Cancer

Phillip J. Koo, MD, division chief of Diagnostic Imaging, Banner MD Anderson Cancer Center in Arizona, discusses new management strategies for patients with prostate cancer.

If a patient presents with biochemical recurrence and a low prostate-specific antigen of 0.5 or 1, conventional imaging will likely show the bone scan or CT as negative, explains Koo. However, if a next-generation imaging agent is used, there is a high likelihood that locally recurrent disease or local metastatic disease will be detected, potentially even detecting oligometastatic disease outside of the pelvis, says Koo.

The next step is to determine how to manage the patient once the test results are received. According to surveys and consensus meetings, such as the Advanced Prostate Cancer Consensus Conference, many providers are treating patients with oligometastatic disease with metastasis-directed therapy and the data regarding this approach are growing, according to Koo. A study from Ghent University showed that the time to initiation of androgen deprivation therapy was longer in patients who had a C11-choline PET/CT scan and then received radiation or surgery on those identified lesions, concludes Koo.

Phillip J. Koo, MD, discusses new management strategies for patients with prostate cancer.

Dr. Koo on New Management Strategies for Prostate Cancer

Phillip J. Koo, MD, division chief of Diagnostic Imaging, Banner MD Anderson Cancer Center in Arizona, discusses next-generation imaging tools in prostate cancer.

18F-fluciclovine (Axumin) is the next-generation imaging tool that is widely available and best performing, explains Koo. The performance of 18F-fluciclovine thus far has been as good or better than choline C-11, which was the first novel radiopharmaceutical PET agent that was approved in the United States, says Koo.

Conventional imaging tools have focused on bone and CT scan, but many lesions were missing on these scans, according to Koo. This is important because when looking at salvage therapies or potential curative interventions, physicians should be aware if the disease is metastatic and where it might be confined, concludes Koo.

Phillip J. Koo, MD, discusses next-generation imaging tools in prostate cancer.

Phillip J. Koo, MD

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