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Clinical Focus

Jason Hafron, MD; Aaron D. Berger, MD; Arpeet Shah, MD

Medical Crossfire® in Adjunctive Testing: Charting a New Course in Prostate Cancer Risk Assessment

, highlights the recent FDA approval of flotufolastat F 18 (POSLUMA), a PSMA-PET imaging agent in prostate cancer. Schuster is a professor of radiology and imaging sciences and the director of the division of nuclear medicine and molecular imaging at Emory University School of Medicine in Atlanta, Georgia.

 in May 2023, and became commercially available in June 2023. The agent is indicated for PET imaging of PSMA-positive lesions in men with prostate cancer with suspected metastasis who are candidates for initial definitive therapy or with suspected recurrence. The approval was based off of findings from the phase 3 SPOTLIGHT and LIGHTHOUSE trials, which Dr. Schuster’s highlights during the discussion.

Don’t forget to subscribe to Speaking of Urology® on 

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"We're excited that the FDA approval of this radiotracer gives us yet more tools at our disposal to diagnose prostate cancer in all its forms, from early to late in the disease process," says David M. Schuster, MD, FACR. 

Dr. Schuster highlights the FDA approval of imaging agent flotufolastat F 18 in prostate cancer

A recap of the FDA submissions and regulatory decisions in urology from March 2025.

FDA updates in urology: March 2025

"I think a take-home message there is that in the prostate/prostate bed, you have to take extra time and caution in reading that region," says Phillip H. Kuo, MD, PhD.

18F-flotufolastat PET/CT shows high inter- and intrareader agreement rates 

The use of pre-diagnostic MRI was 3.8% in 2012, which increased to 32.6% in 2019.

Study finds geographic disparities in MRI use in prostate cancer

Gozellix – after radiolabeling with 68Ga – is indicated for PET imaging of PSMA positive lesions in men with prostate cancer who have suspected metastases and are candidates for initial definitive therapy and those who have suspected recurrence based on an elevated serum prostate-specific antigen level.

FDA approves PET imaging product Gozellix for prostate cancer

The detection rate ranged from 44% to 58% on day 0 and 58% to 80% on day 1.

64Cu-SAR-bisPSMA shows efficacy in detection of biochemically recurrent prostate cancer 

investigators sought to review data regarding combination therapies for the treatment of locally advanced and metastatic hormone-sensitive prostate cancer.

 In their paper, the authors touched on the integration of prostate-specific membrane antigen (PSMA) PET imaging leading to earlier detection of metastatic disease. In an interview with 

®, study author Dr Louise Kostos was asked whether she felt this might affect the balance between treatment intensification and de-escalation strategies, especially in terms of minimizing overtreatment and long-term toxicity.

“That's a really good question, and one we don't have a clear answer to at the moment. I guess what we know about PSMA PET scans is that they are more sensitive compared with conventional imaging, but they also have a lower false positive rate compared with CT and bone scan,” said Kostos, a medical oncologist and PhD candidate at Peter MacCallum Cancer Centre in Victoria, Australia.

Dr Louise Kostos discusses PSMA PET's effect on treatment intensification and de-escalation in mHSPC

PSMA PET and treatment intensification in mHSPC

She added, “The main challenge at the moment is patients are being diagnosed with metastatic disease far earlier than they would have been otherwise, and therefore [are being] considered for combination systemic therapy potentially years earlier than they would have been if we just looked at conventional imaging.”

During the interview, Kostos also made note of the LIBERTAS trial, “which is looking at patients with metastatic hormone-sensitive prostate cancer who go on to start ADT [androgen deprivation therapy] and apalutamide [Erleada], and use PSA [prostate-specific antigen] as a biomarker. [They’re looking] at the whether patients have an undetectable PSA at 6 months, and if they do, they get randomized to stop the ADT or continue with the doublet. And importantly, that study also incorporates PSMA PET into the baseline staging as well,” Kostos said.

1. Azad AA, Kostos L, Agarwal N, et al. Combination therapies in locally advanced and metastatic hormone-sensitive prostate cancer. 

. 2025 Feb 12:S0302-2838(25)00023-5. doi:10.1016/j.eururo.2025.01.010

Videos

“The main challenge at the moment is patients are being diagnosed with metastatic disease far earlier than they would have been otherwise, and therefore [are being] considered for combination systemic therapy potentially years earlier than they would have been if we just looked at conventional imaging," says Dr Louise Kostos.

Amar U. Kishan, MD, shares future research directions based on the MIRAGE trial.

Amar Kishan, MD, highlights ongoing research on reducing toxicity in SBRT 

, shares future research directions based on the MIRAGE trial (NCT04384770), which compared the use of aggressive margin reduction with MRI-guided SBRT to standard CT-guided SBRT. Overall, the study showed that both short-term and long-term toxicity were reduced with the use of aggressive margin reduction with MRI-guided SBRT compared with CT-guided SBRT.

Kishan is a professor and executive vice chair of radiation oncology at the University of California, Los Angeles.

For the MIRAGE trial specifically, we're going to continue following patients and we'll look at [data at] 5 years as well. What are the outcomes at that point? Sometimes these numbers seem arbitrary, but they are benchmark indicators within oncology: 2-year patient reported outcome toxicity and 5-year patient reported outcome toxicity and clinical outcome as well. That will be the next step for the MIRAGE patients specifically.

Our group and others do a lot of work on reducing toxicity. Things that we're looking at are, are there ways to do 2 mm margins with the CT-guided? We are actively looking into that as well. Are there ways to improve on even the MRI-guided with 2 mm, using something called adaptive radiotherapy, where we make changes to the radiation plan on a daily basis based on the patient's anatomy of the day; [that's] the next level of technology. We'll be looking at that also. And then finally, an area of interest of ours is, is there a way to predict which patients are genetically more prone to toxicity after radiotherapy? Obviously, that would be great to be able to identify that beforehand. We're working on that as well. These are what are called germline biomarkers of toxicity, and so we're evaluating those too.

This transcript was AI generated and edited by human editors for clarity.

"For the MIRAGE trial specifically, we're going to continue following patients and we'll look at [data at] 5 years as well," says Amar U. Kishan, MD. 

Amar U. Kishan, MD, highlights some of the implications of findings from the MIRAGE trial (NCT04384770), which compared the use of aggressive margin reduction with MRI-guided SBRT to standard CT-guided SBRT.

Amar Kishan, MD, on implications of MIRAGE trial data

, highlights some of the implications of the MIRAGE trial (NCT04384770), which compared the use of aggressive margin reduction with MRI-guided SBRT to standard CT-guided SBRT. Kishan is a professor and executive vice chair of radiation oncology at the University of California, Los Angeles.

There's a couple of ways to think about how this could move forward. One is, now we have data right that going from 4 mm margins to 2 mm margins, strictly speaking—the MRI allowed us to do that—reduces both short-term toxicity and long-term toxicity. One implication would be if there is an uptake in MRI-guided radiation, that would allow a seamless move from larger margins to smaller margins. Thinking a little bit more broadly, perhaps there may be technological advances, even in the CT-guided, that allow us going from a 4 mm to 2 mm without MRI-guided; that's possible as well. Strictly speaking, it was a trial of reducing the margin. We just used the advanced technology to be able to do that. I would say both there could be an increase in MRI-guided [SBRT] and there may be increase in investigation into shrinking margins with CT-guided SBRT as well. MRI-guided radiation is great. It does require an expensive MRI-guided linear accelerator. CT-guided linear accelerators are, at this point, more common. There, I think, will be parallel streams of research there.

I think another implication is that it's important to note that dropping short-term toxicity did lead to less long-term toxicity, which is intuitive to most people, but it is a controversial point in the field whether short-term toxicity is meaningful in and of itself, because it gets better. These results are supportive, as well as some work that'll be coming out in a month or so, that there is a link between early toxicity and late toxicity. If we can do things to minimize the short-term toxicity, that may very well pan out later, and that's ultimately what we want to do. Ultimately, we aren't concerned about just short-term toxicity. We want to make sure that the whole survivorship, patient quality of life, many years down the line is improved.

“I would say both there could be an increase in MRI-guided [SBRT] and there may be increase in investigation into shrinking margins with CT-guided SBRT as well,” says Amar U. Kishan, MD.

Amar U. Kishan, MD, shares the initial and 2-year outcomes from the MIRAGE trial, which compared the use of aggressive margin reduction with MRI-guided SBRT to standard CT-guided SBRT. 

Amar Kishan, MD, shares 2-year data on MRI-guided vs CT-guided SBRT

, shares the initial and 2-year outcomes from the MIRAGE trial (NCT04384770), which compared the use of aggressive margin reduction with MRI-guided SBRT to standard CT-guided SBRT. Kishan is a professor and executive vice chair of radiation oncology at the University of California, Los Angeles.

The primary end point was short-term toxicity. That was known several years ago at this point. About 2 years ago, we published our primary end point analysis in JAMA Oncology, which found a significant reduction in acute urinary toxicity and acute bowel toxicity with the use of the MRI to reduce margins. Essentially, we reduced acute GU toxicity, grade 2 or greater, from 43.4% to 24.4% and acute GI grade 2 or greater toxicity went from 10.5% to 0% in the MRI-guided arm. We also saw some benefits in patient-reported outcomes. So urinary toxicity, specifically, patients that had a large increase in their IPSS score, which is a marker of lower urinary tract symptoms, the proportion of patients that had a big increase in that was less, and the proportion of patients that had a significant decrease in EPIC quality of life bowel metrics was significantly less as well. That was the acute toxicity, the 3-month end point. This current manuscript, which came out a couple of months ago now in November, was looking at the 2-year patient reported outcomes, so touching a little bit more on one of the comments and criticisms of the earlier report, which was that it was just this short-term toxicity. Now we're looking at longer term toxicity. This was a pre-specified secondary analysis. We had always wanted to look at this, we just didn't power the trial to be able to look at these longer-term end points.

We looked at physician scored toxicity as well. We looked at something called cumulative incidence, which is if a patient has the toxicity at some point, that's counted as an event. Essentially, physician scored GU toxicity grade 2 or greater at 2 years now was 51% with the CT-guided and 27% with the MRI-guided, so a significant reduction there. And GI toxicity grade 2 or greater was 9.4% with CT-guided, and down to 1.4% with the MRI-guided, so significant benefits in late physician score toxicity.

We also looked at patient reported outcomes, as I mentioned. When looking at EPIC bowel domain scores, we looked at the odds of experiencing what's called 2x the minimal clinically [important] difference (MCID), which is well established in patient reported outcomes literature to be a clinically significant decrease in function if you have 2 times the MCID. We saw that the odds of having that were about 60% lower with the MRI-guided radiation. We also looked at this interval at sexual health outcomes; there's something called the SHIM score, the sexual health inventory for men. In that subgroup of patients who had evaluable scores for this—so these are the patients that didn't have androgen deprivation therapy or had a short course androgen deprivation therapy—there was an improvement as well. There was about a 63% decreased odds of a significant decrease in sexual functioning by patient reported outcomes in the patients who had the MRI- guided SBRT.

"Physician scored GU toxicity grade 2 or greater at 2 years was 51% with the CT-guided and 27% with the MRI-guided," says Amar U. Kishan, MD.

Amar U. Kishan, MD, highlights the rationale for the initiation and design of the MIRAGE trial, which compared the use of aggressive margin reduction with MRI-guided SBRT to standard CT-guided SBRT

Amar Kishan, MD, outlines the rationale for the MIRAGE trial 

, highlights the rationale for the commencement and design of the MIRAGE trial (NCT04384770), which compared the use of aggressive margin reduction with MRI-guided SBRT to standard CT-guided SBRT. Kishan is a professor and executive vice chair of radiation oncology at the University of California, Los Angeles.

When you're treating prostate cancer with definitive radiation, it's a highly effective treatment, but of course, one of the major concerns that patients and providers have is post-treatment toxicity. This arises from the organs that are close to the prostate when we're doing the radiation—that includes the bladder and the rectum and also the urethra, which is a tube that carries urine, running through the center of the prostate. All of these normal structures can get affected by the radiation leading to post-radiation toxicity. It's always an area of interest, from the radiation oncology standpoint to try to reduce the toxicity that's involved with radiotherapy.

Now, one important aspect that is intuitive but maybe not obviously apparent when you're treating the prostate with external radiation is you need to account for the fact that the prostate is a moving target. It moves side to side, up and down, front and back, about an average of 2 to 3 millimeters over a several minute time frame. Again, because of the close proximity to these critical structures, we want to make sure that we have a margin around the prostate to encompass that motion, but we don't want it to be so big that it's irradiating large portions of these nearby structures. It's very typical when we're delivering radiation to aim at the prostate with this margin around it but then use sophisticated imaging technologies to limit as best we can how big that margin needs to be. This is called motion management.

In the MIRAGE trial, what we looked at specifically was in the context of doing stereotactic body radiotherapy, which is a 5-day course of radiation for prostate cancer that already uses advanced technology to begin with. One group of patients had what we called CT-guided SBRT, which is our standard of care option that we had been delivering for over a decade at UCLA. Basically, these golden markers are placed into the prostate, and we use that as a proxy for the position of the prostate, and track those markers using an x-ray and a CT to help guide the radiation. We compared that approach with an MRI-guided radiation approach, where we used a newer MRI guided radiation device, linear accelerator, where patients were actually treated inside of an MRI tube. They're getting a continuous MRI, 4 frames per second. That's basically creating a movie that monitors the prostate itself and can start and pause radiation if the prostate is moving too much.

That was a 1:1 randomization, men getting CT-guided radiation and MRI-guided radiation. All the SBRT was 40 Gy in 5 treatments, 8 Gy per fraction, so high dose radiation. In the CT-guided arm, because of the type of monitoring that we were using for motion management, we'd used a 4 mm margin. So, the target plus a 4 mm margin. That's standard of care. If you look at other SBRT reports and ongoing SBRT trials, it's typically 5 mm margins, maybe reduced to 3 mm posteriorly in certain cases. But, 3-5 mm posteriorly; I think our 4 mm margin is well within that range. [In] the MRI-guided arm, that's where we leveraged the abilities of the machine to reduce that margin to 2 mm. So, 4 mm vs 2 mm.

The trial, then, was specifically looking at whether that aggressive margin reduction from 4 mm to 2 mm would lead to a reduction in physician-reported urinary toxicity, specifically in the first 90 days after radiation. A lot of people have asked me why was that the end point, as opposed to long-term urinary toxicity or long-term bowel toxicity, patient reported outcomes? Honestly, it was an issue of practicality. This was a single center randomized trial using a novel device that many other institutions, frankly speaking, had and were using, not on a trial. So, there was a small time window within which we could complete a trial like this in a single institution while we were still able to randomize between the 2 machines. We chose a toxicity that's common. Physician scored urinary toxicity within the first 90 days after radiation is fairly common, so we would be able to detect a difference.

Thankfully, radiation is pretty good when it comes to long-term toxicity. Though, I'm sure there'll be some discussion about that statement, but many men do quite well with radiation in the long-term. To be able to show a difference in long-term toxicity would have required a large multicenter trial with many fold more patients. That's just not practical. I think, to date, the MIRAGE trial, which has now finished accrual over 3.5 years ago, is the only randomized trial that looked at these 2 machines. So, I don't think it would have been practical to have a longer-term toxicity end point. It's also not something you can blind patients to, which is why it wasn't a blinded trial. And it was run in the height of the COVID pandemic, so there were some limitations in how frequently we could ask patients questionnaires and give them other things. We were able to eventually figure that out and do remote visits and electronic patient reported outcomes. But anyone who was practicing during that time knows that was a big shift to move to that format. So, we stuck with a hard end point—for us, physician scored toxicity—which was easy to do remotely if needed to.

“The trial was specifically looking at whether that aggressive margin reduction from 4 mm to 2 mm would lead to a reduction in physician-reported urinary toxicity, specifically in the first 90 days after radiation,” says Amar U. Kishan, MD.

Michael S. Cookson, MD, MMHC, FACS, touches on the current limitations of PSMA-PET imaging in prostate cancer. 

Michael Cookson, MD, on challenges with PSMA-PET imaging

, touches on some of the current limitations of PSMA-PET imaging in prostate cancer. Cookson, who is a professor and the Donald D. Albers Endowed Chair in Urology at the University of Oklahoma Health Sciences Center in Oklahoma City, is a co–editor in chief for Urology Times.

I think having the ability to monitor patients with imaging and using things like PSMA-PET is good, but yet we're we sometimes have pitfalls with PSMA-PET too. Patients can sometimes have false positives. Not everything that's small and shows up on a PSMA-PET is definitely metastatic disease, and some of these particularly low volume areas can be challenging to even get a diagnosis. An example would be a small isolated rib lesion that can also be a false positive. There's benign bone diseases such as Paget's disease, that can also show up in the pelvic area, for example, and lead to over-diagnosis of advanced cancer. So, you have to interpret it, of course, appropriately. But PSMA imaging is being used for staging patients with newly diagnosed advanced, high-risk disease, for locally advanced disease, for metastatic disease, and it's also being used in the monitoring. Then if you get further down the road with castration resistant cancer, and it can be used as the entry to deciding whether or not they be candidates for PLUVICTO, so theranostics. That's evolving too. So, it's an exciting time, and the imaging is really helpful, but it also needs to be interpreted, and then it can also be used in the treatment. There's a lot of ways in which we're learning to use it.

PSMA-PET imaging is a valuable tool in prostate cancer management, aiding in staging, monitoring, and treatment decisions. However, it has limitations, such as false positives, particularly in low-volume lesions, which can lead to over-diagnosis. Conditions like Paget's disease can mimic metastatic disease on imaging. Despite these challenges, PSMA-PET is crucial for assessing newly diagnosed advanced, high-risk, and metastatic prostate cancer. It also plays a role in evaluating candidates for theranostic treatments like PLUVICTO, highlighting its evolving role in prostate cancer care.

“I think having the ability to monitor patients with imaging and using things like PSMA-PET is good, but yet we're we sometimes have pitfalls with PSMA-PET too,” says Michael Cookson, MD. 

Eric Li, MD, shares the take-home message from The Journal of Urology paper “Clinical Factors Associated with Suspicious 18F-DCFPyL PSMA PET Activity in Patients Initially Managed with Radical Prostatectomy including PSA <0.5 ng/mL.” 

Expert: PSMA-PET should be considered at lower PSA levels

 paper “Clinical Factors Associated with Suspicious 18F-DCFPyL PSMA PET Activity in Patients Initially Managed with Radical Prostatectomy including PSA <0.5 ng/mL.” Li is a urology resident at Northwestern University Feinberg School of Medicine in Chicago, Illinois.

What are the next steps for this research?

I think the main question is, how does PSA-directed therapy and metastasis-directed therapy affect recurrent metastasis-free survival and survival outcomes eventually? There are a number of trials and a number of studies looking at that currently. I do think that that's going to be an important step. I think our paper is just kind of getting the word out there that these patients with low PSAs do have suspicious PSMA findings. But really, the question is going to be, how does this affect longer term outcomes? There are a lot of trials ongoing in the area, and the question is, can metastasis-directed therapy also potentially improve quality of life and maybe decrease the amount of androgen deprivation therapy that patients need? These are all questions that are currently be investigated with other studies.

What is the take-home message for the practicing urologist?

I think the main takeaway is just that we can consider PSMA-PET at lower PSA values, below 0.2, certainly below 0.5. There are potentially PSMA findings that would change your management in this situation. I do think it's important to also emphasize that a negative PSMA-PET should not delay salvage therapy such as salvage radiation. It's been shown that these patients should get salvage radiation. But, I think that urologists can use PSMA-PET, along with other factors such as PSA doubling time, pathology, and radical prostatectomy and maybe genomics to just counsel the patient and to really personalize their treatment plan.

The discussion centers on the implications of using PSMA-PET imaging in patients with low PSA levels post-radical prostatectomy. It highlights the potential of PSMA-PET to influence management decisions even at PSA levels below 0.5 ng/mL. The conversation also touches on the importance of not delaying salvage therapies based on negative PSMA-PET results. Ongoing research is exploring how PSA-directed and metastasis-directed therapies impact metastasis-free survival and overall outcomes, including quality of life and the necessity for androgen deprivation therapy.

Eric Li, MD, on “Clinical Factors Associated with Suspicious 18F-DCFPyL PSMA PET Activity in Patients Initially Managed with Radical Prostatectomy including PSA <0.5 ng/mL.” 

Eric Li, MD, on PSMA-PET imaging in men with low PSA levels

 describes the background and notable findings from the 

Please describe the background for this study.

We know that prostate cancer is the most common malignancy in men, and radical prostatectomy remains one of the primary treatments for patients with localized prostate cancer. In the US, we do about 90,000 radical prostatectomies every year. And as you were mentioning, prostate specific membrane antigen or PSMA PET has emerged as a superior modality, both for initial diagnosis before we decide what treatment we want to pursue, but also at the time of recurrence. So our paper focused on patients who got radical prostatectomy as their primary treatment for prostate cancer. Currently, there are limited data on low PSA values. Most of the trials only included patients above 0.2, and so we looked at PSAs below 0.2 and also PSAs below 0.5 just because there hasn't really been a lot of work done in that area.

As I mentioned, this was a retrospective cohort across the Northwestern system across our 11 hospitals for patients initially managed with radical prostatectomy. We had about 415 patients, and surprisingly, over half of them actually had a PSA value of below 0.5. We found that almost half of them had suspicious findings as defined by the radiologist, but also that the positivity rate for PSAs below 0.5 were around 35%, which is much higher than we thought it would be. We looked at what factors were associated with the suspicious PSMA activity, and for the cohort that was below PSA 0.5, we found that prior postoperative radiation was associated with PSMA positive findings. Now, when you look at the entire cohort, we found that age, Gleason grade at radical prostatectomy, and PSA at PSMA-PET were all associated as well.

And then we did a series of sensitivity analyses looking at various risk stratification tools such as PSA doubling time. We used a nomogram called the CAPRA-S, which has been previously published on, as well as the EAU risk stratification that's also been previously published. Those were all associated with suspicious PSMA activity. The part that really excites me is, well, how does this change patient management? And we looked at, of those with suspicion for metastatic disease, how many of those people received metastasis-directed therapy, and we found that about 40% in the overall cohort and about half of patients with PSA below 0.5 actually received metastasis-directed therapy where it changed the radiation plan and radiation field. So to me, that's really the most exciting part about this work.

The study investigates the use of PSMA PET imaging in prostate cancer patients post-radical prostatectomy, focusing on those with PSA levels below 0.5 ng/mL. It reveals that a significant portion of these patients exhibit suspicious PSMA activity, with a positivity rate of 35%. Factors such as prior postoperative radiation, age, Gleason grade, and PSA levels are associated with suspicious findings. The study highlights the impact of PSMA PET on patient management, with a notable percentage receiving metastasis-directed therapy, altering radiation plans and fields.

"We found that almost half of them had suspicious findings as defined by the radiologist, but also that the positivity rate for PSAs below 0.5 were around 35%," says Eric Li, MD.

Jitesh Dhingra, MD, FRCEM, discusses current and future research directions in the field of PSMA-PET imaging for prostate cancer. 

Expert shares anticipated research directions for PSMA-PET in prostate cancer

 discusses current and future research directions in the field of PSMA-PET imaging for prostate cancer. Dhingra is an attending nuclear medicine physician at Allegheny Health Network in Pittsburgh, Pennsylvania.      

What are the current and future research directions in the field of PSMA-PET imaging for prostate cancer, and what advancements can we expect in the coming years?

The tracer that is probably going to be coming soon is called Posluma. Once we have Posluma, which is also a PSMA-based tracer, we'll have a better assessment of patients who will be benefiting from PSMA-based therapies like Lutetium-based theranostics. That's one big thing that I'm looking forward to. The other thing that I think is going to be really, really helpful is the utility of dosimetry. At this point of time, we are not doing dosimetry on any of our patients, but once we start using Posluma, we'll get a better assessment of what lesions and tumor sites are present in a patient, and we'll be able to use and translate that information toward dosimetry and directing our theranostic or PSMA-based therapies in a much more precise manner. That's another thing. The third thing I'm already currently working on clinical trials with these patients is that we are trying to use PSMA-based therapies in an adjuvant setting. So patients who have prostate cancer with a highly aggressive variant, we are using PSMA-based therapies in an adjuvant setting much earlier to even using chemotherapy at this point of time. That's another area that we are very excited about. There are many more things that I can keep talking about, but I would basically look at these 3 things as the major things to be coming up.

The field of PSMA-PET imaging for prostate cancer is advancing with the introduction of new tracers like Posluma, which will enhance patient assessment for PSMA-based therapies such as Lutetium-based theranostics. The integration of dosimetry is anticipated to improve the precision of these therapies by accurately identifying lesions and tumor sites. Additionally, clinical trials are exploring the use of PSMA-based therapies in an adjuvant setting for aggressive prostate cancer variants, potentially preceding chemotherapy. These developments represent significant progress in prostate cancer management.

"I would basically look at these 3 things as the major things to be coming up," says Jitesh Dhingra, MD, FRCEM.

Jeremie Calais, MD, PhD, highlights the background and key findings from the study, “Phase 2 trial of PSMA PET CT versus planar bone scan and CT in prostate cancer patients progressing while on androgen deprivation therapy"

Jeremie Calais, MD, highlights study of PSMA-PET vs bone scan in metastatic prostate cancer

, highlights the background and key findings from the study, “Phase 2 trial of PSMA PET CT versus planar bone scan and CT in prostate cancer patients progressing while on androgen deprivation therapy,” (NCT04928820), for which he served as the senior author. Calais is a nuclear medicine physician at the University of California, Los Angeles.

Bone scan or bone scintigraphy is the main standard of care imaging method for decades to stage metastatic prostate cancer patients. The bone tropism of metastasis from prostate cancer made that bone scan was the method of choice. Bone scan is an indirect imaging method to detect prostate cancer metastasis because it detects the surrounding reaction of the bone, around the bone metastasis, but still using indirect methods. It was used for again, decades, with some strong correlation to outcomes with the Prostate Cancer Working Group Criteria 2+2 rules.

PSMA-PET has been in the landscape of prostate cancer staging now for about 5 to 10 years. So, [there is] a lot about how do we convert and translate from bone scan to PSMA-PET staging? Depending on the patient population, you will have different answers. In the primary staging setting, untreated disease, biochemical recurrence setting, for sure PSMA-PET scan has a lot of superiority of a bone scan. Much more specific, much more accurate. There is a lot of false positive findings on the bone scan. When the prevalence of the metastases is low, such as in the untreated disease stage, early disease, biochemical recurrence, hormone sensitive, you have a lot of false positive findings.

Now when you move to the more advanced patient population, metastatic castration-resistant, for example, then of course the prevalence of bone metastasis is much higher. So, the specificity of the bone scan increases, specifically on a per patient basis. So, that study was an attempt to answer to that question. How do these 2 imaging modality compare to stage metastatic prostate cancer patients who are progressing under hormonal treatment, getting castration-resistant. So, it's an early mCRPC disease stage that we choose here. These are not the super late stage advanced, and we wanted to see how these 2 scans compare.

At the time of the study design, PSMA-PET was not yet FDA approved, so it was an incentive for patients to get a PSMA-PET scan. They could get into the study if they would do also a pair bone scan within 2 weeks of the PSMA-PET. So, it enabled to recruit patients. But during the trial, PSMA-PET got FDA approved, so it got widely available to patients that could get it covered by insurances. At some point there was much more difficulty to recruit patient to the trial because they don't need to do a bone scan, they don't want to do specifically a research trial, they can just get the scan as first-line of care. So, we had to terminate the trial early, instead of having 100 patients—that was the initial study design. The initial study design was based on the hypothesis that there would be a 35% detection rate with PSMA-PET/CT vs bone scan/CT 23% detection rate.

In fact, the 2 imaging modalities were deemed quite equivalent in the study. I'm going to go back on that, but we had to end the study at 20 patients instead of 100. So, the study was underpowered because of difficulty to recruit patients. Also, we were able to show that in the first 20 patient sample we had, the statistical signal that we got would have probably made the study impossible to succeed in terms of detection rate difference because bones scans and PSMA-PET in that specific patient subset performed quite equivalently on a per patient basis. There was no patient with bone scan positive and PSMA-PET negative detection rates, and there was no patient with PSMA-PET positive and bone scan negative detection rates.

Both scans were read by 3 imaging blinded readers. We used 3 blinded readers for the bone scan reads, different than the 3 imaging readers for the PSMA-PET/CT reads. We used a majority score for each imaging modality, 2 vs 1 in case of disagreement. That's the result; at the end there was no major difference observed on a patient level. On a lesion level, there were still more lesions detected with PSMA-PET, but not on a patient level. So, because of that absence of sign of [a statistical difference,] even in the first 20 patient data sets, [and] because of the difficulty to recruit patients after FDA approval, we terminated the study early at 20 patients instead of 100, and that's what we reported here.

The study compared PSMA PET/CT and planar bone scan/CT in prostate cancer patients progressing on androgen deprivation therapy. Historically, bone scans have been the standard for detecting bone metastases, but PSMA-PET offers greater specificity and accuracy, especially in early-stage disease. The trial faced recruitment challenges after PSMA-PET received FDA approval, leading to early termination with only 20 patients instead of the planned 100. Results showed no significant difference in detection rates between the two modalities on a per-patient basis, though PSMA-PET detected more lesions overall.

“On a lesion level, there were still more lesions detected with PSMA-PET, but not on a patient level,” says Jeremie Calais, MD, PhD. 

Michael S. Cookson, MD, MMHC, FACS, touches on the current and future applications of PSMA-PET imaging in prostate cancer.

Michael Cookson, MD, on potential future applications of PSMA-PET

, touches on the current and future applications of PSMA-PET imaging in prostate cancer. Cookson, who is a professor and the Donald D. Albers Endowed Chair in Urology at the University of Oklahoma Health Sciences Center in Oklahoma City, is a co–editor in chief for 

I think about the patients with say, radiation-recurrent disease, we usually get an MRI of their pelvis, and then we get a complimentary PSMA-PET for staging, but it's also showing us disease in the primary as well. In some ways, it can be used to help if you want to get a biopsy to prove or confirm—it can be used to help detect in that range, too. That's a new area. We're not quite to the point—we don't omit the biopsy currently. We still get a piece of tissue from that primary prostate if it does look like it's recurred. But it's starting to be to the point where, when you have an MRI lesion, say, post-radiation, with a rising PSA, and it correlates with the PET scan, then that disease is, for the most part, very real, and it's just confirmed with a biopsy, but you already knew it was there. Stay tuned on that. We're still using tissue to kind of make decisions on treatment in that setting.

“In some ways, it can be used to help if you want to get a biopsy to prove or confirm—it can be used to help detect in that range, too,” says Michael S. Cookson, MD, MMHC, FACS. 

Jeremie Calais, MD, PhD, highlights the key components of the report, “Standardized template for clinical reporting of PSMA PET/CT scans.” 

Jeremie Calais, MD, highlights key elements of PSMA-PET reporting template

, highlights the key components of the report, “Standardized template for clinical reporting of PSMA PET/CT scans.” Calais is a nuclear medicine physician at the University of California, Los Angeles.

It's a table, basically, with boxes. It encompasses and contains the miTNM, PROMISE, PRIMARY, RECIP, PSMA-RADS, and E-PSMA concept and criteria all together. On this you have the relevant prostate cancer history, the indication for the scan, primary staging, BCR, PSMA expression assessment before PSMA targeted therapy, some technical parameters that are important, date of scan, the comparison to prior scans, the treatments the patient is on at the time of the scan, [and] how the CT was made. Then some measurement in the salivary glands, in the liver for tumor to background ratio assessments. Then you go by TNM staging. So, you start from the prostate. Both sides, we divided by left, right, apex, midline-based, anterior, posterior. You can check boxes wherever you see uptake or you find suspicious uptake. Number of lesions, seminal vesicles, then the pelvic lymph nodes, extra pelvic lymph nodes, bone metastasis, 1- 2- 3- oligo vs poly, visceral metastasis, the presence or absence of PSMA-negative lesion noted on CT. All that are all summarized into a table that I personally find quite nice to use. These are the main parameters that you can find in these templates.

“It encompasses and contains the miTNM, PROMISE, PRIMARY, RECIP, PSMA-RADS, and E-PSMA concept and criteria all together,” says Jeremie Calais, MD, PhD. 

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