Actinium-225-PSMA radioligand therapy of metastatic castration-resistant prostate cancer (WARMTH Act): a multicentre, retrospective study.

BACKGROUND: Actinium-225 (225Ac) prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a novel therapy for metastatic castration-resistant prostate cancer (mCRPC). We aimed to report the safety and antitumour activity of 225Ac-PSMA RLT of mCRPC in a large cohort of patients treated at multiple centres across the world. METHODS: This retrospective study included patients treated at seven centres in Australia, India, Germany, and South Africa. We pooled data of consecutive patients of any age and Eastern Cooperative Oncology Group performance status with histopathologically confirmed adenocarcinoma of the prostate who were treated with one or more cycles of 8 MBq 225Ac-PSMA RLT administered intravenously for mCRPC. Previous lines of mCRPC treatment included taxane-based chemotherapy, androgen-receptor-axis inhibitors, lutetium-177 (177Lu) PSMA RLT, and radium-223 dichloride. The primary outcomes were overall survival and progression-free survival. FINDINGS: Between Jan 1, 2016, and May 31, 2023, 488 men with mCRPC received 1174 cycles of 225Ac-PSMA RLT (median two cycles, IQR 2-4). The mean age of the patients was 68·1 years (SD 8·8), and the median baseline prostate-specific antigen was 169·5 ng/mL (IQR 34·6-519·8). Previous lines of treatment were docetaxel in 324 (66%) patients, cabazitaxel in 103 (21%) patients, abiraterone in 191 (39%) patients, enzalutamide in 188 (39%) patients, 177Lu-PSMA RLT in 154 (32%) patients, and radium-223 dichloride in 18 (4%) patients. The median follow-up duration was 9·0 months (IQR 5·0-17·5). The median overall survival was 15·5 months (95% CI 13·4-18·3) and median progression-free survival was 7·9 months (6·8-8·9). In 347 (71%) of 488 patients, information regarding treatment-induced xerostomia was available, and 236 (68%) of the 347 patients reported xerostomia after the first cycle of 225Ac-PSMA RLT. All patients who received more than seven cycles of 225Ac-PSMA RLT reported xerostomia. Grade 3 or higher anaemia occurred in 64 (13%) of 488 patients, leukopenia in 19 (4%), thrombocytopenia in 32 (7%), and renal toxicity in 22 (5%). No serious adverse events or treatment-related deaths were recorded. INTERPRETATION: 225Ac-PSMA RLT shows a substantial antitumour effect in mCRPC and represents a viable therapy option in patients treated with previous lines of approved agents. Xerostomia is a common side-effect. Severe bone marrow and renal toxicity are less common adverse events. FUNDING: None.

90Y post-radioembolization clinical assessment with whole-body Biograph Vision Quadra PET/CT: image quality, tumor, liver and lung dosimetry.

PURPOSE: Evaluation of 90Y liver radioembolization post-treatment clinical data using a whole-body Biograph Vision Quadra PET/CT to investigate the potential of protocol optimization in terms of scan time and dosimetry. METHODS: 17 patients with hepatocellular carcinoma with median (IQR) injected activity 2393 (1348-3298) MBq were included. Pre-treatment dosimetry plan was based on 99mTc-MAA SPECT/CT with Simplicit90Y™ and post-treatment validation with Quadra using Simplicit90Y™ and HERMIA independently. Regarding the image analysis, mean and peak SNR, the coefficient of variation (COV) and lesion-to-background ratio (LBR) were evaluated. For the post-treatment dosimetry validation, the mean tumor, whole liver and lung absorbed dose evaluation was performed using Simplicit90Y and HERMES. Images were reconstructed with 20-, 15-, 10-, 5- and 1- min sinograms with 2, 4, 6 and 8 iterations. Wilcoxon signed rank test was used to show statistical significance (p < 0.05). RESULTS: There was no difference of statistical significance between 20- and 5- min reconstructed times for the peak SNR, COV and LBR. In addition, there was no difference of statistical significance between 20- and 1- min reconstructed times for all dosimetry metrics. Lung dosimetry showed consistently lower values than the expected. Tumor absorbed dose based on Simplicit90Y™ was similar to the expected while HERMES consistently underestimated significantly the measured tumor absorbed dose. Finally, there was no difference of statistical significance between expected and measured tumor, whole liver and lung dose for all reconstruction times. CONCLUSION: In this study we evaluated, in terms of image quality and dosimetry, whole-body PET clinical images of patients after having been treated with 90Y microspheres radioembolization for liver cancer. Compared to the 20-min standard scan, the simulated 5-min reconstructed images provided equal image peak SNR and noise behavior, while performing also similarly for post-treatment dosimetry of tumor, whole liver and lung absorbed doses.

Translational assessment of a DATA-functionalized FAP inhibitor with facile 68Ga-labeling at room temperature.

PURPOSE: The present study aims at evaluating the preclinical and the clinical performance of [68Ga]Ga-DATA5m.SA.FAPi, which has the advantage to be labeled with gallium-68 at room temperature. METHODS: [68Ga]Ga-DATA5m.SA.FAPi was assessed in vitro on FAP-expressing stromal cells, followed by biodistribution and in vivo imaging on prostate and glioblastoma xenografts. Moreover, the clinical assessment of [68Ga]Ga-DATA5m.SA.FAPi was conducted on six patients with prostate cancer, aiming on investigating, biodistribution, biokinetics, and determining tumor uptake. RESULTS: [68Ga]Ga-DATA5m.SA.FAPi is quantitatively prepared in an instant kit-type version at room temperature. It demonstrated high stability in human serum, affinity for FAP in the low nanomolar range, and high internalization rate when associated with CAFs. Biodistribution and PET studies in prostate and glioblastoma xenografts revealed high and specific tumor uptake. Elimination of the radiotracer mainly occurred through the urinary tract. The clinical data are in accordance with the preclinical data concerning the organ receiving the highest absorbed dose (urinary bladder wall, heart wall, spleen, and kidneys). Different to the small-animal data, uptake of [68Ga]Ga-DATA5m.SA.FAPi in tumor lesions is rapid and stable and tumor-to-organ and tumor-to-blood uptake ratios are high. CONCLUSION: The radiochemical, preclinical, and clinical data obtained in this study strongly support further development of [68Ga]Ga-DATA5m.SA.FAPi as a diagnostic tool for FAP imaging.

Nomograms to predict outcomes after 177Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: an international, multicentre, retrospective study.

BACKGROUND: Lutetium-177 (177Lu) prostate-specific membrane antigen (177Lu-PSMA) is a novel targeted treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). Predictors of outcomes after 177Lu-PSMA to enhance its clinical implementation are yet to be identified. We aimed to develop nomograms to predict outcomes after 177Lu-PSMA in patients with mCRPC. METHODS: In this multicentre, retrospective study, we screened patients with mCRPC who had received 177Lu-PSMA between Dec 10, 2014, and July 19, 2019, as part of the previous phase 2 trials (NCT03042312, ACTRN12615000912583) or compassionate access programmes at six hospitals and academic centres in Germany, the USA, and Australia. Eligible patients had received intravenous 6·0-8·5 GBq 177Lu-PSMA once every 6-8 weeks, for a maximum of four to six cycles, and had available baseline [68Ga]Ga-PSMA-11 PET/CT scan, clinical data, and survival outcomes. Putative predictors included 18 pretherapeutic clinicopathological and [68Ga]Ga-PSMA-11 PET/CT variables. Data were collected locally and centralised. Primary outcomes for the nomograms were overall survival and prostate-specific antigen (PSA)-progression-free survival. Nomograms for each outcome were computed from Cox regression models with LASSO penalty for variable selection. Model performance was measured by examining discrimination (Harrell's C-index), calibration (calibration plots), and utility (patient stratification into low-risk vs high-risk groups). Models were validated internally using bootstrapping and externally by calculating their performance on a validation cohort. FINDINGS: Between April 23, 2019, and Jan 13, 2020, 414 patients were screened; 270 (65%) of whom were eligible and were divided into development (n=196) and validation (n=74) cohorts. The median duration of follow-up was 21·5 months (IQR 13·3-30·7). Predictors included in the nomograms were time since initial diagnosis of prostate cancer, chemotherapy status, baseline haemoglobin concentration, and [68Ga]Ga-PSMA-11 PET/CT parameters (molecular imaging TNM classification and tumour burden). The C-index of the overall survival model was 0·71 (95% CI 0·69-0·73). Similar C-indices were achieved at internal validation (0·71 [0·69-0·73]) and external validation (0·72 [0·68-0·76]). The C-index of the PSA-progression-free survival model was 0·70 (95% CI 0·68-0·72). Similar C-indices were achieved at internal validation (0·70 [0·68-0·72]) and external validation (0·71 [0·68-0·74]). Both models were adequately calibrated and their predictions correlated with the observed outcome. Compared with high-risk patients, low-risk patients had significantly longer overall survival in the validation cohort (24·9 months [95% CI 16·8-27·3] vs 7·4 months [4·0-10·8]; p<0·0001) and PSA-progression-free survival (6·6 months [6·0-7·1] vs 2·5 months [1·2-3·8]; p=0·022). INTERPRETATION: These externally validated nomograms that are predictive of outcomes after 177Lu-PSMA in patients with mCRPC might help in clinical trial design and individual clinical decision making, particularly at institutions where 177Lu-PSMA is introduced as a novel therapeutic option. FUNDING: Prostate Cancer Foundation.

Dosing 225Ac-DOTATOC in patients with somatostatin-receptor-positive solid tumors: 5-year follow-up of hematological and renal toxicity.

PURPOSE: The aim of this retrospective analysis is to estimate the most appropriate single cycle and cumulative doses of 225Ac-DOTATOC in patients treated for somatostatin-receptor-expressing cancers. METHODS: 225Ac-DOTATOC was administered to thirty-nine patients with various somatostatin-receptor-positive tumors. Baseline and follow-up 68Ga-DOTATOC PET/CT, lab tests, and renal scintigraphy were obtained. Patients received long-term follow-up either at the local cancer center or in close collaboration with external oncologists. Acute and chronic hematological toxicity was evaluated quantitatively over time. Long-term follow-up of creatinine was used to approximate the annual loss of estimated GFR (eGFR). RESULTS: Dose-dependent acute hematological toxicity was seen at single doses above 40 MBq or repeated doses greater than approximately 20 MBq 225Ac-DOTATOC at 4 month intervals. Treatment-related kidney failure occurred in 2 patients after a delay of >4 years but was independent of administered radioactivity, and other clinical risk factors were important contributors to renal decline. In general, the annual decline of eGFR among patients did not follow a clear dose-effect relationship even in patients with previous ß-therapy. An average eGFR-loss of 8.4ml/min (9.9%) per year was observed which is similar to the experience with ß-therapy studies. CONCLUSION: Treatment activities of approx. 20 MBq per cycle (4 monthly repetition) and cumulative doses up to 60-80 MBq generally avoided both acute and chronic grade 3/4 hematotoxicity in patients with advanced stage malignancies. Chronic renal toxicity was observed at these doses, but pre-existing renal risk factors were important co-factors. These data represent a starting point for additional research to more precisely define safety thresholds of 225Ac-DOTATOC.

The impact of the extent of the bone involvement on overall survival and toxicity in mCRPC patients receiving [177Lu]Lu-PSMA-617: a WARMTH multicentre study.

INTRODUCTION: Prostate-specific membrane antigen (PSMA)-based radioligand therapy (RLT) showed in a multicentre WARMTH (World Association of Radiopharmaceutical and Molecular Therapy) study that the presence of bone metastases is a negative prognosticator for the survival. The current multicentre retrospective analysis aims to evaluate the response rate to RLT, the overall survival (OS) of patients and the safety of the treatment according to the extent of bone involvement. METHODS: The study included patients with progressive metastatic castration-resistant prostate cancer (mCRPC), who underwent RLT with [177Lu]Lu-PSMA-617 and a follow-up of at least 6 months. Tumour burden in the bone was classified prior to RLT as follows: less than 6 lesions, 6-20 lesions, more than 20 lesions and diffuse involvement. The response rate was evaluated using changes of the prostate-specific antigen (PSA) after the first treatment cycle. Overall survival was calculated from the date of the first treatment. Haematological adverse events were classified according to Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. RESULTS: A total of 319 males were included in the analysis. The extent of bone metastases and PSA response did not correlate significantly. Any PSA decline was observed in 73% patients; 44% showed a decline of ≥50%. The median OS of patient in the different subgroups was 18 months (less than 6 lesions), 13 months (6-20 lesions), 11 months (more than 20 lesions) and 8 months (diffuse involvement), respectively (p < 0.0001). Patients with prior Ra-223-therapy showed longer OS in all subgroups, especially in the subgroups with 6-20 lesions (OS: 16 vs. 12 months; p = 0.038) as well as diffuse involvement (OS: 11 vs. 7 months; p = 0.034). Significant negative prognosticators of OS were the existence of liver metastases in all subgroups and prior chemotherapy in patients with <6 bone lesions. Anaemia and thrombocytopenia correlated positively with the extent of bone metastases: p < 0.0001 and 0.005, respectively. No patient showed a high grade leukopenia. CONCLUSION: The extent of bone involvement correlated negatively with the OS after RLT; however, it showed no relevant correlation with the PSA response rate. Prior therapy with Ra-223 may have a positive impact on OS. Haematotoxicity was higher in patients with more than 20 bone lesions; nevertheless, the majority of these patients did not show a relevant haematotoxicity.

Prior therapies as prognostic factors of overall survival in metastatic castration-resistant prostate cancer patients treated with [177Lu]Lu-PSMA-617. A WARMTH multicenter study (the 617 trial).

INTRODUCTION: The impact of prior therapies, especially chemotherapy, on overall survival (OS) in patients with castration-resistant prostate cancer (CRPC) receiving [177Lu]Lu-PSMA-617 therapy has been the subject of controversy. Therefore, WARMTH decided to plan a multicenter retrospective analysis (the "617 trial") to evaluate response rate and OS as well as the impact of prior therapies on OS in more than 300 patients treated with 177Lu-PSMA-617. MATERIALS AND METHODS: The data of 631 metastatic CRPC (mCRPC) patients from 11 different clinics were evaluated. According to the inclusion and exclusion criteria, all patients had to have received at least abiraterone or enzalutamide prior to [177Lu]Lu-PSMA-617 therapy. The patients were divided into three groups: patients who had received prior chemotherapy, patients who avoided chemotherapy, and patients for whom a chemotherapy was contraindicated. RESULTS: The analysis included the data of 416 patients, with a median age of 71.9 years. At the time of analysis, 87 patients (20,9%) were still alive. A total of 53.6% of patients had received both abiraterone and enzalutamide; 75.5% and 26.4% had a history of chemotherapy with docetaxel and cabazitaxel, respectively. A total of 20.4% had had Ra-223. The median OS was 11.1 months. Prior chemotherapy, the existence of bone and liver metastases, as well as Eastern Cooperative Oncology Group (ECOG) status, were significant prognosticators of worse overall survival in both univariate and multivariate analyses. Patients without any prior chemotherapy showed a significantly longer OS (14.6 months). The median OS in patients who received one or two lines of chemotherapy with docetaxel or docetaxel followed by cabazitaxel, respectively, was 10.9 months and 8.9 months. There was no difference in OS between patients who had not received chemotherapy and patients for whom chemotherapy was contraindicated. The other prior therapies did not have any significant impact on OS. CONCLUSION: In the present multicenter analysis, chemotherapy-naïve mCRPC patients receiving [177Lu]Lu-PSMA-617 therapy had a significantly longer OS than patients with a history of chemotherapy. This remained independent in the multivariate analysis besides presence of bone and liver metastases as negative prognosticators for survival, whereas an ECOG of 0-1 is associated with a longer OS.

Initial clinical experience performing sialendoscopy for salivary gland protection in patients undergoing 225Ac-PSMA-617 RLT.

PURPOSE: The main side effect of prostate-specific membrane antigen targeting alpha therapy (PSMA TAT) is dry mouth syndrome. Inflammation of the salivary glands and consequent reduced salivary function have been reported in patients after radioiodine therapy. The beneficial effects of sialendoscopy on radiation-induced inflammation in tissue are well known. Thus sialendoscopy with dilatation, saline irrigation and steroid injections (prednisolone) was performed before and after 225Ac-PSMA-617 TAT to reduce inflammatory effects in the salivary glands and to improve or prevent xerostomia. METHODS: Eleven men with metastatic castration-resistant prostate cancer (mean age 68.5 years, range 58-80 years) underwent sialendoscopy, dilatation, saline irrigation and steroid injection of both submandibular and both parotid glands before or after every cycle of 225Ac-PSMA-617 TAT. Sialendoscopy and steroid injection were performed by a senior ENT physician. Quality of life was evaluated using two health-related quality of life (HRQOL) questionnaires, the Xerostomia Questionnaire (XQ) and the Xerostomia Inventory (XI) before and 3 months after the intervention. RESULTS: In all 11 patients both parotid and both submandibular glands were affected by radiation sialadenitis and sialendoscopy was performed. The patients experienced no complications after sialendoscopy, and showed a significant improvement in HRQOL as measured using the XQ and XI. After sialendoscopy the XQ score decreased significantly from 77.7 ± 13.6 to 42.7 ± 14.8 (p = 0.003) and the XI score decreased from 44.5 ± 6.9 to 25.8 ± 12.8 (p = 0.003). Due to the limited number of patients we only report tendencies. CONCLUSION: Sialendoscopy with dilatation, saline irrigation and steroid injection had beneficial effects on salivary gland function and HRQOL in patients undergoing 225Ac-PSMA-617 RLT. However, even with sialadenoscopic support after multiple cycles of TAT, salivary gland function was reduced and xerostomia was present. Therefore, not only inflammation but also the direct effect of radiation is a putative cause of dry mouth. Further research is necessary to determine the main side effects of PSMA TAT.

Validating the Xerostomia Inventory in a radiation-induced xerostomia population in German language.

OBJECTIVES: Though xerostomia is a frequent oral symptom, there is no validated disease-specific questionnaire in German. The purpose of this study was to translate and validate versions of the Xerostomia Inventory and the Summated Xerostomia Inventory in a German-speaking population. PARTICIPANTS AND METHODS: Thirty-nine patients including 18 patients suffering from radiation-induced xerostomia enrolled in this study. Both questionnaires were translated into German language according to international accepted guidelines. For validation, we evaluated reliability, validity, and responsiveness using the COSMIN manual for cross-cultural adaptation. RESULTS: Cronbach's α was 0.92 for XI and 0.91 for SXI, showing both high internal consistency. Patients suffering from xerostomia showed significantly higher average scores demonstrating its discriminant validity. Confirmatory factor analysis showed excellent "goodness-of-fit" values for SXI and good to moderate values for XI, confirming the assumed factor structures. The Xerostomia Inventory and its summated version both showed excellent test-retest reliability in the non-xerostomia group (ICC = 0.85 and 0.84). CONCLUSIONS: The XI and SXI in their cross-cultural adapted versions are the first validated self-report assessments for xerostomia in German language. They are characterized by practical design and can be easily interpreted by the treating physician.

Targeted alpha therapy of mCRPC: Dosimetry estimate of 213Bismuth-PSMA-617.

PURPOSE: PSMA-617 is a small molecule targeting the prostate-specific membrane antigen (PSMA). In this work, we estimate the radiation dosimetry for this ligand labeled with the alpha-emitter 213Bi. METHODS: Three patients with metastatic prostate cancer underwent PET scans 0.1 h, 1 h, 2 h, 3 h, 4 h and 5 h after injection of 68Ga-PSMA-617. Source organs were kidneys, liver, spleen, salivary glands, bladder, red marrow and representative tumor lesions. The imaging nuclide 68Ga was extrapolated to the half-life of 213Bi. The residence times of 213Bi were forwarded to the instable daughter nuclides. OLINDA was used for dosimetry calculation. Results are discussed in comparison to literature data for 225Ac-PSMA-617. RESULTS: Assuming a relative biological effectiveness of 5 for alpha radiation, the dosimetry estimate revealed equivalent doses of mean 8.1 Sv RBE5/GBq for salivary glands, 8.1 Sv RBE5/GBq for kidneys and 0.52 Sv RBE5/GBq for red marrow. Liver (1.2 Sv RBE5/GBq), spleen (1.4 Sv RBE5/GBq), bladder (0.28 Sv RBE5/GBq) and other organs (0.26 SvRBE5/GBq) were not dose-limiting. The effective dose is 0.56 Sv RBE5/GBq. Tumor lesions were in the range 3.2-9.0 SvRBE5/GBq (median 7.6 SvRBE5/GBq). Kidneys would limit the cumulative treatment activity to 3.7 GBq; red marrow might limit the maximum single fraction to 2 GBq. Despite promising results, the therapeutic index was inferior compared to 225Ac-PSMA-617. CONCLUSIONS: Dosimetry of 213Bi-PSMA-617 is in a range traditionally considered reasonable for clinical application. Nevertheless, compared to 225Ac-PSMA-617, it suffers from higher perfusion-dependent off-target radiation and a longer biological half-life of PSMA-617 in dose-limiting organs than the physical half-life of 213Bi, rendering this nuclide as a second choice radiolabel for targeted alpha therapy of prostate cancer.

Deescalated 225Ac-PSMA-617 Versus 177Lu/225Ac-PSMA-617 Cocktail Therapy: A Single-Center Retrospective Analysis of 233 Patients.

The aim of this work is to evaluate our clinical real-world data obtained with 225Ac-PSMA-617 (AcPSMA), which were acquired under compassionate care regulations in patients with advanced-stage prostate cancer. The objective parameters that could be derived from this evaluation are compared with previous literature about AcPSMA and 177Lu-PSMA-617 (LuPSMA). Methods: The medical files of all patients who had received AcPSMA on an individual patient basis at the Heidelberg University Hospital since January 2014 were analyzed retrospectively. Previously published patients were excluded. The remaining patients were tailored into 2 subgroups with different treatment strategies: group 1 received AcPSMA as a deescalated monotherapy, and group 2 received LuPSMA plus AcPSMA as a cocktail regimen. Baseline characteristics, serum prostate-specific antigen (PSA) response, and overall survival were compared with the most appropriate historical controls. Results: Of 287 patients treated, 54 were excluded because of previous publication and 233 were evaluated, 104 of whom received AcPSMA monotherapy (median, 6 MBq). In this group, 55 patients (53%) presented with a best PSA response of at least 50%. The other 129 patients received a cocktail therapy of AcPSMA (median, 4 MBq) plus LuPSMA (4 GBq). In this group, a best PSA response of at least 50% was observed in 74 patients (57%). The median overall survival in the monogroup was 9 mo and in the cocktail group was 15 mo. If adjusted for prognostic baseline characteristics, the efficacy of both regimens was not significantly different. Conclusion: Deescalated treatment activities of AcPSMA or AcPSMA and LuPSMA cocktail regimens present better tolerability with regard to xerostomia than previous regimens of at least 100 kBq/kg while retaining high antitumor activity in poor-prognosis prostate cancer patients.

Phantom study for 90Y liver radioembolization dosimetry with a long axial field-of-view PET/CT.

PURPOSE: The physical properties of yttrium-90 (90Y) allow for imaging with positron emission tomography/computed tomography (PET/CT). The increased sensitivity of long axial field-of-view (LAFOV) PET/CT scanners possibly allows to overcome the small branching ratio for positron production from 90Y decays and to improve for the post-treatment dosimetry of 90Y of selective internal radiation therapy. METHODS: For the challenging case of an image quality body phantom, we compare a full Monte Carlo (MC) dose calculation with the results from the two commercial software packages Simplicit90Y and Hermes. The voxel dosimetry module of Hermes relies on the 90Y images taken with a LAFOV PET/CT, while the MC and Simplicit90Y dose calculations are image independent. RESULTS: The resulting doses from the MC calculation and Simplicit90Y agree well within the error margins. The image-based dose calculation with Hermes, however, consistently underestimates the dose. This is due to the mismatch of the activity distribution in the PET images and the size of the volume of interest. We found that only for the smallest phantom sphere there is a statistically significant dependence of the Hermes dose on the image reconstruction parameters and scan time. CONCLUSION: Our study shows that Simplicit90Y's local deposition model can provide a reliable dose estimate. On the other hand, the image based dose calculation suffers from the suboptimal reconstruction of the 90Y distribution in small structures.

The Theranostic Optimization of PSMA-GCK01 Does Not Compromise the Imaging Characteristics of [99mTc]Tc-PSMA-GCK01 Compared to Dedicated Diagnostic [99mTc]Tc-EDDA/HYNIC-iPSMA in Prostate Cancer.

PURPOSE: Radiolabeled PSMA-ligands play a major role in today's nuclear medicine. Since approval of [177Lu]Lu-PSMA-617 for therapy of metastatic prostate cancer, availability of 177Lu became bottleneck of supply due to the high demand. Recently, a theranostic PSMA-ligand, PSMA-GCK01, was developed which can be labeled either diagnostically with 99mTc or therapeutically with 188Re with both nuclides available from well-known generator systems. This novel tracer might aid to overcome aforementioned supply limitations. In this investigation, the biodistribution and general imaging characteristics of [99mTc]Tc-PSMA-GCK01 were compared with the diagnostic reference compound [99mTc]Tc-EDDA/HYNIC-iPSMA in patients with advanced stage prostate cancer. In addition, the binding of both ligands to PSMA was analyzed at the molecular level using molecular docking. PROCEDURES: Two cohorts (n = 19 vs. n = 21) of patients with metastatic castration-resistant prostate cancer matched for age, tumor stage, and Gleason score underwent a planar gamma camera imaging with [99mTc]Tc-EDDA/HYNIC-iPSMA or [99mTc]Tc-PSMA-GCK01 prior to PSMA-ligand therapy for PSMA-phenotyping. The imaging data were retrospective analyzed for salivary gland, kidney, liver, soft tissue, and tumor uptake on a semi-automated ROI-analysis using HERMES Medical Solutions AB (HMS, Sweden). RESULTS: The data sets were semi-automated quantified on a ROI-based analysis. The tumor-to-background presented equal results of [99mTc]Tc-PSMA-GCK01 compared to [99mTc]Tc-EDDA/HYNIC-iPSMA. The physiological PSMA-positive organs like salivary gland presented also equal uptake in counts/MBq (salivary gland median 9.48 [99mTc]Tc-PSMA-GCK01 vs. median 9.11 [99mTc]Tc-EDDA/HYNIC-iPSMA), while liver-to-kidney ratio presented a slight shift to the liver parenchyma using [99mTc]Tc-PSMA-GCK01 (0.83) compared to [99mTc]Tc-EDDA/HYNIC-iPSMA (0.55) with no statistical significance. This is in agreement with the results from the docking study revealing only a minor difference in the docking scores for both ligands. CONCLUSIONS: The novel theranostic tracer [99mTc]Tc/[188Re]Re-PSMA-GCK01 demonstrates comparable general imaging characteristic with the reference compound [99mTc]Tc-EDDA/HYNIC-iPSMA. These results pave the way for the PSMA-targeting imaging and theranostic agents for a broader, rather low-cost, generator applied radio-ligand therapy utilization.

PSMA-GCK01: A Generator-Based 99mTc/188Re Theranostic Ligand for the Prostate-Specific Membrane Antigen.

Prostate-specific membrane antigen (PSMA) theranostics have been introduced with 68Ga and 177Lu, the most used radionuclides. However, 188Re is a well-known generator-based therapeutic nuclide that completes a theranostic tandem with 99mTc and may offer an interesting alternative to the currently used radionuclides. In the present work, we aimed at the development of a PSMA-targeted 99mTc/188Re theranostic tandem. Methods: The ligand HYNIC-iPSMA was chosen as the lead structure. Its HYNIC chelator has limitations for 188Re labeling and was replaced by mercaptoacetyltriserine to obtain PSMA-GCK01, a precursor for stable 99mTc and 188Re labeling. 99mTc-PSMA-GCK01 was used for in vitro evaluation of the ligand and comparison with 99mTc-EDDA/HYNIC-iPSMA. Planar imaging using 99mTc-PSMA-GCK01 and organ biodistribution with 188Re-PSMA-GCK01 were performed using LNCaP tumor-bearing mice. Finally, the theranostic tandem was applied for imaging and therapy in 3 prostate cancer patients in compassionate care. Results: Efficient radiolabeling of PSMA-GCK01 with both radionuclides was demonstrated. Cell-based assays with 99mTc-PSMA-GCK01 versus 99mTc-EDDA/HYNIC-iPSMA revealed comparable uptake characteristics. Planar imaging and organ distribution revealed good tumor uptake of both 99mTc-PSMA-GCK01 and 188Re-PSMA-GCK01 at 1 and 3 h after injection, with low uptake in nontarget organs. In patients, similar distribution patterns were observed for 99mTc-PSMA-GCK01 and 188Re-PSMA-GCK01 and in comparison with 177Lu-PSMA-617. Conclusion: The ligand PSMA-GCK01 labels stably with 99mTc and 188Re, both generator-based radionuclides, and thus provides access to on-demand labeling at reasonable costs. Preclinical evaluation of the compounds revealed favorable characteristics of the PSMA-targeted theranostic tandem. This result was confirmed by successful translation into first-in-humans application.

Static and Dynamic 68Ga-FAPI PET/CT for the Detection of Malignant Transformation of Intraductal Papillary Mucinous Neoplasia of the Pancreas.

Pancreatic ductal adenocarcinoma (PDAC) may arise from intraductal papillary mucinous neoplasms (IPMN) with malignant transformation, but a significant portion of IPMN remains to show benign behavior. Therefore, it is important to differentiate between benign IPMN and IPMN lesions undergoing malignant transformation. However, nonoperative differentiation by ultrasound, CT, MRI, and carbohydrate antigen 19-9 (CA19-9) is still unsatisfactory. Here, we assessed the clinical feasibility of additional assessment of malignancy by PET using 68Ga-labeled fibroblast activation protein inhibitors (68Ga-FAPI PET) in 25 patients with MRI- or CT-proven cystic pancreatic lesions. Methods: Twenty-five patients with cystic pancreatic lesions who were followed up in the European Pancreas Center of Heidelberg University hospital and who were led to surgical resection or fine-needle aspiration due to suspicious clinical, laboratory chemistry, or radiologic findings were examined by static (all patients) and dynamic (20 patients) 68Ga-FAPI PET. Cystic pancreatic lesions were delineated and SUVmax and SUVmean were determined. Time-activity curves and dynamic parameters (time to peak, K 1, k 2, K3, k 4) were extracted from dynamic PET data. Receiver-operating curves of static and dynamic PET parameters were calculated. Results: Eleven of the patients had menacing IPMN (high-grade IPMN with [6 cases] or without [5 cases] progression into PDAC) and 11 low-grade IPMN; 3 patients had other benign entities. Menacing IMPN showed significantly elevated 68Ga-FAPI uptake compared with low-grade IPMN and other benign cystic lesions. In dynamic imaging, menacing IPMN showed increasing time-activity curves followed by slow decrease afterward; time-activity curves of low-grade IPMN showed an immediate peak followed by rapid decrease for about 10 min and slower decrease for the rest of the time. Receiver-operating curves showed high sensitivity and specificity (area under the curve greater than 80%) of static and dynamic PET parameters for the differentiation of IPMN subtypes. Conclusion: 68Ga-FAPI PET is a helpful new tool for the differentiation of menacing and low-grade IPMN and shows the potential to avoid unnecessary surgery for nonmalignant pancreatic IPMN.

Repetitive Early 68Ga-FAPI PET Acquisition Comparing 68Ga-FAPI-02, 68Ga-FAPI-46, and 68Ga-FAPI-74: Methodologic and Diagnostic Implications for Malignant, Inflammatory/Reactive, and Degenerative Lesions.

68Ga-labeled fibroblast activation protein (FAP) inhibitor (68Ga-FAPI) PET targets 68Ga-FAPI-positive activated fibroblasts and is a promising imaging technique for various types of cancer and nonmalignant pathologies. However, discrimination between malignant and nonmalignant 68Ga-FAPI-positive lesions based on static PET with a single acquisition time point can be challenging. Additionally, the optimal imaging time point for 68Ga-FAPI PET has not been identified yet, and different 68Ga-FAPI tracer variants are currently used. In this retrospective analysis, we evaluate the diagnostic value of repetitive early 68Ga-FAPI PET with 68Ga-FAPI-02, 68Ga-FAPI-46, and 68Ga-FAPI-74 for malignant, inflammatory/reactive, and degenerative lesions and describe the implications for future 68Ga-FAPI imaging protocols. Methods: Whole-body PET scans of 24 cancer patients were acquired at 10, 22, 34, 46, and 58 min after the administration of 150-250 MBq of 68Ga-FAPI tracer molecules (8 patients each for 68Ga-FAPI-02, 68Ga-FAPI-46, and 68Ga-FAPI-74). Detection rates and SUVs (SUVmax and SUVmean) for healthy tissues, cancer manifestations, and nonmalignant lesions were measured, and target-to-background ratios (TBR) versus blood and fat were calculated for all acquisition time points. Results: For most healthy tissues except fat and spinal canal, biodistribution analysis showed decreasing uptake over time. We analyzed 134 malignant, inflammatory/reactive, and degenerative lesions. Detection rates were minimally reduced for the first 2 acquisition time points and remained at a constant high level from 34 to 58 min after injection. The uptake of all 3 variants was higher in malignant and inflammatory/reactive lesions than in degenerative lesions. 68Ga-FAPI-46 showed the highest uptake and TBRs in all pathologies. For all variants, TBRs versus blood constantly increased over time for all pathologies, and TBRs versus fat were constant or decreased slightly. Conclusion: 68Ga-FAPI PET/CT is a promising imaging modality for malignancies and benign lesions. Repetitive early PET acquisition added diagnostic value for the discrimination of malignant from nonmalignant 68Ga-FAPI-positive lesions. High detection rates and TBRs over time confirmed that PET acquisition earlier than 60 min after injection delivers high-contrast images. Additionally, considering clinical feasibility, acquisition at 30-40 min after injection might be a reasonable compromise. Different 68Ga-FAPI variants show significant differences in time-dependent biodistributional behavior and should be selected carefully depending on the clinical setting.

Two Tumors, One Target: Preliminary Experience With 90Y-FAPI Therapy in a Patient With Metastasized Breast and Colorectal Cancer.

ABSTRACT: We report a patient with breast cancer (BC) diagnosed in 2009 with metachronous lymph node, liver, and bone metastases. In 2017, colorectal cancer with peritoneal metastases was additionally diagnosed and treated with 8 cycles of capecitabine due to its antitumor activity against both malignancies. At progression of both diseases, FAPI PET/CT demonstrated positive tumor targeting in BC-related metastases and colorectal cancer-related metastases. The patient received an experimental therapy with 90Y-FAPI46. Although there was similar tracer uptake in the PET/CT, the radioligand therapy resulted in mixed response with disappearance of peritoneal metastases but minor efficacy treating the BC-related metastases.