Molecular imaging, whereby a positron emitter (radioactive element) is tagged to a small molecule that can accumulate in a cell (more commonly referred to as positron emission tomography—or PET imaging), has revolutionized the management of many cancers. The most common method of PET imaging is with the radiotracer ¹⁸F-labeled glucose, which leverages the aerobic glycolysis (Warburg effect) of cancer cells to more specifically image cancerous tissue. Unfortunately, the most common genitourinary malignancy, prostate cancer, does not utilize this method of metabolism, and therefore ¹⁸F-labeled glucose PET imaging is unsuccessful in evaluating prostate cancer—long limiting the use of PET imaging in prostate cancer. However, in the past decade there have been advances in radiotracer development beginning with ¹¹C-choline (U.S. Food and Drug Administration [FDA]-approved in 2012) and ¹⁸F-fluciclovine (FDA-approved in 2016) for recurrent prostate cancer to now having the prostate specific-membrane antigen (PSMA)-targeting agents ⁶⁸Ga-PSMA-11 (FDA-approved in 2020) and ¹⁸F-piflufolastat (FDA-approved in 2021) for initial staging and restaging of recurrent disease. In this article, the uses of these agents will be reviewed.

The largest experience to date of PET imaging in prostate cancer has been in the recurrence setting. For men experiencing recurrence after curative intent local therapy (surgery, radiation, or the combination), the goal of PET imaging is to rule out the presence of metastatic disease prior to consideration of local salvage or to guide targeted treatment of oligometastatic recurrence.¹ In the EMPIRE-1 trial, 165 men were randomized to either conventional imaging or ¹⁸F-fluciclovine prior to salvage radiation therapy after prostatectomy. PET imaging resulted in changes in treatment plans in 35.4% of men and a resultant twofold improvement in biochemical survival, supporting a survival advantage to using PET imaging in these men prior to treatment.² Similar experiences can be seen in post-radiation recurrences prior to salvage surgery and in the setting of oligometastatic disease, where targeting PET-identified disease can improve biochemical control.^3,4 While there is no preferred agent in this setting, a recent meta-analysis encompassing 2,373 patient evaluations with all approved agents identified that 1) there is a PSA-dependent detection rate among PET radiotracers and 2) PSMA targeting agents are superior to choline and fluciclovine at lower PSA values. Specifically, at a PSA of <0.5, detection rates of 24% (choline), 37% (fluciclovine), and 47% (PSMA) were observed.⁵ Important to note, however, is that PET imaging may identify metastatic sites of disease otherwise missed on conventional imaging. To date, our understanding of the role and efficacy of systemic management (eg chemotherapy, androgen receptor targeting agents, and androgen synthesis inhibitors) of metastatic prostate cancer is limited to conventional imaging-diagnosed metastases, and therefore men with PET-only metastatic disease on recurrence represent a group of patients who would have been excluded from clinical trials of metastatic prostate cancer. As such, their outcomes with traditional management options for metastatic disease are not studied and these men represent a management dilemma if further targeted treatment is not considered.

More recently, PSMA-based PET imaging has been used in the evaluation of men with high-risk localized prostate cancer for initial staging.¹ In the largest experience, a total of 764 men with intermediate- and high-risk disease underwent ⁶⁸Ga-PSMA-11 staging, of whom 277 underwent radical prostatectomy. Using the pathology from the node dissections, ⁶⁸Ga-PSMA-11 was associated with a sensitivity of 40% and specificity of 95%.⁶ These data compare similarly with data from the OSPREY trial, in which 252 patients underwent ¹⁸F-piflufolastat imaging prior to radical prostatectomy, resulting in a sensitivity and specificity for lymph node metastasis of 40.3% and 97.9%, respectively.⁷ Together, these findings support that PSMA-based staging can reliably predict nodal metastasis when present on imaging (guide extent of therapy) but cannot exclude the presence of nodal disease when imaging is negative (cannot replace lymph node dissection or nodal bed irradiation). However, it is important to note that there are no data yet to describe how changes in staging on PET imaging as compared to conventional imaging will alter long-term survival or biochemical control. As such, men with high-risk localized disease on conventional imaging but with nonlocal disease on PET imaging should be counseled on the lack of data to change recommended management on the basis of the PET imaging alone and should therefore be offered local curative intent therapy. In this setting the PET imaging should serve to either modify the local treatment plan or suggest further adjuvant treatment following local therapy.

Finally, and most exciting in this space, is the evolution of theranostics in the form of ¹⁷⁷Lu-PSMA-617. In the landmark VISION trial, 831 men with metastatic castration-resistant prostate cancer, having progressed on prior androgen receptor pathway inhibition and taxane-based chemotherapy, were evaluated with ⁶⁸Ga-PSMA-11 imaging and randomized to receive ¹⁷⁷Lu-PSMA-617 therapy.⁸ Treatment was given in 4–6 cycles, and men were monitored for progression and death. ¹⁷⁷Lu-PSMA-617 therapy resulted in a 4-month survival (15.3 vs 11.3) advantage over standard of care therapies. ¹⁷⁷Lu-PSMA-617 is now FDA-approved for the treatment of men with ⁶⁸Ga-PSMA-11-identified metastatic castration-resistant disease.

However, PET imaging is not universally beneficial in men with prostate cancer. In men with hormone-sensitive prostate cancer there are 2 disease spaces where PET imaging findings may not provide actionable information. The first is in the setting of conventional imaging-nonmetastatic but PET imaging-metastatic disease. These are men who do not meet criteria of modern hormone-sensitive metastatic prostate cancer clinical trials, and their management can be challenging. Without histological confirmation of their metastatic disease, these are men who should be treated as nonmetastatic until we have prospective data to assess the role of conventional imaging-negative PET imaging-positive metastatic disease. The second disease space where PET imaging is of questionable utility is in men with known metastatic disease who have not failed existing therapies. In both hormone-sensitive metastatic and metastatic castration-resistant clinical trials, treatment decision changes were made on the basis of conventional imaging progression or biochemical progression. As such, using PET imaging routinely in disease spaces where there is not an appropriate treatment decision (eg outside of the VISION trial criteria) will not likely result in a patient care benefit.

In summary, PET imaging (PSMA, fluciclovine, and choline) represents a substantial improvement in our ability to evaluate the initial staging of men at high risk for nonlocal disease, in the setting of recurrence after curative intent therapy, and in the management of men with metastatic castration-resistant prostate cancer failing other therapies.