Efficacy and safety of rechallenge with [(177)Lu]Lu-PSMA-I&T radioligand therapy in metastatic castration resistant prostate cancer.

The purpose of this study was to evaluate the safety and outcome of rechallenge [177Lu]Lu-PSMA-I&T in newly progressed mCRPC patients after response to initial [177Lu]Lu-PSMA radioligand therapy (PRLT). We retrospectively included 18 patients who underwent rechallenge with [177Lu]Lu-PSMA-I&T. All patients presented with (i) newly progressed disease after response to initial PRLT; (ii) a [68Ga]Ga-PSMA-11 PET/CT confirming the presence of PSMA-positive metastases; iii) ECOG performance status 0-1. Adverse events were graded according to CTCAE v5.0. Response was assessed by PSA and classified according to PCWG3 recommendations. For patients who underwent restaging with [68Ga]Ga-PSMA-11 PET/CT, imaging response was categorised according to adapted PERCIST v1.0. In patients with discordant [68Ga]Ga-PSMA-11 PET/CT and PSA, other available imaging modalities were evaluated to confirm disease status. Overall survival (OS) was calculated from the first cycle of initial PRLT and rechallenge PRLT, respectively, until last patient contact or death. Patients were initially treated with a median of 5 cycles (range 4-7) and were rechallenged after a median of 9 months (range 3-13). Each patient received a median of 4 (range 2-7) rechallenge cycles (median cumulative activity 26.1 GBq). None of the patients experienced life-threatening G4 adverse events during either treatment period. Grade 3 adverse events included one case of anaemia, one case of thrombocytopenia, and one case of renal failure. In 8/18 patients long-term toxicities were evaluated. Serious toxicities (≥ Grade 3) occurred in 3/8 patients (n = 1 G4 thrombocytopenia, n = 1 G4 renal failure and n = 1 pancytopenia and G4 renal failure). Best PSA50%-response was observed in 44% of patients and PSA-disease control was confirmed in 56% of patients at the last cycle. Of the 12/18 patients restaged by imaging, 6/12 (50%) patients had disease control (partial response/stable disease), 1/12 had a mixed response, and 5/12 had progression. After a median follow-up time of 25 months (range 14-44), 10 patients had died, 7 were still alive, and one patient was lost at follow-up. The median OS was 29 months (95%CI, 14.3-43.7 months) for the initial treatment and 11 months (95%CI, 8.1-13.8 months) for the first rechallenge course. More than half of patients benefit from rechallenge PRLT. Our analysis suggests that rechallenge may prolong survival in selected patients, with an acceptable safety profile.

Santo G ，Di Santo G ，Sviridenko A ，Bayerschmidt S ，Wirth L ，Scherbauer F ，Lehmann P ，von Guggenberg E ，Decristoforo C ，Heidegger-Pircher I ，Bektic J ，Virgolini I ... -  《-》

Comparison of Posttherapy 4- and 24-Hour [(177)Lu]Lu-PSMA SPECT/CT and Pretherapy PSMA PET/CT in Assessment of Disease in Men with Metastatic Castration-Resistant Prostate Cancer.

[177Lu]Lu-prostate-specific membrane antigen (PSMA) is an effective treatment for metastatic castration-resistant prostate cancer (mCRPC). [177Lu]Lu-PSMA SPECT/CT 24 h after injection has shown potential as a response biomarker for [177Lu]Lu-PSMA therapy but is not convenient for patients. This study investigated 4-h [177Lu]Lu-PSMA SPECT/CT as an alternative to 24-h [177Lu]Lu-PSMA SPECT/CT for evaluation of treatment response. Methods: This prospective analysis enrolled 23 patients diagnosed with mCRPC commencing [177Lu]Lu-PSMA-I&T therapy. Two patients were excluded because of incomplete imaging data. Posttherapy SPECT/CT was performed at 4 and 24 h after the first dose and 4 h after the second dose. Baseline [68Ga]Ga-PSMA-11 PET/CT and 4- and 24-h [177Lu]Lu-PSMA SPECT/CT were analyzed both visually and semiquantitatively. Bland-Altman plots assessed agreement of semiquantitative parameters from the 4- and 24-h scans. Quantitative assessment of the change in the total tumor volume (TTV) on the 4-h [177Lu]Lu-PSMA SPECT/CT after the first and second doses was correlated to patient outcomes. Results: All patients had mCRPC previously treated with an androgen receptor pathway inhibitor, and 11 (52%) received prior taxane chemotherapy. Median age was 78 y, and median prostate-specific antigen level was 54 ng/mL. On visual analysis, disease distribution was unchanged among the 3 imaging methods. Eleven patients (52%) had a median of 1 lesion not identified on 4-h [177Lu]Lu-PSMA SPECT/CT compared with 24-h [177Lu]Lu-PSMA SPECT/CT. All missed lesions on the 4-h [177Lu]Lu SPECT/CT were smaller than 2 cm. Mean differences and agreement between 4- and 24-h SPECT/CT quantitative parameters were within acceptable bounds for lesion number, SUVmax, and SUVmean, with higher variation observed for TTV. The change in TTV between dose 1 and 2 [177Lu]Lu-PSMA SPECT/CT predicted prostate-specific antigen progression-free survival. Conclusion: [177Lu]Lu-PSMA SPECT/CT at 4 h after injection appears a promising alternative to 24-h [177Lu]Lu-PSMA SPECT/CT for treatment response assessment, with improved patient convenience.

Swiha M ，Pathmanandavel S ，Papa N ，Sabahi Z ，Li S ，Zheng A ，Khan S ，Ayers M ，Sharma S ，Crumbaker M ，Nguyen A ，Chan L ，Ayati N ，Emmett L ... -  《-》

Prognostic Significance of Baseline Clinical and [68Ga]Ga-PSMA PET Derived Parameters on Biochemical Response, Overall Survival, and PSA Progression-Free Survival in Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients Undergoing [177Lu]Lu-PSM

In this study, we sought to identify the clinical baseline characteristics and pre-therapy 68Ga-PSMA PET derived parameters that can have impact on PSA (biochemical) response, OS and PSA PFS in patients with metastatic castration-resistant prostate cancer (mCRPC) who undergo RLT with [177Lu]Lu-PSMA-617. Various pre-treatment clinical and PSMA PET derived parameters were gathered and computed. We used PSA response as the criteria for more than a 50% decrease in PSA level, and OS and PSA PFS as endpoints. We assessed the collected parameters in relation to PSA response. Additionally, we employed univariable Cox regression and Kaplan-Meier analysis with log rank to evaluate the influence of the parameters on OS and PFS. A total of 125 mCRPC patients were included in this study. The median age was 68 years (range: 49-89). Among the cases, 77 patients (62%) showed PSARS, while 48 patients (38%) did not show PSA response. The median OS was 14 months (range: 1-60), and the median PSA-PFS was 10 months (range: 1-56). Age, prior history of chemotherapy, and SUVmax had a significant impact on PSA response (p<0.05). PSA response, RBC count, hemoglobin, hematocrit, neutrophil to lymphocyte ratio (NLR), alkaline phosphatase (ALP), number of metastases, wbPSMA-TV, and wbTL-PSMA significantly affected OS. GS, platelet count, NLR, and number of metastases were found to have a significant impact on PSA PFS. We have identified several baseline clinical and PSMA PET derived parameters that can serve as prognostic factors for predicting PSA response, OS, and PSA PFS after RLT. Based on the findings, we believe that these clinical baseline characteristics can assist nuclear medicine specialists in identifying RLT responders who have long-term survival and PFS.

Jafari E ，Manafi-Farid R ，Ahmadzadehfar H ，Salek F ，Jokar N ，Keshavarz A ，Divband G ，Dadgar H ，Zohrabi F ，Assadi M ... -  《-》

Outcomes for Patients with Metastatic Castration-Resistant Prostate Cancer and Liver Metastasis Receiving [(177)Lu]Lu-PSMA-617.

It is well known that patients with liver metastasis from metastatic castration-resistant prostate cancer have poor or only transient responses to many forms of systemic therapy. Data on outcomes after treatment with [177Lu]Lu-PSMA-617 (LuPSMA) are scarce. The VISION trial reports a hazard ratio for overall survival (OS) in the subgroup of patients with liver metastasis without disclosing the absolute duration of survival. Using real-world clinical data, we examined this important subgroup of patients, describing prostate-specific antigen (PSA) response and OS. Methods: A single-institution database was assembled to include all patients receiving LuPSMA at Mayo Clinic in Rochester, Minnesota, for whom treatment was initiated between March 2022 and March 2023. Baseline clinicopathologic and imaging characteristics were abstracted. Patients were then categorized by presence or absence of liver metastasis on pretreatment prostate-specific membrane antigen (PSMA) PET. PSA response and OS for the 2 groups (liver metastasis vs. no liver metastasis) were compared using χ2 testing and the Kaplan-Meier method, respectively. A multivariate Cox regression analysis was performed, including established prognostic factors. Finally, those with pretreatment circulating tumor DNA as determined in an 83-gene panel were assessed for the presence of pathogenic and likely pathogenic alterations. These findings were summarized using descriptive statistics and compared between the 2 cohorts using the Fisher exact test. Results: The overall cohort consisted of 273 patients, including 43 (15.75%) with liver metastasis on pretreatment PSMA PET/CT. The median number of cycles received was 3 (range, 1-6) for patients with liver metastasis and 5 (range, 1-6) for those without hepatic involvement. The 50% or greater reduction in PSA from baseline response rate was lower for those with liver metastasis than for those without (30.23% [13/43] vs 49.77% [106/213], P = 0.019). At a median follow-up of 10 mo (interquartile range, 9-13 mo), there was a significant difference in median OS (8.35 mo vs. not reached, P < 0.001). On multivariate analysis, the presence of liver metastasis was independently associated with shorter survival (hazard ratio, 4.06; P < 0.001). Conclusion: Our data suggest that the presence of liver metastasis predicts poorer outcomes in patients receiving LuPSMA treatment. Alternative and combination approaches should be explored to maximize the antitumor activity of radiopharmaceutical therapy in the liver.

Muniz M ，Sartor O ，Orme JJ ，Koch RM ，Rosenow HR ，Mahmoud AM ，Andrews JR ，Kase AM ，Riaz IB ，Belge Bilgin G ，Thorpe MP ，Kendi AT ，Johnson GB ，Ravi P ，Kwon ED ，Childs DS ... -  《-》

Detection of tumour heterogeneity in patients with advanced, metastatic castration-resistant prostate cancer on [(68)Ga]Ga-/[(18)F]F-PSMA-11/-1007, [(68)Ga]Ga-FAPI-46 and 2-[(18)F]FDG PET/CT: a pilot study.

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 [68Ga]Ga-FAPI-46, 2-[18F]FDG and [68Ga]Ga-/[18F]F-PSMA-11/-1007 PET. Patients with advanced, progressive mCRPC underwent clinical [68Ga]Ga-/[18F]F-PSMA-11/-1007, 2-[18F]FDG and [68Ga]Ga-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 [68Ga]Ga-/[18F]F-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. 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%). [68Ga]Ga-/[18F]F-PSMA-11/-1007 (n = 453 (96.0%)) demonstrates the highest detection rate, followed by [68Ga]Ga-FAPI-46 (n = 268 (56.8%))/2-[18F]FDG (n = 241 (51.1%)). Semiquantitative uptake was highest for [68Ga]Ga-/[18F]F-PSMA-11/-1007 (mean SUVmax (interquartile range): 22.7 (22.5), vs. [68Ga]Ga-FAPI-46 (7.7 (3.7)) and 2-[18F]FDG (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 [177Lu]Lu-PSMA-617 RLT and were retrospectively assigned to the PSMA-dominant phenotype (19.7 vs. 9.3 months). Through whole-body imaging, we identify considerable inter- and intra-patient heterogeneity of mCRPC and potential imaging phenotypes. Regarding uptake and tumour detection, [68Ga]Ga-/[18F]F-PSMA-11/-1007 was superior to [68Ga]Ga-FAPI-46 and 2-[18F]FDG, while the latter two were comparable. Patients who underwent [177Lu]Lu-PSMA-617 RLT based on clinical-decision making had a longer overall survival and could be assigned to the PSMA-dominant phenotype.

Pabst KM ，Mei R ，Lückerath K ，Hadaschik BA ，Kesch C ，Rawitzer J ，Kessler L ，Bodensieck LS ，Hamacher R ，Pomykala KL ，Fanti S ，Herrmann K ，Fendler WP ... -  《-》