Detection of tumour heterogeneity in patients with advanced, metastatic castration-resistant prostate cancer on 68GaGa-/18FF-PSMA-11/-1007, 68GaGa-FAPI-46 and 2-18FFDG PET/CT: a pilot study

Abstract Purpose In metastatic castration-resistant prostate cancer (mCRPC), some patients show low/absent PSMA expression in tumour lesions on positron emission tomography (PET) scans, indicating heterogeneity and heightened risk of non-response to PSMA-RLT (radioligand therapy). Imaging cancer-associated fibroblasts and glucose uptake may further characterise tumour heterogeneity in mCRPC patients. Here, we aimed to evaluate tumour heterogeneity and its potential implications for management in mCRPC patients assessed for PSMA-RLT using 68 GaGa-FAPI-46, 2- 18 FFDG and 68 GaGa-/ 18 FF-PSMA-11/-1007 PET. Material and Methods Patients with advanced, progressive mCRPC underwent clinical 68 GaGa-/ 18 FF-PSMA-11/-1007, 2- 18 FFDG and 68 GaGa-FAPI-46 PET/CT to evaluate treatment with PSMA-directed RLT. Tumour detection/semiquantitative parameters were compared on a per-lesion/-region basis. Two phenotypes were defined: Criteria for the mixed phenotype were: (a) PSMA-negative findings for lymph node metastases ≥ 2.5 cm, any solid organ metastases ≥ 1.0 cm, or bone metastases with soft tissue component ≥ 1.0 cm, (b) low 68 GaGa-/ 18 FF-PSMA-11/-1007 uptake and/or (c) balanced tumour uptake of all radioligands. The PSMA-dominant phenotype was assigned if the criteria were not met. Results In ten patients, 472 lesions were detected on all imaging modalities (miTNM regions: M1b: 327 (69.3%), M1a: 95 (20.1%), N1: 26 (5.5%), M1c: 18 (3.8%), T: 5 (1.1%) and Tr: 1 (0.2%). 68 GaGa-/ 18 FF-PSMA-11/-1007 (n = 453 (96.0%)) demonstrates the highest detection rate, followed by 68 GaGa-FAPI-46 (n = 268 (56.8%))/2- 18 FFDG (n = 241 (51.1%)). Semiquantitative uptake was highest for 68 GaGa-/ 18 FF-PSMA-11/-1007 (mean SUV max (interquartile range): 22.7 (22.5), vs. 68 GaGa-FAPI-46 (7.7 (3.7)) and 2- 18 FFDG (6.8 (4.7)). Seven/three patients were retrospectively assigned to the PSMA-dominant/mixed phenotype. Median overall survival was significantly longer for patients who underwent 177 LuLu-PSMA-617 RLT and were retrospectively assigned to the PSMA-dominant phenotype (19.7 vs. 9.3 months). Conclusion Through whole-body imaging, we identify considerable inter- and intra-patient heterogeneity of mCRPC and potential imaging phenotypes. Regarding uptake and tumour detection, 68 GaGa-/ 18 FF-PSMA-11/-1007 was superior to 68 GaGa-FAPI-46 and 2- 18 FFDG, while the latter two were comparable. Patients who underwent 177 LuLu-PSMA-617 RLT based on clinical-decision making had a longer overall survival and could be assigned to the PSMA-dominant phenotype. Graphical Abstract