Navigating the Landscape of PSMA PET Imaging Agents in Prostate Cancer

The experts

Prostate-specific membrane antigen (PSMA) PET imaging has revolutionized the detection and management of prostate cancer, particularly in recurrence settings. A recent Around the Practice that took place during the 2025 American College of Radiation Oncology Summit focused on the evolution of PSMA PET agents, starting with the earlier metabolic tracer fluciclovine F 18 (Axumin). Panelists then spoke about gallium-68 PSMA-11 (Illuccix, Locametz) and the fluorine–18 (F 18) labeled agents piflufolastat F 18 (Pylarify) and the more recently approved flotufolastat F 18 (Posluma).

The panel was led by Jason Efstathiou, MD, DPhil, professor of radiation oncology at Harvard Medical School, vice-chair of faculty and academic affairs, director of the Genitourinary Service in the Department of Radiation Oncology, and clinical codirector of The Claire and John Bertucci Center for Genitourinary Cancers at Massachusetts General Hospital.

He was joined by Brandon Mancini, MD, MBA, FACRO, medical director at BAMF Health and clinical associate professor at Michigan State University College of Human Medicine; Comron Hassanzadeh, MD, MPH, assistant professor of Radiation Oncology at The University of Texas MD Anderson Cancer Center and bone metastasis clinical director; and Bridget F. Koontz, MD, FASTRO, medical director for radiation oncology at Advent Health.

The discussion highlights the mechanisms of action, typical image characteristics, and key differences between these agents, including sensitivity, specificity, and biodistribution. Furthermore, the panelists touched upon the unique advantages offered by newer agents such as flotufolastat F 18 in challenging postprostatectomy recurrence scenarios due to its reduced bladder activity.

PSMA PET Options

Efstathiou / Dr Mancini, could you provide us with an overview of the currently available PSMA PET imaging agents, and highlight some key differences to compare those agents?

Mancini / Before PSMA PET was widely available, we had fluciclovine F 18, which was FDA approved in May 2016. It wasn’t the first, but it was one of the first FDA-approved PET imaging agents, specifically for patients with recurrent prostate cancer after primary management. This is an interesting tracer because it’s a metabolic tracer, utilizing increased amino acid transport activity that is increased in prostate cancer cells. Fluciclovine F18 was far more sensitive and specific than conventional imaging but was a step in the right direction for advancing the imaging and the accuracy of [diagnosing] prostate cancer.

Now for PSMA itself, there are 2 major categories, one being gallium-68 PSMA-11 gozetotide [Ga-68; Illuccix], which was approved more than 4 years ago in December 2020 by the FDA. There are 2 different FDA-approved kits to manufacture and make available for us to perform PSMA PET scans for our patients: [Ga-68] and [Ga-68 injection]. [These are] specific to targeting PSMA, which, as we know, is a protein highly expressed in prostate cancer cells, and that’s using a radiolabeled ligand. Instead of a metabolic-based tracer, it’s a radiolabeled ligand that binds to PSMA to illuminate the problem. For patients undergoing PSMA PET, a patient with multifocal metastatic disease, there’s a lot less background “noise” when compared with fluciclovine F 18 because of increased sensitivity and specificity.

All the PSMA tracers are very similar. If we look now to piflufolastat F 18, which was FDA approved about 6 months after Ga-68 PSMA-11, again, this will also target that same PSMA protein. What’s interesting about F 18 is that you typically have a slightly higher signal-to-noise ratio, which can lead to high resolution, but in a similar manner, both piflufolastat F 18 and other F 18 agents, etc, have this similar biodistribution within the normal tissues.

One of the more recent FDA approvals, in May 2023, was flotufolastat F 18. This is a unique radio-hybrid because it can target PSMA just like the other Ga-68 PSMA-11 and F 18 agents. It has a unique radio-hybrid property where it has decreased bladder activity or urinary excretion. You can imagine this could be incredibly beneficial in this recurrence setting after prostatectomy, where other PSMA PET tracers have a lot of urinary excretion and can obscure a potential small recurrence within the prostate bed or even in the base of the prostate.

For FDA-approved tracers, the big difference is F 18 vs Ga-68. The advantage of F 18 can be a higher positron yield, which means more positrons are available for imaging, so more signals coming off the tumor can be localized. At the same time, it has a lower positron energy, meaning a shorter range and higher image resolution. Again, between more positrons being produced and the lower positron energy, you’re not going to have a slightly higher resolution. Other advantages are the slightly longer half-life, 109.8 minutes to be exact vs 67.8 minutes with Ga-68. The logistics of producing something like F 18 vs Ga-68 come into play with that longer half-life, allowing for larger batch production, delayed imaging, etc, when you look at the comparison between those two.

Some studies have found that F 18 agents have a higher SUV [standard uptake value] max within the cancer lesions and potentially a marginally higher detection rate than Ga-68 agents. However, to contradict that, other studies have shown that Ga-68 PSMA agents detect more lesions. For all intents and purposes currently, these are thought to be equivalent opportunities to image our patients and can be utilized in an institution or regional-dependent manner. We also spoke about the unique attribute of flotufolastat F 18 with low urinary excretion, which can offer a unique opportunity to better assist us in the postprostatectomy study setting or recurrent setting. From a production perspective, F 18 is made in a cyclotron, so it’s a little more logistically challenging with lots of big machines that need coordination to produce it vs Ga-68, [which requires only] a small generator. From a footprint and ease of production perspective, that would favor Ga-68 for most.

Efstathiou / That’s a fantastic overview. Dr Koontz, are all those agents that Dr Mancini went over in the NCCN [guidelines]?

Koontz / All those agents are FDA approved, and they’re all [part of the NCCN] guidelines.

Efstathiou / There are some real pros and cons to these different agents. There are good options available. Dr Hassanzadeh, what factors are you considering when selecting a PSMA PET tracer for a particular patient or a particular clinical scenario? When might you opt for F 18 or Ga-68, and how do the available data inform your decision-making?

Hassanzadeh / There was a meta-analysis that was pivotal in this space and helped discern when certain radiotracers may be more beneficial. This meta-analysis looked at both gallium [and] fluorine PET radiotracers, revealing a few interesting points. One issue with PSMA PET is benign bone uptake, leading to uncertain rib lesions.

Interestingly, gallium showed lower uptake in benign bone, potentially resulting in fewer false positives and less need for MRIs and biopsies. This is one area where gallium excelled compared with fluorine or F 18. Conversely, as Dr Mancini noted, the SUV cutoff for differentiating true tumors from benign lesions on F 18 PSMA PET can be difficult, although the literature explores thresholds such as SUV greater than 3. The higher SUV with F 18 may offer a clearer interpretation for nuclear medicine physicians determining lesion positivity. However, the study concluded no meaningful differences in detection rates, sensitivity, and specificity between gallium and F 18. Therefore, agent selection may depend on the clinical context. If less benign bone uptake with gallium is potentially beneficial, that’s one advantage. Conversely, F 18’s higher SUV offers another. Regarding flotufolastat F 18, Dr Mancini highlighted its potential in the postprostatectomy setting due to [its] lower bladder uptake, aiding in discerning residual disease in the prostate bed or lymph nodes near the bladder. Thus, flotufolastat F 18 has a unique advantage in that setting compared with gallium and fluorine.

Efstathiou / This is a rapidly evolving field and area; it’s been so disruptive and has been transformative in how we’re [treating] our patients. Dr Koontz, similar questions for you: How do you distinguish between the available F 18 agents, and what factors guide your decision to use one over another? How do the available data inform your decisions?

Koontz / The first part of the question is practical: often an institutional bias, as Dr Mancini mentioned. This depends on what’s available for the physician to order and, initially, tracer types, how they were made, and their availability for timely imaging. Fortunately, this access issue has largely been addressed for many institutions. The decision then becomes about patient and tracer characteristics. For F 18 agents, there’s 1 metabolic agent, fluciclovine F 18, and 2 PSMA agents. PSMA imaging has become dominant, and the 2 F 18 PSMA agents are very similar, with the caveat mentioned by my colleagues regarding flotufolastat F 18 in the recurrence setting.

Due to its tight binding, while still being renally excreted and appearing in the bladder, it tends to do so later. This creates more contrast between bladder filling and a potential uptake in the prostate bed, a challenging imaging scenario, suggesting a potential benefit. Ongoing studies, with early data, also explore flotufolastat F 18 in very low PSA recurrence after prostatectomy, an area where we await more evidence but with suggested potential benefit. That’s often how I balance choosing one over the other. Otherwise, I often let nuclear medicine decide based on first availability to expedite the patient’s test and act on the results.

Efstathiou / You highlight a lot of important things. All the panelists have eloquently talked about the pros and cons of these different agents. Sometimes, it’s just practical issues in terms of what’s available at our institution and the general availability of agents in the region where you may be practicing as well. Let’s go back to fluciclovine F 18, just for a moment. Dr Mancini, you talked about fluciclovine F 18. Do you still see a role for [this agent]? Fluciclovine F 18 was the early kid on the block. This led to this disruptive, transformative phase in prostate cancer imaging. Is there still a role for fluciclovine F 18, and if so, in what specific scenarios?

Role of PSMA PET Imaging

Mancini / It’s a great question because PSMA has been all the rage since December 2020. We’re only about 4 years into this PSMA PET era, and just everything that’s come about has been truly remarkable in the fluciclovine F 18 setting. PSMA is not perfect, so there are about 10% to 20% of prostate cancer tumors that don’t express or underexpress PSMA. That is a role for some metabolic tracers to assist with more accurate imaging and staging of our patients. Additional scenarios take place in patients with stage IV metastatic prostate cancer. When you have patients who are heavily pretreated with chemotherapies and androgen suppression, etc, you can have de-differentiation, or neuroendocrine differentiation of prostate cancer, and you lose that PSMA expression. Sometimes you have a discordance where the PSMA level is low or nonexistent, but now here come the metabolic aspects of those tumors. Fluciclovine F 18, along with FDG [fludeoxyglucose], has a role within that space when it’s said and done.

Koontz / Fluciclovine F 18 is a great stunt test, and it changed how we treated prostate cancer for years before PSMA came out. If you look at the data comparing the 2 while the PSA [levels are] under 1 for the recurrent setting, there is a benefit to PSMA PET imaging over accident testing. When you look at higher PSA tests, the detection rates are similar, although high overall. That’s one where we are still figuring it out, but as we think about costs of health care, one of the questions that we still have to figure out is: Is there a complimentary role so that we’re keeping patient co-pays down as we use these different agents?

Hassanzadeh / As we’re seeing not only de-differentiated but things such as intraductal carcinoma in the up-front setting, that’s where fluciclovine F 18 may shine over PSMA PET. [Because] the prostate cancers may not be expressing as much PSMA, fluciclovine F 18 probably still has a role. We’re seeing [that] a lot of [younger] patients are not coming [in] with prostate adenocarcinoma. They’re coming [in] with something completely different, and they’re potentially not expressing PSMA, so we’re not able to detect the full extent of their disease.

Efstathiou / To drill down a bit, it seems like at first pass, we’d get a PSMA PET scan, and let’s say the PSMA PET scan is negative. Have you ever considered following that with fluciclovine F 18 because the patient scenario fits into one of these clinical scenarios that we’ve been discussing?

Hassanzadeh / Especially if it’s neuroendocrine or small cell [cancer], we’ve gotten FDG PET quite commonly. Fluciclovine F 18 potentially has a role in things [such as] intraductal or other histology. It still has a potential indication there, but especially in the small cell setting, that’s where FDG probably still has a significant role. We’re seeing patients with bone metastases, and extensive things [such as] spinal metastases that have changed [disease] management for them significantly.

Efstathiou / Fluciclovine F 18 was there first, but PSMA PET has taken over. There still might be a role in certain scenarios for fluciclovine F 18. That’s the take-home there. Dr Mancini, do you want to talk about the importance of image quality in guiding treatment decisions in prostate cancer and how these quality differences impact your clinical decision-making?

Mancini / Quality is bar none the No. 1 most important thing. When I think quality, I think resolution, the ability to detect things that are real and to differentiate [them]…so that you’re not overdiagnosing, but you’re getting the most accurate picture of that person before you make definitive treatment decisions. A lot of what we’ve witnessed is this stage migration or the discovery of things we didn’t know were present when we went to treat someone definitively with curative intent/radiation therapy. You can only get to that point and do the best by the patient by having the most accurate imaging. To have the most accurate imaging, you need the best quality. The production of PET tracers, and their quality, is the No. 1 thing. You have to meet quality metrics, purity metrics, and timing metrics to do these things and get the best imaging possible. There are a lot of things that align to [ensure] that ultimate accuracy.

Efstathiou / What goes into having the best image? Does it matter [which] scanner you have? What are those components to make that perfect energy?

Mancini / Access is still super important. Whether that’s a mobile PET or a high-resolution PET that’s within a unique department, having PET scan availability is still No. 1. What we’re now seeing within the pipeline is the development of these high-definition PET hardware and scanners, whether it’s almost total body or total body PETs that can acquire imaging with 40 times higher resolution in 1 to 3 minutes, which is incredible and will be the future. The mobile PET [can give imaging] access to that person [who] otherwise wouldn’t have had that PET. It’s not only the tracer quality, production, and logistics [but also] the hardware. It’s also the reading nuclear medicine physician and team. Following the guidelines allows us to describe lesions, their location, how confident we are, [determine whether] they are related. It’s a multiheaded approach to making sure that we’re producing the best outcome.

Efstathiou / For us radiation oncologists, we just like a pretty image [that] just lights up perfectly where there’s an anatomic component to it, whereas there’s the functional uptake component to it. A lot goes [into creating] that perfect image for us to use in the [treatment] of patients.