Prostate-Specific Membrane Antigen: The Target of the Decade, from Biochemical Recurrence to Widespread Adoption (perspective on “Evaluation of hybrid ⁶⁸Ga-PSMA Ligand PET/CT in 248 Patients with Biochemical Recurrence After Radical Prostatectomy” J Nucl Med. 2015;56:668–674)

FDG—the molecule of the (last) century. PSMA—the target of this and the next decade.

—Richard P. Baum, fourth Theranostics World Congress (2016), Melbourne, Australia

Every year, a myriad of promising new radiopharmaceuticals is described in The Journal of Nuclear Medicine, but few become a new standard of care that changes clinical management paradigms and improves patient outcomes. Even fewer are rapidly adopted. Against this trend, in an era when choline PET/CT was undergoing extensive clinical evaluation in men with prostate cancer, from seemingly nowhere arrived the small-molecule–targeting prostate-specific membrane antigen (PSMA) ⁶⁸Ga-PSMA(Glu-NH-CO-NH-Lys-(Ahx)-[⁶⁸Ga(HBED-CC)]), more concisely known as ⁶⁸Ga-PSMA-11.

In January 2015, when few urologists had heard of ⁶⁸Ga-PSMA-11, Matthias Eiber et al. from the group led by Markus Schwaiger submitted a seminal piece of research to The Journal of Nuclear Medicine, evaluating ⁶⁸Ga-PSMA-11 PET/CT in 248 men with biochemical recurrence after radical prostatectomy (1). Already cited over 800 times, it remains one of the earliest and most practice-changing pieces of research in the still-growing evidence base for PSMA PET/CT. It spearheaded researchers around the globe to further evaluate PSMA PET/CT for a variety of other clinical indications and discover next-generation PSMA ligands for both imaging and therapy.

Urologists and nuclear medicine specialists with experience using ¹¹¹In-capromab pendetide (ProstaScint; EUSA Pharma), an antibody targeting the intracellular domain of PSMA that had relatively poor tumor targeting with SPECT/CT, were initially skeptical of this “new-generation” PSMA-targeting radiotracer. However, images showing extraordinary tumor-to-background contrast in tiny lymph nodes smaller than 5 mm on CT, combined with early data, provided compelling evidence for a game-changing radiopharmaceutical. This occurred on the back of another seminal paper from the German Cancer Research Center (DKFZ) demonstrating superior lesion detection and tumor-to-background contrast with ⁶⁸Ga-PSMA-11 compared with choline PET/CT (2). These data, combined with click chemistry production; the availability of ⁶⁸Ge/⁶⁸Ga, already adopted for imaging neuroendocrine tumors; and, intriguingly, lack of intellectual property protection, led to an early tipping point toward widespread clinical adoption in some countries such as Germany and Australia.

A further key element to the success of the research by Eiber was close collaboration between nuclear medicine and urology, as is evident in the methodology and selected population. Despite the retrospective nature of the research, it used a homogeneous series of patients with early biochemical recurrence after prostatectomy, in whom no imaging is usually performed because of the low detection rate of CT or bone scintigraphy. The result is a research paper with high clinical relevance and, accordingly, read widely by specialists in genitourinary oncology. I had the pleasure of visiting the center while on sabbatical in 2016, and it was a delight to witness how closely the two specialties were collaborating to improve outcomes for men with prostate cancer.

Strikingly, 90% of patients in the study showed one or more localized areas of abnormal uptake suggestive of recurrent prostate cancer. The detection efficacy of ⁶⁸Ga-PSMA-11 was 97% for a prostate-specific antigen (PSA) value of 2 ng/mL or more, 93% for a PSA value of 1 to less than 2 ng/mL, 73% for a PSA value of 0.5 to less than 1 ng/mL, and 58% for a PSA value of 0.2 to less than 0.5 ng/mL. Multiple other groups have successfully repeated and replicated the findings of this research, as demonstrated in several metaanalyses, including our own, in nearly 5,000 patients (3) and inclusion in the latest European Association of Urology guidelines.

The results also formed the basis of subsequent research exploring the utility of PSMA PET/CT in other clinical scenarios. This research includes staging with the ProPSMA study, a 300-patient randomized trial conducted at 11 sites around Australia (4). This trial recently demonstrated that PSMA PET/CT represents a suitable replacement for conventional scanning with CT and bone SPECT/CT, with a 27% absolute improvement in accuracy. Another study redefined nonmetastatic castration-resistant prostate cancer and showed that more than 50% of men with no abnormality on conventional imaging had metastatic disease on PSMA PET/CT and the other 50% had either localized or pelvic nodal disease (5).

As a result of the work of Eiber et al., and other nuclear medicine groups, it seems a fait accompli that PSMA PET/CT will soon be featured in clinical practice guidelines as the new imaging standard of care, replacing CT, bone scanning, and choline PET/CT. Reimbursement in many countries is also likely to begin soon. As the target of the decade, there is still much work to be done in validating PSMA PET/CT for the initial diagnosis in men with suspected prostate cancer, as a response biomarker in men with metastatic prostate cancer, and optimizing the selection of men for PSMA theranostic treatment. Concurrently, we must better define the complementary role of ¹⁸F-FDG PET/CT, the molecule of the last century.

• © 2020 by the Society of Nuclear Medicine and Molecular Imaging.

• Received for publication June 23, 2020.
• Accepted for publication August 13, 2020.