Prostate cancer can be targeted by ligands to the prostate-specific membrane antigen (PSMA). We aimed to evaluate dosimetry, safety and efficacy of 177Lu-PSMA-617 radioligand therapy (RLT) in patients with metastatic castration-resistant prostate cancer (mCRPC).

We evaluated the accuracy of ⁶⁸Ga-PSMA-HBED-CC (⁶⁸Ga-PSMA) positron emission tomography/computed tomography (PET/CT) to localize cancer in the prostate and surrounding tissue at initial diagnosis. Methods: Twenty-one patients with biopsy-proven prostate cancer (PCa) underwent ⁶⁸Ga-PSMA PET/CT at a median of 4 (range: 0 to 47) days prior to radical prostatectomy. Based on a 6-segment model, the Gleason score (GS) and segmental tumor burden (STBHP) as determined by histopathology were correlated with maximum standardized uptake value (SUV_max) and tumor burden as determined by different SUV cut-off values for ⁶⁸Ga-PSMA PET (STBPET1-6). Furthermore, the involvement of seminal vesicles and other extracapsular extension were assessed by histopathology and PET/CT. Results: Histopathology positive (+) segments (n = 100 of 126, 79%) demonstrated a significantly higher mean±standard deviation (SD) SUV_max (11.8±7.6) as compared to histopathology negative (-) segments (4.9±2.9; p<0.001). Receiver-operating-characteristic revealed an optimal SUV_max cut-off value of 6.5 for discrimination of histopathology+/- segments (area under the curve, AUC: 0.84; p<0.001) which gave 67% sensitivity, 92% specificity, 97% positive predictive value, 42% negative predictive value, and 72% accuracy. STBPET3 as determined by 2xSUVblood+2xSD correlated best with STBHP (Pearson’s rho=0.68; p<0.001; mean difference±SD = 19±15%). PET/CT correctly detected invasion of seminal vesicles (n = 11 of 21 patients; 52%) with 86% accuracy, and tumor spread through the capsule (n = 12; 57%) with 71% accuracy. Conclusion: ⁶⁸Ga-PSMA PET/CT accurately detects location and extent of primary prostate cancer. Our preliminary findings warrant further investigation of ⁶⁸Ga-PSMA PET/CT in conjunction with needle biopsy.

Purpose: We report efficacy and safety of 90Y-labeled FAPI-46 (90Y-FAPI-46-RLT) in patients with advanced sarcoma, pancreatic cancer, and other cancer entities. Experimental Design: Up to four cycles of radioligand therapy (RLT) were offered to patients with (i) progressive metastatic malignancy, (ii) exhaustion of approved therapies, and (iii) high fibroblast activation protein (FAP) expression, defined as SUVmax ≥ 10 in more than 50% of tumor. Primary endpoint was RECIST response after RLT. Secondary endpoints included PET response (PERCIST), overall survival (OS), dosimetry, and safety of FAP-RLT. Results: Among 119 screened patients, 21 (18%) were found eligible [n = 16/3/1/1 sarcoma/pancreatic cancer/prostate/gastric cancer; 38% Eastern Cooperative Oncology Group (ECOG) ≥ 2] and received 47 90Y-FAPI-46-RLT cycles; 16 of 21 (76%) patients underwent repeat RLT. By RECIST, disease control was confirmed in 8 of 21 patients [38%; 8/16 (50%) of evaluable patients). There was one partial response (PR) and seven stable diseases after RLT. Disease control was associated with prolonged OS (P = 0.013). PERCIST response was noted in 8 of 21 patients [38%; 8/15 (53%) of evaluable patients]. Dosimetry was acquired in 19 (90%) patients. Mean absorbed dose was 0.53 Gy/GBq in kidney, 0.04 Gy/GBq in bone marrow, and <0.14 Gy/GBq in liver and lung. Treatment-related grade 3 or 4 adverse events were observed in 8 (38%) patients with thrombocytopenia (n = 6) and anemia (n = 6) being most prevalent. Conclusions: 90Y-FAPI-46-RLT was safe and led to RECIST PR in one case as well as stable disease in about one third of patients with initially progressive sarcomas, pancreatic cancer, and other cancers. Discontinuation after the first cycle and a low rate of PR requires future improvement of FAP-RLT.

Introduction: Fibroblast activation protein (FAP) is overexpressed in several solid tumors and therefore represents an attractive target for radiotheranostic applications. Recent investigations demonstrated rapid and high uptake of small-molecule inhibitors of FAP (⁶⁸Ga-FAPI-46) for PET imaging. Here, we report our initial experience in terms of feasibility and safety of ⁹⁰Y-labelled FAPI-46 (⁹⁰Y-FAPI-46) for radioligand therapy (RLT) of extensively pretreated patients with solid tumors. Methods: Patients were considered for ⁹⁰Y-FAPI-46 therapy in case of (a) exhaustion of all approved therapies based on multidisciplinary tumor board decision and (b) high FAP expression, defined as SUV_max ≥ 10 in more than 50% of all lesions. If tolerated, post-therapeutic ⁹⁰Y-FAPI-46 bremsstrahlung scintigraphy was performed to visually confirm systemic distribution and focal tumor uptake, and ⁹⁰Y-FAPI-46 PET scans at multiple time-points were performed to determine absorbed dose. Blood-based dosimetry was used to determine bone-marrow absorbed dose. Adverse Events were graded using CTCAE v.5.0. Results: Nine patients with either metastatic soft tissue or bone sarcoma (N = 6) and pancreatic cancer (N = 3) were treated between June 2020 and March 2021. Patients received a median of 3.8 (IQR 3.25-5.40) GBq for the first cycle and three patients received subsequent cycles with a median of 7.4 (IQR 7.3-7-5) GBq. Post-therapy ⁹⁰Y-FAPI-46 bremsstrahlung scintigraphy demonstrated sufficient ⁹⁰Y-FAPI-46 uptake in tumor lesions in 7 of 9 patients (78%). Mean absorbed dose was 0.52 Gy/GBq (IQR 0.41-0.65) in kidney, 0.04 Gy/GBq (IQR 0.03-0.06) in bone marrow and below 0.26 Gy/GBq in the lung and liver. Measured tumor lesions received up to 2.28 Gy/GBq (median 1.28 Gy/GBq). Hematologic G3/G4 toxicities were noted in four patients (44%), of which thrombocytopenia was most prevalent (N = 6; 67%), whereas other G3/G4 laboratory-based adverse events were N ≤ 2. No acute toxicities attributed to ⁹⁰Y-FAPI-46 were noted. Radiographic disease control was noted in three patients (33 %). Conclusion: FAP-targeted RLT with ⁹⁰Y-FAPI-46 was well tolerated with a low rate of attributable adverse events. Low radiation doses to organs at risk suggest feasibility of repeat cycles of ⁹⁰Y-FAPI-46. We observe signs of clinical activity, but further studies are warranted to determine efficacy and toxicity profile in a larger cohort.

Introduction: Bone and soft tissue sarcomas express fibroblast activation protein (FAP) on tumor cells and associated fibroblast. Therefore, FAP is a promising therapeutic and diagnostic target. Novel radio-labelled FAP-Inhibitors (e.g. ⁶⁸Ga-FAPI46) have shown high tumor uptake in positron emission tomography (PET) in sarcoma patients. Here we report endpoints of the FAPI-PET prospective observational trial. Methods: Forty-seven patients with bone or soft tissue sarcomas undergoing clinical ⁶⁸Ga-FAPI-PET were eligible for enrollment into the FAPI-PET observational trial. Of these patients, 43 patients also underwent ¹⁸F-Fluordesoxyglucose PET (FDG). The primary study endpoint was the association of ⁶⁸Ga-FAPI-PET uptake intensity and histopathological FAP-expression analyzed with Spearman’s r correlation. Secondary endpoints were detection rate, positive predictive value (PPV), interreader reproducibility, and change in management. Datasets were interpreted by two blinded readers. Results: Primary endpoint was met and the association between FAPI-PET uptake intensity and histopathological FAP-expression was significant (Spearman’s r = 0.43; P = 0.03). By histopathological validation PPV was 1.00 (95% CI, 0.87-1.00) on a per-patient and 0.97 (95% CI, 0.84-1.00) on a per-region basis. In cases with histopathologic validation, 27 of 28 (96%) confirmed patients and 32 of 34 (94%) confirmed regions were PET positive resulting in an SE of 0.96 (95%CI, 0.82-1.00) on a per-patient and 0.94 (95%CI, 0.80-0.99) on a per-region basis. The detection rate on a per-patient basis in FAPI- and FDG-PET was 76.6% and 81.4%, respectively. In 8 (18.6%) patients FAPI-PET resulted in an upstaging compared to FDG-PET. FAPI-PET readers showed substantial to almost perfect agreement for the defined regions (Fleiss kappa: primary κ = 0.78; local nodal κ = 0.54; distant nodal κ = 0.91; lung κ = 0.86; bone κ = 0.69 and other κ = 0.65). Clinical management changed in 13 (30%) patients after FAPI-PET. Conclusion: We confirm an association of tumoral FAPI-PET uptake intensity and histopathological FAP expression in sarcoma patients. Further, using blinded reads and independent histopathological validation we report high PPV and sensitivity of FAPI-PET for sarcoma staging.