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Addressing Knowledge Gaps and Clinical Challenges of PSMA PET in Prostate Cancer

More than three years after the first FDA approval of a PSMA radiotracer for detecting prostate cancer (PCa), we are seeing an evolution and maturation of use in the clinic. The availability of PSMA PET with different tracers enables us to detect lesions that conventional imaging misses, identify disease recurrence at very low (<0.5 ng/mL) PSA levels, and distinguish between benign and malignant tissue.1-3 In some countries and regions, PSMA PET is now standard practice for initial PCa staging, treatment planning, and monitoring treatment response. However, questions persist about how to manage patients in the PSMA PET era, particularly because registrational trials of current therapies predated the widespread availability of PSMA PET and therefore used only conventional imaging (i.e., CT, bone scan). Here, I discuss current knowledge gaps pertaining to the use of PSMA PET in various scenarios and how we can best steward this resource.

For patients with high-risk biochemical recurrence (BCR)—e.g., a short time to biochemical failure, rapid PSA doubling time, and/or high-grade disease after definitive local treatment—PSMA PET can potentially enhance risk stratification and inform decisions about further treatment. However, limited data are available to guide us because most clinical studies of these patients were designed before PSMA PET was widely available. A recent example is the large pivotal phase 3 EMBARK trial, in which patients with high-risk BCR (defined in this study as PSA doubling time < 9 months after definitive local treatment) derived a significant metastasis-free survival (MFS) benefit from treatment with enzalutamide, given alone or with ADT, compared with ADT alone.4 These are practice-changing data, but how might advanced imaging fit into this picture, considering that EMBARK opened in 2015 and hence did not employ PSMA PET? In a post-hoc analysis of five PSMA PET studies of “EMBARK-like” patients (n=146), 83% were PSMA PET-positive, 40% had distant metastatic disease, and more than 20% had at least 5 metastatic lesions.5 These findings suggest that PSMA-PET may help risk-stratify EMBARK-like patients with high-risk BCR but do not address questions about the independent prognostic value of PSMA PET in this setting, nor whether it is useful for treatment selection.

A related question pertains to using PSMA PET to guide metastases-directed therapy (MDT). MDT is used to treat oligometastatic (low-volume) PCa, a heterogeneous disease state that lacks a consensus definition based on PSMA PET but is often described as consisting of 3 to 5 bone or lymph node metastases.6-8 Due to the enhanced sensitivity of PSMA PET for detecting early metastases, many physicians will consider PSMA PET-guided MDT as an alternative to immediate ADT. Phase 2 studies and retrospective observational data suggest that stereotactic radiation guided by PET can delay metastatic progression, postpone the need for androgen deprivation therapy (ADT), and possibly improve MFS in the setting of oligometastatic PCa.9,10 Limited data also suggest that combining MDT with intermittent hormone therapy might be superior to hormone therapy alone in these patients.11 However, the lack of phase 3 studies of MDT, including PSMA-guided MDT, makes its true clinical impact unclear. Future studies should investigate if PSMA PET can improve MDT outcomes in patients with oligometastatic PCa and how we can combine treatments in this space in the PSMA PET era. We should also look at risk-stratifying patients with biochemical recurrence to see if MDT might be better for certain groups, such as patients whose disease is not at high risk for recurrence. Exploring the impact of MDT in patients with biochemical recurrence after systemic treatment is a significant area of opportunity.

For patients with early castration-resistant PCa, phase 3 registrational trials of apalutamide, enzalutamide, and darolutamide (PROSPER, SPARTAN, ARAMIS) predated the PSMA-PET era; patients had no detectable metastases on conventional imaging (CT and bone scans). Post-hoc single-center and multi-institutional studies have since confirmed that PSMA PET is positive in the majority of such patients.12-14 In one such study of a SPARTAN-like population, 55% of patients had distant metastases detected on PSMA PET.15 In another study of patients resembling those in SPARTAN, PROSPER, and ARAMIS, PSMA PET was positive in 98% of individuals 39% had M1 disease involving extrapelvic nodes, while 24% had bone metastases and 6% had visceral organ involvement.12 While these data are useful, they do not clarify how PSMA PET can best be used to guide treatment decision-making in these high-risk patients. Prospective studies are needed that incorporate PSMA PET and conventional imaging in the setting of early ADT failure.

PSMA PET also is being explored as a tool for primary PCa staging, particularly in patients with high-risk disease features. PSMA PET in this setting is much more specific and also more sensitive than conventional imaging, but it remains unclear whether using PSMA PET for primary staging affects patient outcomes. Based on what we know now, PSMA PET should be considered for evaluating newly diagnosed intermediate or higher-risk PCa, and its performance suggests that prior conventional imaging need not be a prerequisite for its use. PSMA PET has been found to be more sensitive for nodal staging than MRI, abdominal contrast-enhanced CT, or choline PET/CT, but it can miss small lymph node metastases.16,17 This is a great reminder that PSMA PET does not replace the microscope and should not be regarded as a substitute for pelvic node dissection—indeed, its sensitivity for detecting nodal metastases was only 40% in two recent studies where histopathology was the reference standard.18,19

PSMA PET also shows potential for response monitoring, with the important caveat that PSMA expression can decrease for reasons other than treatment response. Recent studies show that exposure to PSA radioligand therapy, ADT, androgen receptor inhibitors, and immunotherapy all have been shown to affect PSMA expression.20 Furthermore, for patients with limited PCa disease burden, tumor volume might not be suitable for assessing response to therapy. Experts have sought to address these potential pitfalls by refining interpretation criteria and taking a whole-body approach to quantifying tumor burden. This work has produced several frameworks for using PSMA PET to objectively measure treatment response, including the PSMA PET Progression criteria (PPP) in earlier disease and the Response Evaluation Criteria in PSMA PET/CT (RECIP) in later (metastatic castration-resistant) PCa.21,22

Building on such efforts, researchers are directly comparing PSMA PET-based response monitoring with conventional monitoring alone to guide management decisions in high-risk PCa. The phase 3 PRIMORDIUM study (NCT04557059), which evaluates the efficacy of adding 6 months of apalutamide to ADT in patients with high-risk BCR after prostatectomy, incorporates PSMA PET imaging both at baseline and as a primary endpoint (PSMA-PET metastatic progression-free survival).23 This study is expected to be completed in 2030. In addition, the phase 3 PATRON (NCT04557501) trial compares 5-year failure-free survival in patients with high-risk untreated PCa or high-risk BCR who are randomly assigned to PSMA PET plus conventional imaging or conventional imaging alone to guide treatment intensification with radiotherapy or surgery.24 This study also evaluates cost-effectiveness of PSMA PET-guided therapy and its effects on side effects and quality of life. Primary results are expected in 2029.

Another application of PSMA PET is to identify patients whose disease is predicted to respond to radioligand therapy. When selecting patients for 177Lu-PSMA-617 therapy, VISION used the criterion of standardized uptake value (SUV) greater than liver in all measurable lesions based on visual assessment, while TheraP required that SUVmax > 20 in a single lesion and SUVmax > 10 in all measurable lesions.25,26 The Society of Nuclear Medicine and Molecular Imaging recommends using the VISION criteria (uptake greater than liver) because these patients have demonstrated superior OS in the largest patient cohort to date.27 Prior to deciding on radioligand therapy, contrast-enhanced CT or MRI also is recommended to detect PSMA-negative disease. While its detection does not necessarily preclude radioligand treatment, the extent of PSMA-negative disease burden should be considered and treatment planned accordingly. PSMA PET is also used to assess response to radioligand therapy; while its enhanced sensitivity could lead to earlier treatment changes, we lack clear evidence showing that this improves patient outcomes over monitoring with conventional imaging alone (in VISION and TheraP, patients were restaged by using conventional imaging). Furthermore, we lack established criteria for assessing radioligand therapy response with PSMA PET; relevant data are limited to retrospective and small prospective studies.28,29

Of note, some data indicate that liver-based SUV thresholds are of limited value for predicting individual lesion response to radioligand therapy, and that some lesions with uptake below liver are non-progressive.29 Such findings suggest that other approaches to patient selection and/or response monitoring may be of value. Such strategies might include planar imaging or SPECT quantitation, multi-tracer approaches, or even liquid biopsy (i.e., measuring PSMA expression on circulating tumor cells or DNA damage repair markers on peripheral blood lymphocytes).30-32 At the end of the day, SUV values are a biomarker. We need to start exploring what more PSMA PET images can tell us when we assess these and other values, such as total tumor volume.33 I envision a future in which we can harness multimodal AI based on radiomics and clinical data to help predict treatment response, which could improve patient outcomes and help make these treatments more cost-effective.

When using PSMA PET for patient/treatment selection, we have thus far taken a fairly binary approach, classifying patients as either positive or negative based on scan results. As we develop and improve reporting criteria and study PSMA PET performance in various therapeutic scenarios, we may be able to further refine categories and adopt a more comprehensive, semi-quantitative approach to image-based response assessment. In classical Hodgkin lymphoma, interim FDG-PET/CT is standard for monitoring treatment response and adapting treatment accordingly.34,35 My hope is that PSMA PET in PCa also can move toward treatment adaptation that better justifies its utility for providing improved care at lower costs. Although “a picture is worth a thousand words,” we should question the true value and impact of PSMA PET for detecting progression if other indicators, such as patient’s symptoms and PSA levels, are unequivocal (i.e., if they clearly indicate a good response or they clearly point to progression/relapse). We must keep in mind the costs of these tests, which vary globally and will inevitably impact utilization.

In summary, PSMA PET is clearly more sensitive and specific than conventional imaging for detecting early metastatic PCa and may be useful for risk stratification, but we lack level 1 evidence for its impact on clinical management. Using PSMA PET without a clear clinical rationale is not only a potential waste of resources but could lead to unnecessary or premature treatment escalation, which could expose patients to additional potential adverse events and possible financial toxicity without improving clinical outcomes or quality of life. We have a growing body of evidence that PSMA PET can help identify higher-risk, clinically significant PCa, but we need to be more thoughtful as to how we utilize this tool and the information it provides. Overutilization remains a significant concern today as we see rapid adoption of this technology in our clinics. We need to be stewards of these resources and understand which applications of PSMA PET are ready for prime time and which are not based on available evidence. Use of PSMA PET in low-risk patients should be avoided, and PSMA PET should be used only if the clinical management team is ready to use the findings to take actionable steps that will improve clinical outcomes and/or quality of life.

Written by: Phillip J. Koo, MD, Division Chief of Diagnostic Imaging at the Banner MD Anderson Cancer Center, Arizona

References:

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