Historically, patients with advanced prostate cancer have been imaged using conventional imaging, including nuclear medicine bone scan and CT scans. These images were widely available, economical, and familiar to urologists, who used them for decades in clinical practice. Importantly, conventional imaging was used in clinical trials to define patient selection and stratification. However, next generation imaging has been developed with the goal of improving prostate cancer detection. The widespread adoption of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) has brought about a new era of imaging. With this change, the guidelines have shifted from considering novel PET scans after negative conventional imaging to now preferentially recommending PSMA PET.

There are currently 3 approved next generation PET imaging modalities, including C-11 choline PET, F-18 fluciclovine, and PSMA PET. Choline PET was the first approved prostate cancer PET imaging technique that relies on cellular membrane synthesis, which is increased in prostate cancer cells. However, choline PET has limited access due to a very short half-life (20 minutes) and the need for an on-site cyclotron. The next approved PET imaging technique was fluciclovine. This is a synthetic amino acid PET that has increased uptake in prostate cancer cells due to increased metabolism. Minimal urinary excretion makes fluciclovine PET ideal for detection of recurrence after prostatectomy. Lastly, PSMA PET has become widely adopted after its approval. It relies on detection of a transmembrane glycoprotein overexpressed on prostate cancer cells. There are 2 approved PSMA PET agents, F-18 piflufolastat (DCFPyL) PSMA and Ga-68 PMSA-11. Studies comparing PSMA PET to other next generation imaging techniques have found that PMSA PET has a higher sensitivity.

The first PSMA PET agent approved by the Food and Drug Administration (FDA) was gallium 68 PSMA-11 PET in December 2020. The approval was initially limited to sites in California based on studies from the University of California, San Francisco and the University of California, Los Angeles. The first study was a prospective trial of 635 men with biochemical recurrence after radical prostatectomy, radiation therapy, or both. PSMA PET successfully localized recurrent cancer in 75% of patients.¹ The second study was a phase 3 study, once again at the University of California, San Francisco and the University of California, Los Angeles that evaluated 277 men with intermediate-or high-risk prostate cancer undergoing PET prior to radical prostatectomy. The positive study found that PSMA PET detected lymph node disease with a specificity of 95%.²

The next approved PSMA PET agent was F-18 PSMA PET, which was approved based on the OSPREY and CONDOR studies in 2021. In the OSPREY study, men with high prostate cancer undergoing prostatectomy and those with suspected recurrent cancer were evaluated.³ In total, 385 patients were evaluated and the primary end point for prostate cancer specificity was met. In the CONDOR trial, 208 men at risk for recurrence after radical radiation therapy were evaluated. The study successfully found the correct localization occurrence in up to 87% of men.⁴ The proPSMA study compared PSMA PET to conventional imaging.⁵ It evaluated 302 men with high-risk prostate cancer randomized to PSMA PET or conventional imaging. The study found that PSMA PET was significantly more accurate and resulted in lower radiation exposure.

With the FDA approval of PSMA PET there have been updates to advanced prostate cancer guidelines that recommend PSMA PET preferentially. The updated AUA guidelines recommend PSMA PET for patients with biochemical recurrence after local treatment. The guidelines also recommend PSMA PET for patients with castrate-resistant prostate cancer who may have metastases. In patients with metastatic castrate-resistant prostate cancer, guidelines suggest PSMA PET may help identify patients who are candidates for novel PSMA-targeted treatments. The guidelines also clarify that conventional imaging is not needed prior to PSMA PET. Both the National Comprehensive Cancer Network and European Association of Urology guidelines express caution that PSMA PET may cause a Will Rogers phenomenon, moving patients with worse prognosis to higher-risk groups, thereby appearing to improve the outcomes of both.

The adoption of PSMA-targeted imaging has also allowed for the development of a new field of treatment called theranostics. This is the combination of both therapy and diagnostics. Theranostic treatments use radiolabel ligands as both a predictive biomarker and therapeutic agent. The first approved theranostic treatment for prostate cancer occurred in 2022 with the FDA approval of lutetium. This is a β-particle radioligand therapy targeting PSMA-expressing cells. The approval of lutetium was based on the VISION Trial, a phase 3 trial of lutetium plus standard of care compared to standard of care alone.⁶ The study found that lutetium improved progression-free survival and overall survival compared to standard of care alone.

Over the last 4 years, there has been a rapid transition from conventional imaging to next generation PSMA PET imaging for patients with advanced prostate cancer. PSMA PET has been found to be more sensitive for the detection of prostate cancer, both in pretreated and recurrent states. Because historical studies have used conventional imaging to define the clinical states of advanced prostate cancer, future clinical trials evaluating the impact of new imaging will be important to determine the benefit. PSMA PET has provided a new treatment modality using the theranostic agent luteum in patients with a history of castration-resistant prostate cancer.