Matched-Pair Comparison of ⁶⁸Ga-PSMA-11 and ¹⁸F-rhPSMA-7 PET/CT in Patients with Primary and Biochemical Recurrence of Prostate Cancer: Frequency of Non–Tumor-Related Uptake and Tumor Positivity

Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands are a new class of prostate cancer theranostic agents. ¹⁸F-rhPSMA-7 offers the advantages of ¹⁸F labeling and low urinary excretion compared with ⁶⁸Ga-PSMA-11. Here, we compare the frequency of non-tumor-related uptake and tumor positivity with ⁶⁸Ga-PSMA-11 and ¹⁸F-rhPSMA-7 in patients with primary or recurrent prostate cancer. <b>Methods:</b> This retrospective matched-pair comparison matched 160 ¹⁸F-rhPSMA-7 with 160 ⁶⁸Ga-PSMA-11 PET/CT studies for primary staging (<i>n</i> = 33) and biochemical recurrence (<i>n</i> = 127) according to clinical characteristics. Two nuclear medicine physicians reviewed all scans, first identifying all PET-positive lesions and then differentiating lesions suggestive of prostate cancer from those that were benign, on the basis of known pitfalls and ancillary information from CT. For each region, the SUV_max of the lesion with the highest PSMA ligand uptake was noted. Tumor positivity rates were determined, and SUV_max was compared separately for each tracer. <b>Results:</b>¹⁸F-rhPSMA-7 and ⁶⁸Ga-PSMA-11 PET revealed 566 and 289 PSMA ligand-positive lesions, respectively. Of these, 379 and 100 lesions, equaling 67.0% and 34.6%, respectively, of all PSMA-positive lesions, were considered benign. The distribution of their etiology was similar (42%, 24%, and 25% with ¹⁸F-rhPSMA-7 vs. 32%, 24%, and 38% with ⁶⁸Ga-PSMA-11 for ganglia, bone, and unspecific lymph nodes, respectively). All primary tumors were positive with both agents (<i>n</i> = 33 each), whereas slightly more metastatic lesions were observed with ⁶⁸Ga-PSMA-11 in both disease stages (113 for ¹⁸F-rhPSMA-7 and 124 for ⁶⁸Ga-PSMA-11). The SUV_max of ¹⁸F-rhPSMA-7 and ⁶⁸Ga-PSMA-11 did not differ (<i>P</i> > 0.05) in local recurrence or primary prostate cancer; however, the tumor-to-bladder ratio was significantly higher with ¹⁸F-rhPSMA-7 (4.9 ± 5.3 vs. 2.2 ± 3.7, <i>P</i> = 0.02, for local recurrence; 9.8 ± 9.7 vs. 2.3 ± 2.6, <i>P</i> < 0.001, for primary prostate cancer). <b>Conclusion:</b> The tumor positivity rate was consistently high for ⁶⁸Ga-PSMA-11 and ¹⁸F-rhPSMA-7. Both tracers revealed a considerable number of areas of uptake that were reliably identified as benign by trained physicians making use of corresponding morphologic imaging and known PSMA pitfalls. These were more frequent with ¹⁸F-rhPSMA-7. However, the matched-pair comparison could have introduced a source of bias. Adequate reader training can allow physicians to differentiate benign uptake from disease and be able to benefit from the logistical and clinical advantages of ¹⁸F-rhPSMA-7.