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Clinical Focus

Howard I. Scher, MD; Scott T. Tagawa, MD, MS, FACP; Mary-Ellen Taplin, MD

Medical Crossfire®: How Does Recent Evidence on PARP Inhibitors and Combinations Inform Treatment Planning for Prostate Cancer Now and In the Future?

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

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

Articles

The agency approved the first PSMA-targeted PET imaging drug for men with prostate cancer.

FDA approves Gallium 68 PSMA-11 for prostate cancer

EMPIRE-1 is the first randomized trial to demonstrate an improvement in failure-free survival with treatment based on advanced molecular imaging versus conventional imaging in men with recurrent prostate cancer.

Radiotracer fluciclovine (18F) PET leads to improved cancer control in recurrent prostate cancer

The imaging modality detected nodal metastasis with a sensitivity of 55.3% and a specificity of 84.8% in each patient.

18F-fluciclovine PET/CT accurately detects metastases in high-risk prostate cancer

, 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 

, or anywhere that podcasts are available.

"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

The trial is evaluating the diagnostic performance of copper Cu 64 PSMA I&T PET/CT in men with suspected biochemical recurrence of prostate cancer following treatment with curative intent.

Enrollment goal met in phase 3 SOLAR-RECUR trial 

The primary objective is to compare the detection rate of sites of prostate cancer recurrence between the 2 agents. 

Head-to-head trial to compare 64Cu-SAR-bisPSMA and 68Ga-PSMA-11 PET/CT 

The phase 1/2a SECuRE trial is evaluating the safety and efficacy of 67Cu-SAR-bisPSMA in the treatment of patients with mCRPC.

Collaboration to support phase 3 SECuRE trial of 67Cu-SAR-bisPSMA

The sensitivity of 99mTc-sestaMIBI SPECT/CT was 97%, and the specificity was 53.8%. 

Study to inform definitive trial of 99mTc-sestaMIBI SPECT/CT for T1 renal tumors

The revised policy will take effect on January 1, 2025. 

CMS adjusts reimbursement for diagnostic radiopharmaceuticals

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 

 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.

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.

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

Videos

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. 

Bridget F. Koontz, MD, FASTRO, discusses the integration of PSMA-PET findings into radiation treatment planning.

Bridget Koontz, MD, on PSMA-PET’s impact on treatment planning

, discusses the integration of PSMA-PET findings into radiation treatment planning. Koontz is radiation oncologist and the medical director of radiation oncology programs at AdventHealth Cancer Institute in Orlando, Florida.

PET for prostate cancer specifically, so markers that highlight prostate recurrence, have really changed the way we treat prostate cancer. As a radiation oncologist, we're sort of surgeons without the knife. We need that imaging. We aim the radiation beam at targets that we see on CT and PET-based imaging. For us, being able to know where the cancer is allows us to target it, and I think that lets us be much more effective with our treatment.

There was actually a study done at Emory, where they looked at radiation after prostatectomy based on what we've done over the years––looking at the tumor markers and looking at the stage based on pathology and the PSA––and compared that to guide-designed radiation based on a PET result. They found that the PET result improved progression-free survival, even considering that some men were found to have metastatic disease and not treated at all. What that suggests is that if we know where we're treating, we can fine tune the radiation and be much more effective with our treatment options.

We're using it now for diagnosis in high-risk disease, so that we're not operating or focusing just on the prostate when it turns out they have a lymph node involved. Then we're using it if they recur after original treatment to make sure we're effective with the secondary treatment, like the study for GU-011. Then, even being able to understand in the metastatic space, which patients might still benefit from radiation vs which really need a more aggressive systemic therapy. So, it's helped us across the board.

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

The integration of PSMA-PET imaging has significantly transformed prostate cancer treatment by enhancing the precision of radiation therapy. This advanced imaging allows radiation oncologists to accurately target cancerous areas, improving treatment efficacy. A study at Emory demonstrated that PET-guided radiation post-prostatectomy improved progression-free survival compared to traditional methods. PSMA-PET is now utilized for diagnosing high-risk disease, assessing recurrence, and determining treatment strategies in metastatic cases. This approach aids in distinguishing patients who may benefit from radiation versus those requiring systemic therapy.

“For us, being able to know where the cancer is allows us to target it, and I think that lets us be much more effective with our treatment,” says Bridget F. Koontz, MD, FASTRO.

Jitesh Dhingra, MD, FRCEM, discusses the impact of prostate-specific membrane antigen (PSMA)-PET imaging in prostate cancer.

Jitesh Dhingra, MD, FRCEM, on PSMA-PET imaging’s impact on treatment decisions in prostate cancer

 discusses the impact of prostate-specific membrane antigen (PSMA)-PET imaging in prostate cancer. Dhingra is an attending nuclear medicine physician at Allegheny Health Network in Pittsburgh, Pennsylvania.

How does PSMA-PET imaging impact treatment decisions for patients with prostate cancer, and can it help guide therapy options?

This is basically another [area where PSMA supersedes other imaging]. As I said earlier, PSMA is prostate-specific membrane antigen. So it is basically targeted to prostate cancer cells. When we are using different modalities, we are trying to look for PSMA expression going up or down, and seeing whether the PSMA expression is going down, does that mean response to treatment? Now, having said that, there are multiple studies done, and I'll just give you a brief summary of how studies are being done is that if, whenever we are using androgen deprivation therapy, which is basically like the first line of treatment for patients with prostate cancer, because whenever the prostate cancer is detected, they get a prostatectomy, they get radiation, and are eventually placed on androgen deprivation therapy. Androgen deprivation therapy is supposedly going to lead to an over expression of PSMA in the first 6 months, which is also known as a flare response. But after 6 months of using the same androgen deprivation therapy, we will start seeing a reduction in PSMA levels. Once we start seeing that reduction in PSMA levels, that basically confirms that our treatment is going in the right direction. But instead, if, even after like, 6 months of using androgen deprivation therapy, the PSMA expression keeps going up, that is basically a time for the oncologist or urologist to say, this is time for me to change treatment, because this treatment doesn't seem to be working at this point of time. That's just for androgen deprivation therapy. Now the second thing that was the utility of Pluvicto. So when we are using radionuclide therapies, which are lutetium-based PSMA therapies, we should expect the PSMA expression to go down every time we treat them. But there are patients where I personally have had a decent amount of patients where we are treating patients with Pluvicto, and there are patients where the PSMA expression keeps going up, so now PSMA expression, if it keeps going up on Pluvicto treatment may be a situation and a discussion for the oncologist, urologist, as well as the nuclear medicine physician, to come to a point where they may think, okay, the PSMA is going up with giving Pluvicto. I should start thinking about stopping treatment or trying to do other diagnostic imaging at this point of time. Now, PSMA expression can also go down during Pluvicto. When it goes down, it is usually considered a reassuring step that the patient is getting treated. But then also, I would also like to introduce here another thing that the urologist and the oncologist should be aware of, which is that PSMA expression coming down on Pluvicto doesn't always mean that the patient is doing well. It could also mean that the patient is undergoing neuroendocrine differentiation of prostate cancer, and that's basically where our imaging modalities of clubbing PSMA paired with CT come into the picture, and we just come to a decision that this patient is not progressing on imaging, PSMA expression is coming down, so this means that the patient is doing well vs PSMA expression is coming down, but the patient is progressing on imaging, so I'm concerned about neuroendocrine differentiation, and I need to do other imaging or tissue relation.

PSMA-PET imaging significantly influences treatment decisions in prostate cancer by monitoring PSMA expression levels. Initially, androgen deprivation therapy may cause a PSMA flare, but a subsequent decrease indicates effective treatment. Conversely, persistent PSMA elevation suggests treatment inefficacy, necessitating a change. In radionuclide therapies like Pluvicto, decreasing PSMA levels are reassuring, but persistent elevation requires reevaluation. However, a decrease in PSMA during Pluvicto treatment might also indicate neuroendocrine differentiation, necessitating further imaging to confirm disease progression or response.

Dhingra discusses the utility of PSMA-PET imaging when treating patients with prostate cancer.

Jitesh Dhingra, MD, FRCEM, discusses the sensitivity and specificity of prostate-specific membrane antigen (PSMA)-PET imaging in prostate cancer

Expert on sensitivity and specificity of PSMA-PET in prostate cancer

 discusses the sensitivity and specificity of prostate-specific membrane antigen (PSMA)-PET imaging in prostate cancer. Dhingra is an attending nuclear medicine physician at Allegheny Health Network in Pittsburgh, Pennsylvania.

How sensitive and specific is PSMA-PET in detecting recurrent prostate cancer, particularly in patients with a rising PSA level but negative conventional imaging?

This is basically where PSMA-PET imaging supersedes any other modality. When we are treating prostate cancer, some patients get radiation, some patients get prostatectomy. In patients with prostatectomy, there are different cut-off levels for PSMA positivity with a PSA level. In patients who have had a prostatectomy, they usually have a low PSA level. They have a PSA below 1 ng/mL. Now in these patients, detecting an MRI abnormality becomes a challenge, and this is where PSMA-PET is basically [superior]. [That is] because even at molecular level, at a PSA of less than 1, PSMA-PET is able to detect lesions, which MRI may be missing at this point of time, and that's basically where many studies have been done, and they have come to an algorithm where the sensitivity of PSMA-PET with the PSA level of less than 1, is somewhere in the range of 60% and in PSA above 2, the sensitivity is almost in the range of 95% to 97%, so that means that above 2 and between 2 to 5, a PSA level can be detected with positive PSMA imaging, which may be missed on MRI.

PSMA-PET imaging demonstrates superior sensitivity and specificity in detecting recurrent prostate cancer, especially in patients with rising PSA levels and negative conventional imaging. It is particularly effective in post-prostatectomy patients with low PSA levels, where MRI may fail to identify abnormalities. PSMA-PET can detect lesions at a molecular level, with sensitivity ranging from 60% for PSA levels below 1 ng/mL to 95-97% for PSA levels above 2 ng/mL. This makes it a valuable tool in identifying prostate cancer recurrences that might be missed by MRI.

Jitesh Dhingra, MD, FRCEM, outlines advantages of prostate-specific membrane antigen (PSMA)-PET imaging compared with conventional imaging methods. 

Jitesh Dhingra, MD, FRCEM, on the advantages of PSMA-PET in prostate cancer

 outlines advantages of prostate-specific membrane antigen (PSMA)-PET imaging compared with conventional imaging methods. Dhingra is an attending nuclear medicine physician at Allegheny Health Network in Pittsburgh, Pennsylvania.

What are the specific advantages of PSMA-PET imaging over conventional imaging methods in the diagnosis and staging of prostate cancer?

This is a very exciting time for nuclear medicine and molecular medicine. Basically, PSMA stands for prostate-specific membrane antigen. When we are using PSMA, we are actually able to image specific cells which should have prostate cancer in them, under the camera. This is basically where PSMA imaging is superseding any other imaging modality like CT or MRI, because we are at the molecular level, figuring out where the prostate cancer cells are, and ideally, molecular medicine usually precedes radiology. So whenever you have prostate cancer cells enough to express PSMA, you start seeing it, but you may not even see a CT or MRI abnormality at that time. There have been many studies done about sensitivity and specificity comparisons between PSMA and PSMA-PET/CT and MRI, and they have come to a conclusion that utility of PSMA-PET/CT and MRI usually come and meet together in numbers, but PSMA is superseding MRI in many other areas. For example, like when we are using PSMA-PET/CT for patients with the recurrent prostate cancers...the sensitivity of PSMA is around about 86% with the PSA level of above 2 nanograms per ml, but above 5, the sensitivity actually goes higher and is like 97%. The specificity, on the other hand, for recurrent disease and prostate cancer is pretty high. It is in the ranges of 95% to 97% in multiple studies. It's difficult to give a number because there are so many studies that have been done, but the numbers are pretty reassuring with the sensitivity and specificity of about 90% in recurrent prostate cancers. Overall summary sensitivity and specificity of PSMA in patients with initial staging as well as recurrent disease is again in the range of 85% to 90%, which is again a pretty good number, and it's pretty comparative to MRI.

PSMA-PET imaging offers significant advantages over conventional imaging methods like CT and MRI in diagnosing and staging prostate cancer. It allows for molecular-level imaging, identifying prostate cancer cells before abnormalities appear on CT or MRI. PSMA-PET/CT demonstrates high sensitivity and specificity, particularly in recurrent prostate cancer cases, with sensitivity reaching up to 97% and specificity between 95% to 97%. These metrics are comparable to MRI, but PSMA-PET often surpasses MRI in certain areas, making it a valuable tool in nuclear and molecular medicine.

"This is a very exciting time for nuclear medicine and molecular medicine," says Jitesh Dhingra, MD, FRCEM.

Shyam Natarajan, PhD, discusses future research involving Unfold AI. 

Next steps in research for AI prostate cancer mapping

 discusses future research involving Unfold AI. He is an author of the recent 

study, “Extracapsular extension risk assessment using an artificial intelligence prostate cancer mapping algorithm.” Natarajan is the founder and CEO of Avenda Health.

What are the next steps in developing and refining AI-generated cancer maps for prostate cancer?

[Although] we were very excited about the finding in this study showing that Unfold AI could be superior to MRI in detecting extracapsular disease, our next step is to validate this in a multi-institutional, prospective manner. [Although] Unfold AI was trained on multi-institutional data, this particular study was concerning a single institution's experience, and so the next research phase for AI cancer maps and technologies like Unfold AI really is to understand, now we have a way to map prostate cancer, sort of within and potentially around the prostate, what other types of correlates or covariates can we predict? Can we predict biochemical recurrence? Can we predict long-term success or failure? I think those are very fruitful avenues of research.

This is exciting because Unfold AI is one of the first multimodal AI systems for patients with prostate cancer. I think it's a testament to our collaborators and the senior author of the study, Dr. Wayne Brisbane, of being able to acquire a very robust and large data set to perform this kind of unique analysis, because typically, AI-based systems use consensus panels of experts as their sort of final ground truth or gold standard, and that can only show you, are you as good as an expert clinician? Whereas in this study and other studies of this nature, we actually use the surgical pathology, sort of the ground truth, tissue information as our gold standard, showing that we could potentially be superior to the standard of care.

"[Although] we were very excited about the finding in this study showing that Unfold AI could be superior to MRI in detecting extracapsular disease, our next step is to validate this in a multi-institutional, prospective manner," says Shyam Natarjan, PhD. 

Shyam Natarajan, PhD, shares how Unfold AI compares with other AI-based tools that are currently available for prostate cancer detection and staging

How Unfold AI compares with other AI-based tools in prostate cancer

 shares how Unfold AI compares with other AI-based tools that are currently available for prostate cancer detection and staging. He is an author of the recent 

How does Unfold AI compare to other AI-based tools that are currently available for prostate cancer detection and staging?

Other AI-based algorithms and systems typically happen earlier in the diagnostic process. They either are applied on an MRI alone in the early screening or diagnostic stage, or in the later stage, when patients need to understand what is the 10-year risk of developing metastases. There are a number of AI generated tests that support that. But in the period where a patient receives a diagnosis of favorable intermediate-risk cancer or higher and doesn't know what to do, there is a big unmet need/gap that we aim to serve with Unfold AI. The advantage of bringing in multiple kinds of data, like imaging, pathology, prostate fusion biopsy, PSA and other clinical factors, we see that multimodal approaches can actually be much more powerful than just looking at 1 parameter alone.

“In the period where a patient receives a diagnosis of favorable intermediate-risk cancer or higher and doesn't know what to do, there is a big unmet need/gap that we aim to serve with Unfold AI,” says Shyam Natarajan, PhD.

Dr Natarajan on “Extracapsular extension risk assessment using an artificial intelligence prostate cancer mapping algorithm.”

Unfold AI shows efficacy for predicting ECE risk in prostate cancer

The motivation for this research was that today, in determining prostate cancer that goes beyond the prostate, specifically, extracapsular, extraprostatic disease, is typically identified prior to surgery with MRI. And there are some other novel imaging technologies that could potentially be used to identify ECE, as well as a number of nomograms and risk calculators that have been out there. And so with the AI technology that we had developed Unfold AI, it reveals a clinically significant disease extent within the prostate. There was a hypothesis of, could this be used to calculate risk or understand how disease actually spreads beyond the prostate compared with MRI, and so we performed a retrospective study on, ultimately, 147 patients after patients were screened out, to compare how Unfold AI could predict performance the presence of extracapsular disease vs MRI and some of these other risk calculators and advanced imaging like PSMA PET.

We actually found something very exciting with this study. First of all, the performance of MRI is quite good at detecting extracapsular disease. However, we know that MRI, just imaging alone has limitations in finding disease that typically is invisible surrounding the central focus of the lesion. And so the finding here was that not only was Unfold AI superior in terms of the area under the curve or a measure of sensitivity-specificity compared with MRI, it was also superior to all of these other nomograms and risk calculators and advanced imaging tests, albeit with a smaller sample size. But the most exciting finding was that when we looked at prediction of extracapsular disease on a quadrant-by-quadrant basis, understanding that most of the most prostate cancers happen in the peripheral zone. And so we wanted to look at the performance of the peripheral zone vs the anterior prostate. We found that the performance of Unfold AI was actually an AUC of .89. This is one of the highest detection performance criterion that we've seen in the literature. But it was also superior to MRI, notably finding basically reducing false negatives over MRI by half.

"We found that the performance of Unfold AI was actually an AUC of .89," says Shyam Natarajan, PhD.

Jason Hafron, MD, describes the impact of PSMA-PET on the management of oligometastatic prostate cancer

Jason Hafron, MD, on PSMA-PET in oligometastatic disease

, explains how PSMA-PET has enabled the use of more targeted treatment approaches in the management of oligometastatic prostate cancer. Hafron is the chief medical officer and medical director of clinical research of Michigan Institute of Urology.

PSMA-PET is very helpful in the oligometastatic space. It identifies tumor location. And in my practice, we've identified disease where we could offer radiation therapy in combination with ARPI or without ARPI and ADT, so it allows us to do stereotactic. I've definitely developed a closer relationship with our rad oncs. And before, where we would just consider systemic disease, systemic disease, we've looked at, can we do metastasis-directed therapy and apply and look at the disease differently. The data on metastasis-directed therapy is still developing. It's not fully mature, but in our practice, we found it very impactful. Time will tell as we move forward, but it has allowed us to use MDT, with or without ADT and ARPIs, to potentially look at hormone-free treatments.

PSMA-PET imaging has significantly advanced the management of oligometastatic prostate cancer by enabling more precise treatment strategies. It facilitates the identification of tumor locations, allowing for the application of metastasis-directed therapies (MDT) such as stereotactic radiation, potentially in combination with androgen receptor pathway inhibitors (ARPIs) and androgen deprivation therapy (ADT). Although the data on MDT is still evolving, its integration into clinical practice has shown promising results. This approach may lead to hormone-free treatment options, fostering closer collaboration between urologists and radiation oncologists.

“Time will tell as we move forward, but it has allowed us to use MDT, with or without ADT and ARPIs, to potentially look at hormone-free treatments,” says Jason M. Hafron, MD, CMO. 

Jason M. Hafron, MD, discusses the impact of PSMA-PET imaging on prostate cancer management

Jason Hafron, MD on the disruptive nature of PSMA-PET imaging

, discusses the impact of PSMA-PET imaging on prostate cancer management. Hafron is the chief medical officer and medical director of clinical research of Michigan Institute of Urology.

PSMA-PET imaging is disruptive technology. It's been out for a couple of years now, and it's really changed how we treat this disease. It's changed how we look at this disease, how we intervene. It's a very powerful tool. It's a very exciting tool to use in the clinic. When I use this, the indications are pretty clear. There's basically 2 indications. One is in patients with localized disease. So, the newly diagnosed patient. If they have a grade group 3 or higher, 4 plus 3 equals 7 Gleason score, they qualify for a PET scan. My practice, I try to get all these patients PSMA-PET scans if they if they're 4 plus 3 or higher. We're finding disease when we wouldn't expect disease, and it really helps us identify patients that are candidates for local therapy or may not qualify for local therapy. And you look at most of the trials that were done in this space, about 2/3 of time, over 60% of time, management was changed based on a PET scan. I think we're seeing that in the real world.

The other great indication for PET scanning is a biochemical recurrence or progression of disease. Again, it's the best tool we have to find cancer. It's our best tool to stage the cancer, and when I say it changes our disease, we will identify potential targets for radiation therapy. It will identify micro-metastatic disease and appropriately stage these patients so we can appropriately treat these patients. So, PET imaging is amazing. It's here to stay. We're going to see in the next year or 2, some different agents that are even better, that have longer half-lives, that are more specific and higher affinity. So, I think this space is just going to blossom and continue to grow, which is great for our patients.

PSMA-PET imaging has significantly transformed prostate cancer management by enhancing disease detection and intervention strategies. It is particularly beneficial for patients with localized disease, especially those with a Gleason score of 4+3 or higher, and for cases of biochemical recurrence or disease progression. The imaging technique has led to changes in management in over 60% of cases, aiding in the identification of candidates for local therapy and staging of micro-metastatic disease. Future advancements in PSMA-PET agents promise even greater specificity and efficacy.

“And you look at most of the trials that were done in this space, about 2/3 of time, over 60% of time, management was changed based on a PET scan,” says Jason Hafron, MD.  

Bridget F. Koontz, MD, FASTRO, highlights the role that PSMA-PET imaging has played in enabling more targeted treatment for prostate cancer

Dr. Koontz on how PSMA-PET improves targeted treatment strategies

, highlights the role that PSMA-PET imaging has played in enabling more targeted treatment for prostate cancer. Koontz is radiation oncologist and the medical director of radiation oncology programs at AdventHealth Cancer Institute in Orlando, Florida.

The main thing is that prior to PET, we would know that there was cancer because the PSA would rise after treatment, but we didn't know where it was. What that meant is there were times where we would say,"Well, based on the clinical data that I have––based on the prostatectomy report, or your Gleason score, or the timing that it took for the PSA to recur––I think that it is most likely in this spot. It's in your prostate bed. It's in your pelvic lymph nodes." We would say, "We don't know for sure, but do you want us to give a go and try?" And actually, that's what I did for many years; that was the data we had at the time.

Nowadays with PET, it's not perfect, but even with a PSA less than 1 ng/mL, we can detect the site of recurrence about 2/3 of the time. So, that means that in 2/3 of those men, rather than treating broadly with best guess, we're able to specifically target. SBRT is a type of radiation that is very tightly focused. I'll be honest, I don't always use SBRT. Sometimes, if it's in a pelvic node, for example, I want to treat the other nodes, because if it's in that node, how did it get there? It probably traveled up the lymph node chain, and there might be other lymph nodes involved. So, I tend to treat a little bit broader. We're still getting more thoughtful about what we know about cancer [and] what we know about how prostate cancer progresses, but it has allowed us to be more targeted and more patient-specific with the treatment. That, I think, has created a whole new stage for patients. You used to have limited stage or metastatic disease, and now there's this limited volume of recurrent oligometastatic. That's where the oligometastatic came from, is the fact that we can now find the cancer before it has spread broadly.

PSMA-PET imaging has significantly advanced prostate cancer treatment by enabling more precise targeting of recurrent disease sites, even with low PSA levels. Previously, treatment decisions were based on clinical data and educated guesses. Now, PSMA-PET allows for more accurate localization of cancer recurrence, facilitating targeted therapies like SBRT. While not perfect, this imaging technique has improved the ability to tailor treatments to individual patients, leading to the identification of oligometastatic disease stages. This advancement has transformed the management of prostate cancer, offering more personalized and effective treatment options.

“Nowadays with PET, it's not perfect, but even with a PSA less than 1 ng/mL, we can detect the site of recurrence about 2/3 of the time,” says Bridget Koontz, MD. 

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