This presentation is a Satellite Symposium put on in conjunction with the Society of Nuclear Medicine and Molecular Imaging (SNNMI) and funded in part by Lantheus Medical (producer of Pylarify agent).
The first part of the presentation was by Dr. Gorin and focused primarily on introducing PSMA technology and its current role within urology. To kick off the presentation he first began by addressing conventional imaging modalities for prostate cancer – mpMRI (for primary/localized prostate cancer) and CT A/P and NM Bone Scan (for metastatic evaluation and staging). The limitations of multi-parametric MRI are its low specificity, High relative expense, and issues with reproducibility. In contrast, CT A/P has demonstrated low sensitivity while NM Bone Scan has both low sensitivity and specificity.
Molecular vs. anatomic imaging – as previously published in the literature, “the term molecular imaging can be broadly defined as the in vivo characterization and measurement of biologic processes at the cellular and molecular level. In contradistinction to classical “anatomic” diagnostic imaging, it sets forth to probe the molecular abnormalities that are the basis of disease rather than to image at the end effect of these molecular alterations.”
As such, these technologies have the possibility for both limitless sensitivity and exception specificity.
He next introduced the concept of positron emission tomography (PET), which forms the basis of much of this presentation. Below is the mechanism of action of PET imaging.
In PET imaging, a radiotracer attached to ligand is administered to the patient. Once the ligand reaches its target, the radiotracer emits a positron. This positron then interacts with an electron in an “annihilation” event that releases 511 kEV photons bidirectionally. This is then identified by a photon detector. As seen below, only true annihilation events are recognized and included but the PET imaging software – requires two antiparallel photons to be considered a true event. Photons released by non-annihilation events (background noise) are not recognized as true events and are subtracted from the final image, as seen below.
In contrast, SPECT (Single-photon emission tomography), usually utilizing technetium-99 and indium-111, releases a single photon and will recognize naturally occurring single photons as true events. This allows for more sensitivity, but also more background noise.
The summary of these two modalities as seen below:
At this time, the options for molecular imaging for prostate care are nicely summarized in the table below:
The mechanism of action of these various agents is seen below:
His main take-home points about each:
- FDG PET – most utilized amongst all malignancies, but not ideal for prostate cancer due to the relatively lower glucose metabolism in hormone-sensitive prostate cancer. Therefore, not really utilized.
- Sodium-Flouride PET and Tc-99 SPECT – utilized primarily for bone lesions, but not very useful outside of bone lesions. Also non-specific.
- Choline PET and Fluciclovine PET (Axumin) – both depend on increased amino acid activity and had been used for some time in the prostate cancer realm until the identification of the increasingly specific PSMA PET scans. Axumin is approved and utilized. However, the sensitivity is not a match for PSMA PET imaging.
- Gallium-68 and F-18 PSMA PET imaging – these will be the focus of the talk moving forward.
Since the introduction of PSMA PET CT, there has been explosive growth in the published literature on the topic. The publications have increased from under 100 per year in 2014 up to 700 in 2020. But what is PSMA (prostate-specific membrane antigen)? PSMA is a dimerized type II transmembrane glycoprotein that catalyzes the hydrolysis of NAAG to glutamate. More importantly, it is extremely overexpressed by prostate cancer epithelial cells, though it is also found in the neovasculature of a number of other solid malignancies, including renal cell carcinoma.
- PSMA is increasingly expressed in higher-grade prostate cancer (compared to low-grade prostate cancer)
- But, its expression can be lost in advanced-stage disease (typically with loss of the AR pathway and transformation to treatment-induced neuroendocrine histology)
However, as its use is primarily in the earlier stages of disease, and especially for Urologists, this caveat is not likely to be clinically relevant.
As for targeting the PSMA, there are two main mechanisms:
- Monoclonal antibody against PSMA (ie J591 antibody or 7E11 antibody)
- Active small molecule inhibitors against PSMA
The latter appears to be the primary approach at this point. Most of the current ligands are urea-based small molecules which are then linked to radiotracers. These include Gallium-68, F-18 DCFBC, and F-18 DCFPyl (Pylarify). Two new ones that are being developed include F-18 PSMA 1007 and F-18-rhPSMA-7.3 (Blue Earth Diagnostics).
He briefly discussed the Prostascint scan which was popular in the 1990’s – this was a SPECT scan that utilized a monoclonal antibody (7E11) against the intracellular component of PSMA. Never achieved widespread utilization for a few reasons:
- Since the target was intracellular, it was not able to reach its target effectively in large numbers to achieve adequate sensitivity
- Since it was a SPECT scan, there was significant background noise (signal-to-noise ratio), limiting its clinical utility.
Currently, there are two PSMA targeted Radiotracers approved the United States:
He then summarized the important differences between these two agents. The difference lies in the radiotracer. These differences are nicely summarized in this table:
From a practical standpoint, a cyclotron allows larger quantities of radiotracer production and due to a longer half-life, F-18 can be made in larger quantities and shipped to more sites – while Gallium-68 is made in smaller quantities and has to be made relatively nearby.
In addition, due to shorter path length of the positron, the annihilation event is likely to happen closer to the true site of disease – leading to less signal-to-noise ratio in imaging, as seen below:
In a single small 14-patient study comparing these two agents head-to-head, Dietlien et al. found that F-18 DCFPyl PSMA identified all the same sites as Ga-68 PSMA PET – but found at least one additional site of disease in 3 patients. This suggests a higher level of sensitivity.
While the potential applications of PET Imaging in Prostate cancer are numerous, including:
- Guiding initial prostate biopsy
- Initial staging of patients at risk of harboring occult metastatic disease
- To direct therapy upon biochemical failure following failed local therapy
- Confirm extent of disease in patient self to be oligometastatic
- Evaluation of response to treatment
- Judge candidacy for endoradiotherapy (theranostics)
It is currently only approved for (and will likely only be covered for):
- Men with suspected metastasis who are candidates for initial definitive therapy == high-risk localized prostate cancer staging
- Men with suspective recurrence based on elevated PSA == biochemical recurrence
He finished off his section of the talk by reviewing the OSPREY2 and CONDOR3 trials, which were the trials that led to the approval of Pylarify (F-18 DCFPyl).
Osprey was the Phase 2/3 trial that looked at men with high-risk prostate cancer undergoing radical prostatectomy (cohort A) or metastatic prostate cancer undergoing biopsy of metastatic site (Cohort B). In this study, they found that the PSMA scan had very high sensitivity for metastatic prostate cancer (upwards of 95% for all metastatic sites – lymph nodes, bone, visceral mets), but the in pre-operative setting, sensitivity was ~40% for all lymph nodes, but 60% for lymph nodes > 5 mm. Its specificity in this setting was remarkably high at ~98% however.
In the CONDOR study, a phase 3 open-label study evaluating the F-18 DCFPyl PET in men with biochemical recurrence, they found that it had increasing sensitivity with rising PSA – but had moderate detection even at PSA < 0.5.
He briefly touched on studies that demonstrated that these PET studies outperformed conventional staging studies (proPSMA trial),4 particularly from a specificity standpoint, and were superior to Axumin in men with biochemical recurrence.
More importantly, in work by Hope et al.,5 they demonstrated that given the information from these PSMA PET CTs (in the study, Gallium-68), it resulted in a change in management in ~53% of cases. However, Dr. Gorin was clear to note that this has not been demonstrated to impact survival outcomes yet.
He concluded his portion of the talk with the following statements:
- Conventional imaging modalities have proven insufficient for detecting prostate cancer, particularly in patients with low PSA values
- PSMA targeted PET has improved our ability to image prostate cancer, both in terms of sensitivity and specificity, across multiple disease states
- PSMA targeted PET has been shown to outperform both conventional imaging and other pet radiotracers in rigorous clinical trials
- Although imaging with PSMA targeted PET has been shown to frequently lead to changes in prostate cancer management, it is unclear if this is associated with improved patient outcomes
At this point, Dr. Rowe took over the talk and focused more on the role in patients with metastatic disease, its potential for theranostics, and future directions (including non-prostate cancer GU malignancies).
First, it's becoming increasingly evident that PSMA PET imaging has increased sensitivity at picking up the extent of metastatic disease better than conventional imaging. In a small study of their group of patients (9 total patients), F-18 DCFPyl PSMA identified significantly more disease than conventional imaging – including bone, lymph node, and visceral mets.6 It is also superior to NaF PET and bone scan for metastatic lesions in the bone.
But, what does the high sensitivity of PSMA PET imply?
- Can we identify all sites of metastatic disease and provide a chance for cure to men with limited volume disease (oligometastatic disease)?
- Can we leverage PSMA-targeted therapy to effectively treat widespread metastatic disease?
He then touched on a few clinical scenarios to highlight the potential for PSMA PET.
- Man s/p prostatectomy with rising PSA, now 3.9 mg/dL. PSMA PET avid peri-rectal node (visible on CT, but likely would not have been attributed to prostate cancer). The patient underwent SBRT with no systemic therapy and remains with undetectable PSA – avoided systemic therapy.
- Man with staging bone scan with 1 possible site of metastatic disease in the right rib. However, on PSMA PET scan has widespread marrow-based bone lesions (not sclerotic on CT imaging) and sub-cm lymph nodes. This patient potentially avoided unnecessary focal therapy to a presumed single lesion that would have had no benefit. Goes on to systemic therapy earlier.
- Male with prostatectomy and PSA 10.9. Has small retroperitoneal and presacral lymph nodes that he undergoes SBRT for – but PSA continues to rise to 19.8. Unclear if that local therapy helped or not. But PSMA PET imaging without any other evident disease
Similarly, he discussed the role of theranostics, specifically with Lutetium (Lu-177) PSMA. In this modality, this is a radiotracer with radioactive properties that are linked to a PSMA avid ligand. The delivery of this therapeutic agent to the target using a ligand allows more focused delivery. Meta-analyses have demonstrated the PSA response in heavily pretreated mCRPC patients, with PFS and relatively limited toxicity. Toxicity is typically mild nephrotoxicity or xerostomia (which is manageable and usually mild for Lu-177). However, this led to the recently published VISION trial.8 In this study, heavily pre-treated men with mCRPC were included in an international, open-label, phase 3 trial evaluating 177Lu-PSMA-617. They found that 177Lu-PSMA-617 significantly prolonged both imaging-based progression-free survival (median, 8.7 vs. 3.4 months; hazard ratio for progression or death, 0.40; 99.2% confidence interval [CI], 0.29 to 0.57; P<0.001) and overall survival (median, 15.3 vs. 11.3 months; hazard ratio for death, 0.62; 95% CI, 0.52 to 0.74; P<0.001). The incidence of adverse events of grade 3 or above was higher with 177Lu-PSMA-617 than without (52.7% vs. 38.0%), but quality of life was not adversely affected.
The next session of his talk focused on response assessment with PSMA PET imaging.
- Inhibition of the androgen signaling axis leads to increased PSMA expression
- Short term response assessment in men starting on AR targeted therapy is challenging
- However, there may be early prognostic findings within the changes in PSMA uptake
As these findings don’t directly impact most Urologists, I won’t delve into the full details of each of the studies he presented. Suffice it to say that within each of these small institutional studies, in response to AR directed therapy (ADT, enzalutamide, abiraterone), the PSMA response for metastatic sites was often variable – even in the same patient, with some lesions growing, others stable and some decreasing. To address this inter-lesional heterogeneity, they had to come up with (somewhat arbitrary) metrics to estimate overall response on PSMA imaging.
As seen below, they found that the overall trend of response did correlate with percent change in PSA -
Patients with predominantly increased response had an immediate rise in PSA, while those with predominantly decreased response had generally decreased PSAs. However, this clearly requires some work and PSMA is not a great marker of response to therapy.
Next, he focused on future directions for PSMA PET Imaging:
1. In the near term, we can expect artificial intelligence (AI) to provide:
- Lesion classification
- Whole-body tumor burden assessment
- Prognostication and decision-making based on scan findings and clinical data
2. Applications in non-prostate malignancies – but this has only just started to be investigated.
With regards to AI, he notes that the elephant in the room is that this may eventually replace the need for radiologists – but is nowhere near that at this point.
- AI algorithms are potentially ready for “hotspot”classification – but are very dependent on CT/anatomic data
- He and his team are woking on the next step – which is not only identification of a hotspot, but then classifying that lesion according to an established read paradigm (ie PIRSADS for mpMRI or similar read paradigms for PSMA/PET)
With regards to non-prostate histology, he notes that PSMA is expressed in a lot of non-prostate cancers:
These include renal cell carcinoma, for which there is increasing data. As an angiogenic tumor, PSMA is often overexpressed in the neovasculature that arises.
He shared the story of a single patient with metastatic RCC who was on hospice who agreed to a PSMA PET scan and rapid autopsy soon after he passed – and the scan correctly identified all sites of metastatic RCC.9 He also noted that while PSMA does not usually cross the blood-brain barrier, if the barrier is disrupted (as it may be in RCC), it can identify metastatic sites in the brain (with potential 94.7% sensitivity). In similar work, they found it was superior to FDG PET for metastatic RCC. Hence, it may play a greater role in the future for RCC.
He noted potential pitfalls of PSMA due to increased uptake in neovascularity, including:
- Non-pathologic fractures
- Peripheral ganglia, including Celiac axis ganglia
The last section of his presentation focused on reading paradigms, which is a developing area of PSMA/PET imaging reporting. There are two currently read-paradigms:
1. PSMA-RADS – which is out of his group from Johns Hopkins, and focused more on reporting a single lesion. It has a high degree of inter-reader reliability – but unfortunately, those lesions with PSMA-RADS 3 are truly equivocal based on corresponding pathologic studies.
2. PROMISE (miTNM) – which is more in-depth, provides granular anatomic data, and requires the reader to essentially provider a radiographic TNM score. However, it sacrifices detail about the individual lesion and is much more complex – so requires more training and is time-intensive.
Both have their advantages and disadvantages, but both provide a structured approach to scan interpretation. However, both groups are collaborating to create a combined read paradigm that optimizes both current paradigms.
At the end of his talk, he concluded with the following statements:
- PSMA PET imaging is useful for men with metastatic disease to guide therapy options
- Response assessment will improve with AI and larger trials
- More questions than answers at this point so far for the interface of PSMA PET and AI and for the role of PSMA PET in non-prostate cancers
- A combined adaptable read paradigm is on the horizon
Presented by:
Steven Rowe, MD, Associate Professor of Radiology and Radiological Science, Johns Hopkins Medicine Department of Radiology and Radiological Science
Michael Gorin, MD, Staff Urologist, Urology Associates & UPMC Western Maryland
Written by: Thenappan (Thenu) Chandrasekar, MD – Urologic Oncologist, Assistant Professor of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, @tchandra_uromd on Twitter during the 2021 American Urological Association, (AUA) Annual Meeting, Fri, Sep 10, 2021 – Mon, Sep 13, 2021.
References:
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