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 ([¹⁸F]FDG) 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 [¹⁸F]FDG and [⁶⁸Ga]Ga-PSMA-11 maximum standardized uptake value (SUV_max), and calculated the [¹⁸F]FDG SUV_max/[⁶⁸Ga]Ga-PSMA-11 SUV_max quotient (FPQ). From follow-up [¹⁸F]FDG 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 [¹⁸F]FDG 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 [⁶⁸Ga]Ga-PSMA-11 SUV_max was significantly lower (p < 0.001), median FPQ significantly higher (p < 0.001), and median [¹⁸F]FDG SUV_max similar in progressing versus non-progressing lesions. [⁶⁸Ga]Ga-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: [⁶⁸Ga]Ga-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 Ga]Ga-PSMA-11 SUV_max and a high FPQ predict early lesional progression under RLT; [¹⁸F]FDG SUV_max does not. A score combining [⁶⁸ Ga]Ga-PSMA-11 SUV_max and FPQ predicts early lesional progression even more effectively and might therefore be useful to quantitatively identify mismatch lesions.

Scott David

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