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Background  PSMA-targeted radioligand therapy (PSMA-RLT) yielded impressive results in the metastasized castration-resistant prostate carcinoma (mCRPC) setting. High expression of PSMA is essential for successful PSMA-RLT. However, some patients develop [ 18 F]FDG-avid lesions with low or no PSMA expression ([ 18 F]FDG/[ 68 Ga]Ga-PSMA-11 mismatch findings on PET/CT) in the course of treatment. Those lesions are not affected by PSMA-RLT and a change in therapy management is needed. To enable early mismatch detection, possible blood parameters as indicators for the occurrence of [ 18 F]FDG/[ 68 Ga]Ga-PSMA-11 mismatch findings on PET/CT were evaluated.    Methods  Retrospective study of  N  = 66 advanced mCRPC patients with dual [ 68 Ga]Ga-PSMA-11 and [ 18 F]FDG PET/CT imaging within 4 weeks, who were referred for or received [ 177 Lu]Lu-PSMA-617 radioligand therapy. Prostate-specific antigen (PSA), neuron-specific enolase (NSE), gamma-glutamyltransferase (GGT), and alkaline phosphatase (ALP) were tested as indicators for the occurrence of [ 18 F]FDG/[ 68 Ga]Ga-PSMA-11 mismatch findings. Additional to absolute values, relative changes (ΔPSA, ΔNSE, ΔGGT, ΔALP) over a period of 4 ± 1 weeks prior to [ 18 F]FDG PET/CT were analyzed.    Results  In total, 41/66 (62%) patients revealed at least one [ 18 F]FDG/[ 68 Ga]Ga-PSMA-11 mismatch finding on PET/CT. These mismatch findings were detected in 13/41 (32%) patients by screening for and in 28/41 (68%) patients during PSMA-RLT. NSE serum level (55.4 ± 44.6 μg/l vs .  18.5 ± 8 μg/l,  p  < 0.001) and ΔNSE (93.8 ± 124.5% vs .  2.9 ± 39.5%,  p  < 0.001) were significantly higher in the mismatch group than in the non-mismatch group. No significant differences were found for serum PSA ( p  = 0.424), ΔPSA ( p  = 0.417), serum ALP ( p  = 0.937), ΔALP ( p  = 0.611), serum GGT ( p  = 0.773), and ΔGGT ( p  = 0.971). For NSE and ΔNSE, the maximum value of the Youden index in ROC analysis was at a cut-off level of 26.8 μg/l (sensitivity 78%, specificity 96%) and at + 13.9% (sensitivity 84%, specificity 75%), respectively. An introduced scoring system of both parameters achieved a sensitivity of 90% and a specificity of 88% for the occurrence of [ 18 F]FDG/[ 68 Ga]Ga-PSMA-11 mismatch.    Conclusion  We observed a significantly higher absolute serum concentration and a higher relative increase of NSE in advanced mCRPC patients with [ 18 F]FDG-avid and insufficient PSMA expressing metastases ([ 18 F]FDG/[ 68 Ga]Ga-PSMA-11 mismatch findings on PET/CT) in our cohort. NSE might be used as a potential laboratory indicator for [ 18 F]FDG/[ 68 Ga]Ga-PSMA-11 mismatch findings, if this observation is confirmed in future, ideally prospective, studies in larger patient cohorts.

Neuron-specific enolase has potential value as a biomarker for [18F]FDG/[68Ga]Ga-PSMA-11 PET mismatch findings in advanced mCRPC patients