Dual FDG/PSMA PET imaging to predict lesion-based progression of mCRPC during PSMA-RLT

Abstract Candidates for prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) of metastatic castration-resistant prostate cancer (mCRPC) frequently have “mismatch” lesions with pronounced 18-fluorodeoxyglucose ( 18 FFDG) but attenuated PSMA ligand uptake on positron emission tomography (PET). However, no quantitative criteria yet exist to identify mismatch lesions and predict their response to RLT. To define such criteria, we retrospectively analyzed 267 randomly-selected glucometabolic mCRPC metastases from 22 patients. On baseline PET, we determined 18 FFDG and 68 GaGa-PSMA-11 maximum standardized uptake value (SUV max ), and calculated the 18 FFDG SUV max / 68 GaGa-PSMA-11 SUV max quotient (FPQ). From follow-up 18 FFDG PET after two lutetium-177-PSMA-617 RLT cycles, we evaluated the treatment response and categorized the lesions into three subgroups (partial remission, stable disease, progression) based on change in 18 FFDG SUV max . Lastly, we compared the baseline PET variables in progressing versus non-progressing lesions. Variables differing significantly, and a score incorporating them, were assessed via receiver operator characteristic (ROC) curve analysis, regarding ability to predict lesional progression, with area under the curve (AUC) as metric. Cut-offs with optimal sensitivity and specificity were determined using the maximum value of Youden's index. Fifty-one of 267 lesions (19.1%) progressed, 102/267 (38.2%) manifested stable disease, and 114/267 (42.7%) partially responded after two RLT cycles. At baseline, median 68 GaGa-PSMA-11 SUV max was significantly lower ( p < 0.001), median FPQ significantly higher ( p < 0.001), and median 18 FFDG SUV max similar in progressing versus non-progressing lesions. 68 GaGa-PSMA-11 SUV max and FPQ showed predictive power regarding progression (AUCs: 0.89, 0.90). An introduced clinical score combining both further improved predictive performance (AUC: 0.94). Optimal cut-offs to foretell progression were: 68 GaGa-PSMA-11 SUV max < 11.09 (88.2% sensitivity, 81.9% specificity), FPQ ≥ 0.92 (90.2% sensitivity, 78.7% specificity), clinical score ≥ 6/9 points (88.2% sensitivity, 87.5% specificity). At baseline, a low 68 GaGa-PSMA-11 SUV max and a high FPQ predict early lesional progression under RLT; 18 FFDG SUV max does not. A score combining 68 GaGa-PSMA-11 SUV max and FPQ predicts early lesional progression even more effectively and might therefore be useful to quantitatively identify mismatch lesions.