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Purpose: Small cell lung cancer (SCLC) is a highly aggressive tumor with neuroendocrine origin. Although SCLC frequently express somatostatin receptor type 2 (SSTR2), a significant clinical benefit of SSTR2-targeted radionuclide therapies of SCLC was not observed so far. We hypothesize that combination treatment with a PARP inhibitor (PARPi) could lead to radiosensitization and increase the effectiveness of SSTR2-targeted therapy in SCLC. Methods: SSTR2-ligand uptake of the SCLC cell lines H69 and H446 was evaluated in vitro using flow cytometry, and in vivo using SPECT imaging and cut-and-count biodistribution. Single-agent (Olaparib, Rucaparib, [177Lu]Lu-DOTA-TOC) and combination treatment responses were determined in vitro via cell viability, clonogenic survival and γH2AX DNA damage assays. In vivo, we treated athymic nude mice bearing H69 or H446 xenografts with Olaparib, Rucaparib, or [177Lu]Lu-DOTA-TOC alone or with combination treatment regimens to assess the impact on tumor growth and survival of the treated mice. Results: H446 and H69 cells exhibited low SSTR2 expression, i.e. 60 to 90% lower uptake of SSTR2-ligands compared to AR42J cells. In vitro, combination treatment of [177Lu]Lu-DOTA-TOC with PARPi resulted in 2.9- to 67-fold increased potency relative to [177Lu]Lu-DOTA-TOC alone. We observed decreased clonogenic survival and higher amounts of persistent DNA damage compared to single-agent treatment for both Olaparib and Rucaparib. In vivo, tumor doubling times increased to 1.6-fold (H446) and 2.2-fold (H69) under combination treatment, and 1.0 to 1.1-fold (H446) and 1.1 to 1.7-fold (H69) in monotherapies compared to untreated animals. Concurrently, median survival was higher in the combination treatment groups in both models compared to monotherapy and untreated mice. Fractionating the PRRT dose did not lead to further improvement of therapeutic outcome. Conclusion: The addition of PARPi can markedly improve the potency of SSTR2-targeted PRRT in SCLC models in SSTR2 low-expressing tumors. Further evaluation in humans seems justified based on the results as novel treatment options for SCLC are urgently needed. [ABSTRACT FROM AUTHOR]

Aim: Rechallenge of [177Lu]Lu-PSMA-617 radioligand therapy (RLT) was proposed for patients who initially responded to PSMA-RLT experiencing partial remission, but relapsed into progression after a certain period of remission. However, only limited data is available regarding this approach. In this study, we analyzed the efficacy and safety profile of one or more series of [177Lu]Lu-PSMA-617 RLT rechallenge in patients from a prospective registry (REALITY Study, NCT 04833517) after they initially benefited from PSMA-RLT. Methods: Forty-seven patients with metastatic castration-resistant prostate cancer (mCRPC) who had biochemical response to initial [177Lu]Lu-PSMA-617 RLT followed by disease progression received at least one (up to three) series of [177Lu]Lu-PSMA-617 RLT rechallenge. Biochemical response rates based on prostate-specific antigen (PSA) serum value, PSA-based progression-free survival (PFS) and overall survival (OS) were calculated. Adverse events of the treatment were assessed according to 'common terminology criteria for adverse events' (CTCAE). Results: After one series of RLT rechallenge, a PSA decline of at least 50% was achieved in 27/47 patients (57.4%). The median PFS of all patients was 8.7 mo and the median OS was 22.7 mo, each calculated from the administration of the first rechallenge series. Patients who responded (PSA decline > 50%) to the rechallenge showed a median OS of 27.3 mo. Regarding PFS, a significant correlation (r = 0.4128, p = 0.0323) was found for these patients comparing initial and rechallenge RLT. Ten patients received a second and 3 patients received a third rechallenge series with 8/10 and 3/3 patients responding to repeated RLT rechallenge. No severe deterioration of adverse events rated by CTCAE criteria was observed. Conclusion: [177Lu]Lu-PSMA-617 RLT rechallenge is associated with significant PSA response and encouraging survival outcome as well as a very favourable safety profile and should therefore be considered as a straight-forward treatment option in mCRPC patients, who previously benefited from PSMA-RLT. [ABSTRACT FROM AUTHOR]

Simple Summary: Augmentation of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) by alpha emitting 225Ac, known as the tandem therapy concept, is a promising escalating treatment option in patients with advanced metastatic castration-resistant prostate cancer (mCRPC). The aim of this study was to analyze the value of imaging parameters in baseline [18F]FDG PET/CT for predicting response and outcome to PSMA tandem RLT in patients with insufficient response to the initial [177Lu]Lu-PSMA-617 monotherapy. The quantitative whole-body imaging biomarker total lesion glycolysis (TLG) was identified as a prognostic biomarker for overall survival (OS), while response could not be predicted by any of the tested parameters. Using [18F]FDG PET/CT in clinical practice could help predict outcomes and may provide more personalized care for mCRPC patients. Background/Objectives: The augmentation of [177Lu]Lu-PSMA-617 radioligand therapy by alpha emitting [225Ac]Ac-PSMA-617, known as the tandem therapy concept, is a promising escalating treatment option in advanced mCRPC. In this study, we evaluated the value of [18F]FDG PET/CT-derived molecular imaging biomarkers for predicting response and outcome to PSMA tandem RLT in n = 33 patients with insufficient response on [177Lu]Lu-PSMA-617 monotherapy. Methods: Six different molecular imaging parameters at baseline, i.e., before initiation of PSMA tandem RLT with respect to SUVmax, SUVpeak, SUV5, SUVmean, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were tested for association with response and overall survival (OS). Results: After the initiation of augmentation, 24.2% of patients with a previously insufficient response experienced partial remission, and 39.4% experienced stable disease. The median OS was 7 months (95% CI: 4–11 months). None of the tested parameters were able to predict the response (all p > 0.529). In contrast, the [18F]FDG PET/CT-derived whole-body molecular imaging parameter TLG was significantly (p = 0.029) associated with OS of patients undergoing [225Ac]Ac-PSMA-617 augmented [177Lu]Lu-PSMA-617 RLT after insufficient response to [177Lu]Lu-PSMA-617 monotherapy. Conclusion: Implementing [18F]FDG PET/CT in the management of PSMA-RLT in clinical practice may contribute to outcome prediction and provide a route to more individualized management in mCRPC. [ABSTRACT FROM AUTHOR]

Objective [ 177 Lu]Lu-prostate-specific membrane antigen (PSMA)-617 radioligand therapy (RLT) shows promise for metastatic castration-resistant prostate cancer (mCRPC) patients with positive PSMA positron emission tomography (PET) imaging. Identifying high-risk patients is crucial. We evaluated pretherapeutic PSMA PET-derived parameters to predict prostate-specific antigen (PSA) response in patients undergoing [ 177 Lu]Lu-PSMA-617 RLT. Materials and Methods We conducted a retrospective analysis among 27 patients (mean age: 71.0 ± 9.5 years; range: 52–85 years) who underwent PSMA PET/computed tomography (CT) and subsequent [ 177 Lu]Lu-PSMA-617 RLT between March 2019 and January 2023. After excluding patients with liver metastases, the number of patients left for analysis was 21 (14 responders and 7 nonresponders). Tumors were semiautomatically delineated with calculation of total tumor volume (PSMA-TV), lesion uptake (PSMA-TLU = PSMA-TV * standardized uptake value [SUV]mean), and lesion quotient (PSMA-TLQ = PSMA-TV/SUVmean) for each patient. Semiquantitative parameters were analyzed only in patients with mCRPC and no liver metastasis. Results In total, 17/27 patients (62.96%) had a decline in PSA levels; 15/27 patients (55.56%) experienced a decline of > 50%. Pretherapeutic PSMA PET/CT results revealed significant differences in PSMA-TV (p = 0.003), PSMA-TLU (p = 0.013), and PSMA-TLQ (p = 0.011) between responders and nonresponders. SUVmax was significantly correlated to the best percentage change in PSA response after 177 Lu-PSMA-617 treatment (r = −0.79, p = 0.006). No association was observed between PSMA-TV (p = 0.367), PSMA-TLU (p = 0.128), and PSMA-TLQ (p = 0.556), with the best percentage change in PSA response after 177 Lu-PSMA-617 therapy. Conclusion Pretherapeutic PSMA PET-derived PSMA-TV, PSMA-TLU, and PSMA-TLQ were significant negative predictors of PSA response in patients with mCRPC and no liver metastasis receiving [ 177 Lu]Lu-PSMA-617 RLT. [ABSTRACT FROM AUTHOR]

Prostate specific membrane antigen (PSMA) radioligand therapy (PRLT) has become an important new therapy，especially suitable for the treatment of metastatic castration resistant prostate cancer (mCRPC) which cannot be effectively controlled by conventional therapy. PRLT，represented by Lutetium-177 (177Lu)-PSMA-617，has good safety，can effectively prolong the survival time of mCRPC patients, and improve their quality of life. Despite the success of 177Lu-PSMA-617 in the treatment of mCRPC，some patients are still insensitive or even unresponsive to treatment，so the disease progresses and relapse is inevitable. Terbium-161 (161Tb) has the same β-rays as 177Lu，but its biggest advantage compared with 177Lu is to release Auger electrons and internal conversion electrons for the treatment of small lesions. This synergistic therapy of β-rays and Auger electron has the advantage of meeting the treatment of lesions of different sizes，which has led to a rising interest in 161Tb for tumor therapy worldwide. In this paper，the preparation，labeling，quality control，radiation dose，preclinical research，clinical research and prospects of 161Tb-PSMA will be reviewed，aiming to provide references for medical staff and patients who carry out PRLT.

Objective [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 radioligand therapy (RLT) shows promise for metastatic castration-resistant prostate cancer (mCRPC) patients with positive PSMA positron emission tomography (PET) imaging. Identifying high-risk patients is crucial. We evaluated pretherapeutic PSMA PET-derived parameters to predict prostate-specific antigen (PSA) response in patients undergoing [177Lu]Lu-PSMA-617 RLT.

Abstract Background Prostate-specific membrane antigen positron emission tomography (PSMA-PET) is an essential tool for patient selection before radioligand therapy (RLT). Interim-staging with PSMA-PET during RLT allows for therapy monitoring. However, its added value over post-treatment imaging is poorly elucidated. The aim of this study was to compare early treatment response assessed by post-therapeutic whole-body scans (WBS) with interim-staging by PSMA-PET after 2 cycles in order to prognosticate OS. Methods Men with metastasized castration-resistant PC (mCRPC) who had received at least two cycles of RLT, and interim PSMA-PET were evaluated retrospectively. PROMISE V2 framework was used to categorize PSMA expression and assess response to treatment. Response was defined as either disease control rate (DCR) for responders or progression for non-responders. Results A total of 188 men with mCRPC who underwent RLT between February 2015 and December 2021 were included. The comparison of different imaging modalities revealed a strong and significant correlation with Cramer V test: e.g. response on WBS during second cycle compared to interim PET after two cycles of RLT (cφ = 0.888, P

Abstract Background Internal dosimetry in individual patients is essential for safe and effective radioligand therapy. Multiple time point imaging for accurate dosimetry is time consuming and hence can be demanding for nuclear medicine departments as well as patients. The objectives of this study were (1) to assess absorbed doses to organs at risk and tumor lesions for [177Lu]Lu-PSMA-I&T using whole body SPECT imaging and (2) to investigate possible simplified dosimetry protocols. Methods This study included 16 patients each treated with 4 cycles of [177Lu]Lu-PSMA-I&T. They underwent quantitative whole body SPECT/CT imaging (3 bed positions) at four time points (TP) comprising 2 h, 24 h, 48 h and 72–168 h post-injection (p.i.). Full 3D dosimetry (reference method) was performed for all patients and dose cycles for organs at risk (kidneys, parotid glands and submandibular glands) and up to ten tumor lesions per patient (resulting in 90 lesions overall). The simplified dosimetry methods (SM) included (1) generating time activity curves for subsequent cycles using a single TP of imaging applying the kinetics of dose cycle 1, and for organs at risk also (2) simple extrapolation from dose cycle 1 and (3) from both, dose cycle 1 and 2. Results Normalized absorbed doses were 0.71 ± 0.32 mGy/MBq, 0.28 ± 0.12 mGy/MBq and 0.22 ± 0.08 mGy/MBq for kidneys, parotid glands and submandibular glands, respectively. Tumor doses decreased from 3.86 ± 3.38 mGy/MBq in dose cycle 1 to 2.01 ± 2.65 mGy/MBq in dose cycle 4. Compared to the full dosimetry approach the SM 1 using single TP imaging at 48 h p.i. resulted in the most accurate and precise results for the organs at risk in terms of absorbed doses per cycle and total cumulated dose. For tumor lesions better results were achieved using the fourth TP (≥ 72 h p.i.). Conclusion Simplification of safety dosimetry protocols is possible for [177Lu]Lu-PSMA-I&T therapy. If tumor dosimetry is of interest a later imaging TP (≥ 72 h p.i.) should be used/added to account for the slower kinetics of tumors compared to organs at risk.

Background: Enzalutamide is an antiandrogen drug used prior to lutetium-177 prostate specific membrane antigen (Lu-PSMA) radioligand therapy and has shown promising results for upregulating the PSMA expression on prostate cancer cells. In this study, we aim to compare prostate specific antigen (PSA) level changes in prostate cancer patients who received enzalutamide to those who did not. Methods: Prostate cancer patients who underwent Lu-PSMA between 2021 and 2023 were retrospectively included. Patients were grouped based on prior enzalutamide therapy: those who received enzalutamide (EZ+) for at least 14 days and those who did not (EZ−). PSA changes and F-18 DCFPyL SUV (Standardized Uptake Values) were compared. Results: Thirty-seven patients were included, 18 EZ+ and 19 EZ−. The median age, Gleason score, and prior chemo/hormonal therapies were similar for EZ+ and EZ−, except for radium-223. Eleven patients (61%) in EZ+ and 13 patients (68%) in EZ− showed a decrease in PSA after the first cycle (p = 0.64). Four patients (22%) in EZ+ and seven patients (37%) in EZ− had more than 50% decrease in PSA after the first cycle (p = 0.33). The average percent decline at the end of the treatment was 23.3% in EZ+ and 50.4% in EZ− (p = 0.4). There was no difference in terms of lesion with highest SUVmax, mean SUV, total tumor volume or activity on pre-therapy PSMA imaging. Conclusion: Enzalutamide treatment prior to Lu-PSMA does not improve patient outcomes when applied remotely. Larger studies evaluating the combination therapies and the timing of enzalutamide are needed to assess its correlation with Lu-PSMA outcomes. [ABSTRACT FROM AUTHOR]

Background: Internal dosimetry in individual patients is essential for safe and effective radioligand therapy. Multiple time point imaging for accurate dosimetry is time consuming and hence can be demanding for nuclear medicine departments as well as patients. The objectives of this study were (1) to assess absorbed doses to organs at risk and tumor lesions for [177Lu]Lu-PSMA-I&T using whole body SPECT imaging and (2) to investigate possible simplified dosimetry protocols. Methods: This study included 16 patients each treated with 4 cycles of [177Lu]Lu-PSMA-I&T. They underwent quantitative whole body SPECT/CT imaging (3 bed positions) at four time points (TP) comprising 2 h, 24 h, 48 h and 72–168 h post-injection (p.i.). Full 3D dosimetry (reference method) was performed for all patients and dose cycles for organs at risk (kidneys, parotid glands and submandibular glands) and up to ten tumor lesions per patient (resulting in 90 lesions overall). The simplified dosimetry methods (SM) included (1) generating time activity curves for subsequent cycles using a single TP of imaging applying the kinetics of dose cycle 1, and for organs at risk also (2) simple extrapolation from dose cycle 1 and (3) from both, dose cycle 1 and 2. Results: Normalized absorbed doses were 0.71 ± 0.32 mGy/MBq, 0.28 ± 0.12 mGy/MBq and 0.22 ± 0.08 mGy/MBq for kidneys, parotid glands and submandibular glands, respectively. Tumor doses decreased from 3.86 ± 3.38 mGy/MBq in dose cycle 1 to 2.01 ± 2.65 mGy/MBq in dose cycle 4. Compared to the full dosimetry approach the SM 1 using single TP imaging at 48 h p.i. resulted in the most accurate and precise results for the organs at risk in terms of absorbed doses per cycle and total cumulated dose. For tumor lesions better results were achieved using the fourth TP (≥ 72 h p.i.). Conclusion: Simplification of safety dosimetry protocols is possible for [177Lu]Lu-PSMA-I&T therapy. If tumor dosimetry is of interest a later imaging TP (≥ 72 h p.i.) should be used/added to account for the slower kinetics of tumors compared to organs at risk. [ABSTRACT FROM AUTHOR]

Purpose: Pluvicto™ ([177Lu]Lu-PSMA-617), a radioligand therapeutic targeting prostate-specific membrane antigen (PSMA), has been recently approved for the treatment of metastatic castration-resistant prostate cancer (mCRPR). The drug suffers from salivary gland and kidney uptake that prevents its dose escalation to potentially curative doses. In this work, we sought to potentiate the in vivo anti-cancer activity of Pluvicto™ by combining it with L19-IL2, a clinical-stage investigational medicinal product based on tumor-targeted interleukin-2. Methods: We established a new PSMA-expressing model (HT-1080.hPSMA) and validated it using a fluoresceine analogue of PSMA-617 (compound 1). The HT-1080.hPSMA model was used to study the saturation and tumor retention of Pluvicto™ (compound 2) and to run combination therapy studies with L19-IL2. To complement our understanding of the mechanism of action of this novel combination, we conducted proteomics experiments on tumor samples after therapy with Pluvicto™ alone or in combination with the immunocytokine. Results: High, selective, and long-lived tumor uptake was observed for Pluvicto™ (2) in the novel HT-1080.hPSMA model. Therapy studies in HT-1080.hPSMA tumor-bearing mice revealed that the combination of Pluvicto™ (2) plus L19-IL2 mediated curative and durable responses in all animals. Potent in vivo anti-cancer activity was observed solely for the combination modality, at doses that were well tolerated by treated animals. Proteomics studies indicated that L19-IL2 boosts the activation of the immune system in animals pre-treated with Pluvicto™. Conclusion: The therapeutic efficacy of Pluvicto™ at low radioactive doses can be effectively enhanced by the combination with L19-IL2. Our findings warrant further clinical exploration of this novel combination modality. [ABSTRACT FROM AUTHOR]

Introduction: The term theragnostic refers to the combination of a predictive imaging biomarker with a therapeutic agent. The promising application of prostate-specific membrane antigen (PSMA)-based radiopharmaceuticals in the imaging and treatment of prostate cancer (PCa) patients opens the way to investigate a possible role of PSMA-based radiopharmaceuticals in cancers beyond the prostate. Therefore, the aim of this review was to evaluate the role of 177Lu-PSMA radioligand therapy (RLT) in malignancies other than prostate cancer by evaluating preclinical, clinical studies, and ongoing clinical trials. Methods: An extensive literature search was performed in three different databases using different combinations of the following terms: "Lu-PSMA", "177Lu-PSMA", "preclinical", "mouse", "salivary gland cancer", "breast cancer", "glioblastoma", "solid tumour", "renal cell carcinoma", "HCC", "thyroid", "salivary", "radioligand therapy", and "lutetium-177". The search had no beginning date limit and was updated to April 2024. Only articles written in English were included in this review. Results: A total of four preclinical studies were selected (breast cancer model n = 3/4). PSMA-RLT significantly reduced cell viability and had anti-angiogenic effects, especially under hypoxic conditions, which increase PSMA binding and uptake. Considering the clinical studies (n = 8), the complexity of evaluating PSMA-RLT in cancers other than prostate cancer was clearly revealed, since in most of the presented cases a sufficient tumour radiation dose was not achieved. However, encouraging results can be found in some types of diseases, such as thyroid cancer. Some clinical trials are still ongoing, and results from prospective larger cohorts of patients are awaited. Conclusions: The need for larger patient cohorts and more RLT cycles administered underscores the need for further comprehensive studies. Given the very preliminary results of both preclinical and clinical studies, ongoing clinical trials in the near future may provide stronger evidence of both the safety and therapeutic efficacy of PSMA-RLT in malignancies other than prostate cancer. [ABSTRACT FROM AUTHOR]

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Introduction: The prostate cancer (PCa) consists the most frequently diagnosed malignancy of urogenital system in males. Traditionally, treatment of localized PCa was based on surgery or radiotherapy while hormonotherapy was used in more advanced stages. However, the implementation of radiolabels has revolutionized the landscape of prostate cancer. Specifically, prostate-specific membrane antigen (PSMA) has been investigated in different aspects of PCa therapeutic era. Areas covered: A literature review is presented about the implications of PSMA radiolabels on prostate cancer treatment. PSMA tracers were initially used as an imaging technique. Afterwards, PSMA labeled with isotopes presenting cytotoxic abilities, such as lutetium-117 and actinium-225, while reports exist about the use of radioligand immunotherapy. Meanwhile, ongoing trials examine the development of novel radionuclides as well as the evolution of the PSMA-targeted ligands. Expert opinion: Currently, PSMA radioligand treatment of prostate cancer is approved in the metastatic stage of the disease. Meanwhile, a variety of trials exist about its possible role in less advanced stages. However, plenty of parameters should be addressed before these implementations, such as PSMA dosage, dosimetry issues, and its safety profile. A future well-designed study with proper patient selection is mandatory to further explore PSMA radioligand theranostics perspectives. [ABSTRACT FROM AUTHOR]

Understanding the spatial distribution of radiation levels outside of a patient undergoing 177Lu radioligand therapy is not only helpful for conducting correct tests for patient release, but also useful for estimation of its potential exposure to healthcare workers, caregivers, family members, and the general public. In this study, by mimicking the 177Lu-labeled prostate-specific membrane antigen radioligand therapy for prostate cancers in an adult male, the spatial distribution of radiation levels outside of the phantom was simulated based on the Monte Carlo software of Particle and Heavy Ion Transport System, and verified by a series of measurements. Moreover, the normalized dose rates were further formulized on the three transverse planes representing the heights of pelvis, abdomen and chest. The results showed that the distributions of radiation levels were quite complex. Multi-directional and multi-height measurements are needed to ensure the external dose rate to meet the release criteria. In general, the radiation level was higher at the horizontal plane where the source was located, and the levels in front and behind of the body were higher than those of the left and right sides at the same height. The ratio of simulated dose rates to measured ones ranged from 0.82 to 1.19 within 1 m away from the body surface in all directions. Based on the established functions, the relative root mean square deviation between the calculated and simulated values were 0.21, 0.25 and 0.23 within a radius of 1 m on the pelvis, abdomen and chest transverse planes, respectively. It is expected that the results of this study would be helpful for guiding the test of extracorporeal radiation to determine the patient's release, and of benefit to estimate the radiation exposure to others. [ABSTRACT FROM AUTHOR]

Simple Summary: The recent approval of [177Lu]Lu-prostate-specific membrane antigen (PSMA) for managing metastatic castration-resistant prostate cancer (mCRPC) has catalyzed the innovation of various PSMA-targeted radiopharmaceuticals. In our retrospective study, we explored both safety and efficacy of two beta-emitting PSMA radioligands, [177Lu]Lu and [161Tb]Tb, for mCRPC therapy. Our study included 53 patients and reinforced prior evidence validating the clinical safety and efficacy of these radioligands. Our research suggested that these treatments are characterized by a favorable safety profile with negligible toxicity. Moreover, [161Tb]Tb-PSMA recipients, though trialed in a smaller patient sample, yielded concordant outcomes on par with those receiving [177Lu]Lu-PSMA, highlighting its promise as an alternative therapy and warrants additional investigation. The objective of this retrospective study is to assess the effectiveness and safety of two beta-emitting prostate-specific membrane antigen (PSMA) radioligands, [177Lu]Lu and [161Tb]Tb, in heavily treated patients with metastatic castration-resistant prostate cancer (mCRPC). A total of 148 cycles of beta-emitting PSMA radioligand therapy were given to 53 patients at a specialized cancer care center in Amman, Jordan. This treatment was offered following the exhaustion of all prior treatment modalities. Approximately half of the cases (n = 26) demonstrated an initial partial response to PSMA radioligand therapy. Moreover, roughly one-fourth of the patients (n = 13) exhibited a sustained satisfactory biochemical response, which qualified them to receive a total of six PSMA radioligand therapy cycles and maintain continued follow-up for additional treatment cycles. This was reflected by an adequate prostate-specific antigen (PSA) decline and a concomitant partial response evident on [68Ga]Ga-PSMA positron emission tomography/computed tomography imaging. A minority of patients (n= 18; 34%) experienced side effects. Generally, these were low-grade and self-limiting toxicities. This study endorses previous research evidence about PSMA radioligand therapy's safety and efficacy. It also provides the first clinical insight from patients of Arab ethnicity. This should facilitate and promote further evidence, both regionally and internationally. [ABSTRACT FROM AUTHOR]

Abstract Candidates for prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) of metastatic castration-resistant prostate cancer (mCRPC) frequently have “mismatch” lesions with pronounced 18-fluorodeoxyglucose ([18F]FDG) but attenuated PSMA ligand uptake on positron emission tomography (PET). However, no quantitative criteria yet exist to identify mismatch lesions and predict their response to RLT. To define such criteria, we retrospectively analyzed 267 randomly-selected glucometabolic mCRPC metastases from 22 patients. On baseline PET, we determined [18F]FDG and [68Ga]Ga-PSMA-11 maximum standardized uptake value (SUVmax), and calculated the [18F]FDG SUVmax/[68Ga]Ga-PSMA-11 SUVmax quotient (FPQ). From follow-up [18F]FDG PET after two lutetium-177-PSMA-617 RLT cycles, we evaluated the treatment response and categorized the lesions into three subgroups (partial remission, stable disease, progression) based on change in [18F]FDG SUVmax. Lastly, we compared the baseline PET variables in progressing versus non-progressing lesions. Variables differing significantly, and a score incorporating them, were assessed via receiver operator characteristic (ROC) curve analysis, regarding ability to predict lesional progression, with area under the curve (AUC) as metric. Cut-offs with optimal sensitivity and specificity were determined using the maximum value of Youden's index. Fifty-one of 267 lesions (19.1%) progressed, 102/267 (38.2%) manifested stable disease, and 114/267 (42.7%) partially responded after two RLT cycles. At baseline, median [68Ga]Ga-PSMA-11 SUVmax was significantly lower (p

Abstract Background Liver uptake in [68Ga]Ga-PSMA-11 PET is used as an internal reference in addition to clinical parameters to select patients for [177Lu]Lu-PSMA-617 radioligand therapy (RLT). Due to increased demand, [68Ga]Ga-PSMA-11 was replaced by [18F]F-PSMA-1007, a more lipophilic tracer with different biodistribution and splenic uptake was suggested as a new internal reference. We compared the intra-patient tracer distribution between [68Ga]Ga-PSMA-11 and [18F]F-PSMA-1007. Methods Fifty patients who underwent PET examinations in two centers with both [18F]F-PSMA-1007 and [68Ga]Ga-PSMA-11 within one year were included. Mean standardized uptake values (SUVmean) were obtained for liver, spleen, salivary glands, blood pool, and bone. Primary tumor, local recurrence, lymph node, bone or visceral metastasis were also assessed for intra- and inter-individual comparison. Results Liver SUVmean was significantly higher with [18F]F-PSMA-1007 (11.7 ± 3.9) compared to [68Ga]Ga-PSMA-11 (5.4 ± 1.7, p

Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer and a therapeutic target. Lutetium-177 (177Lu)-PSMA-617 is the first radioligand therapy to be approved in Canada for use in patients with metastatic castration-resistant prostate cancer (mCRPC). As this treatment represents a new therapeutic class, guidance regarding how to integrate it into clinical practice is needed. This article aims to review the evidence from prospective phase 2 and 3 clinical trials and meta-analyses of observational studies on the use of 177Lu-PSMA-617 in prostate cancer and discuss how Canadian clinicians might best apply these data in practice. The selection of appropriate patients, the practicalities of treatment administration, including necessary facilities for treatment procedures, the assessment of treatment response, and the management of adverse events are considered. Survival benefits were observed in clinical trials of 177Lu-PSMA-617 in patients with progressive, PSMA-positive mCRPC who were pretreated with androgen receptor pathway inhibitors and taxanes, as well as in taxane-naïve patients. However, the results of ongoing trials are awaited to clarify questions regarding the optimal sequencing of 177Lu-PSMA-617 with other therapies, as well as the implications of predictive biomarkers, personalized dosimetry, and combinations with other therapies.

Candidates for prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) of metastatic castration-resistant prostate cancer (mCRPC) frequently have "mismatch" lesions with pronounced 18-fluorodeoxyglucose ([18F]FDG) but attenuated PSMA ligand uptake on positron emission tomography (PET). However, no quantitative criteria yet exist to identify mismatch lesions and predict their response to RLT. To define such criteria, we retrospectively analyzed 267 randomly-selected glucometabolic mCRPC metastases from 22 patients. On baseline PET, we determined [18F]FDG and [68Ga]Ga-PSMA-11 maximum standardized uptake value (SUVmax), and calculated the [18F]FDG SUVmax/[68Ga]Ga-PSMA-11 SUVmax quotient (FPQ). From follow-up [18F]FDG PET after two lutetium-177-PSMA-617 RLT cycles, we evaluated the treatment response and categorized the lesions into three subgroups (partial remission, stable disease, progression) based on change in [18F]FDG SUVmax. Lastly, we compared the baseline PET variables in progressing versus non-progressing lesions. Variables differing significantly, and a score incorporating them, were assessed via receiver operator characteristic (ROC) curve analysis, regarding ability to predict lesional progression, with area under the curve (AUC) as metric. Cut-offs with optimal sensitivity and specificity were determined using the maximum value of Youden's index. Fifty-one of 267 lesions (19.1%) progressed, 102/267 (38.2%) manifested stable disease, and 114/267 (42.7%) partially responded after two RLT cycles. At baseline, median [68Ga]Ga-PSMA-11 SUVmax was significantly lower (p < 0.001), median FPQ significantly higher (p < 0.001), and median [18F]FDG SUVmax similar in progressing versus non-progressing lesions. [68Ga]Ga-PSMA-11 SUVmax and FPQ showed predictive power regarding progression (AUCs: 0.89, 0.90). An introduced clinical score combining both further improved predictive performance (AUC: 0.94). Optimal cut-offs to foretell progression were: [68Ga]Ga-PSMA-11 SUVmax < 11.09 (88.2% sensitivity, 81.9% specificity), FPQ ≥ 0.92 (90.2% sensitivity, 78.7% specificity), clinical score ≥ 6/9 points (88.2% sensitivity, 87.5% specificity). At baseline, a low [68 Ga]Ga-PSMA-11 SUVmax and a high FPQ predict early lesional progression under RLT; [18F]FDG SUVmax does not. A score combining [68 Ga]Ga-PSMA-11 SUVmax and FPQ predicts early lesional progression even more effectively and might therefore be useful to quantitatively identify mismatch lesions. [ABSTRACT FROM AUTHOR]

Simple Summary: Radioligand therapy plays a crucial role in the management of prostate cancer patients, for whom despite all available treatments, natural progression is almost inevitable. The failure of therapeutic options is likely to refer to the intrinsic tumor heterogeneity and the development of oncologic resistance pathways. To address this resistance, different trials are attempting to study the effectiveness and safety of combined therapies. This review provides a comprehensive overview of the current and future applications of radioligand therapy in prostate cancer from its initial application, moving towards future perspectives, and encompassing the main characteristics of ongoing trials related to this topic. In the last decades, the development of PET/CT radiopharmaceuticals, targeting the Prostate-Specific Membrane Antigen (PSMA), changed the management of prostate cancer (PCa) patients thanks to its higher diagnostic accuracy in comparison with conventional imaging both in staging and in recurrence. Alongside molecular imaging, PSMA was studied as a therapeutic agent targeted with various isotopes. In 2021, results from the VISION trial led to the Food and Drug Administration (FDA) approval of [177Lu]Lu-PSMA-617 as a novel therapy for metastatic castration-resistant prostate cancer (mCRPC) and set the basis for a radical change in the future perspectives of PCa treatment and the history of Nuclear Medicine. Despite these promising results, primary resistance in patients treated with single-agent [177Lu]Lu-PSMA-617 remains a real issue. Emerging trials are investigating the use of [177Lu]Lu-PSMA-617 in combination with other PCa therapies in order to cover the multiple oncologic resistance pathways and to overcome tumor heterogeneity. In this review, our aim is to retrace the history of PSMA-targeted therapy from the first preclinical studies to its future applications in PCa. [ABSTRACT FROM AUTHOR]

Simple Summary: Radioligand therapies targeting prostate-specific membrane antigen (PSMA) receptors are currently being investigated in several ongoing trials for their application in early stages of prostate cancer (PCa). The aim of this study is to identify the PSMA-ligand binding in patients with early and advanced stages of PCa by measuring changes in the PSMA uptake in various organs, including non-physiologically PSMA-expressing organs, as differences in PSMA expression could lead to unpredictable radiotoxicity in early-stage PCa patients. In addition, total tumor volume (TTV) was determined to evaluate differences in PSMA-ligand uptake related to TTV in the investigated cohorts. The efficacy of radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) is currently being investigated for its application in patients with early-stage prostate cancer (PCa). However, little is known about PSMA expression in healthy organs in this cohort. Collectively, 202 [68Ga]Ga-PSMA-11 positron emission tomography (PET) scans from 152 patients were studied. Of these, 102 PET scans were from patients with primary PCa and hormone-sensitive biochemically recurrent PCa and 50 PET scans were from patients with metastatic castration-resistant PCa (mCRPC) before and after three cycles of [177Lu]Lu-PSMA-RLT. PSMA-standardized uptake values (SUV) were measured in multiple organs and PSMA-total tumor volume (PSMA-TTV) was determined in all cohorts. The measured PET parameters of the different cohorts were normalized to the bloodpool and compared using t- or Mann–Whitney U tests. Patients with early-stage PCa had lower PSMA-TTVs (10.39 mL vs. 462.42 mL, p < 0.001) and showed different SUVs in the thyroid, submandibular glands, heart, liver, kidneys, intestine, testes and bone marrow compared to patients with advanced CRPC, with all tests showing p < 0.05. Despite the differences in the PSMA-TTV of patients with mCRPC before and after [177Lu]Lu-PSMA-RLT (462.42 mL vs. 276.29 mL, p = 0.023), no significant organ differences in PET parameters were detected. These suggest different degrees of PSMA-ligand binding among patients with different stages of PCa that could influence radiotoxicity during earlier stages of disease in different organs when PSMA-RLT is administered. [ABSTRACT FROM AUTHOR]

Background: Liver uptake in [68Ga]Ga-PSMA-11 PET is used as an internal reference in addition to clinical parameters to select patients for [177Lu]Lu-PSMA-617 radioligand therapy (RLT). Due to increased demand, [68Ga]Ga-PSMA-11 was replaced by [18F]F-PSMA-1007, a more lipophilic tracer with different biodistribution and splenic uptake was suggested as a new internal reference. We compared the intra-patient tracer distribution between [68Ga]Ga-PSMA-11 and [18F]F-PSMA-1007. Methods: Fifty patients who underwent PET examinations in two centers with both [18F]F-PSMA-1007 and [68Ga]Ga-PSMA-11 within one year were included. Mean standardized uptake values (SUVmean) were obtained for liver, spleen, salivary glands, blood pool, and bone. Primary tumor, local recurrence, lymph node, bone or visceral metastasis were also assessed for intra- and inter-individual comparison. Results: Liver SUVmean was significantly higher with [18F]F-PSMA-1007 (11.7 ± 3.9) compared to [68Ga]Ga-PSMA-11 (5.4 ± 1.7, p <.05) as well as splenic SUVmean (11.2 ± 3.5 vs.8.1 ± 3.5, p <.05). The blood pool was comparable between the two scans. Malignant lesions did not show higher SUVmean on [18F]F-PSMA-1007. Intra-individual comparison of liver uptake between the two scans showed a linear association for liver uptake with SUVmean [68Ga]Ga-PSMA-11 = 0.33 x SUVmean [18F]F-PSMA-1007 + 1.52 (r =.78, p <.001). Conclusion: Comparing biodistribution of [68Ga]Ga and [18F]F tracers, liver uptake on [68Ga]Ga-PSMA-11 PET is the most robust internal reference value. Liver uptake of [18F]F-PSMA-1007 was significantly higher, but so was the splenic uptake. The strong intra-individual association of hepatic accumulation between the two scans may allow using of a conversion factor for [18F]F-PSMA-1007 as a basis for RLT selection. [ABSTRACT FROM AUTHOR]

Purpose: To assess the prognostic value of pre-treatment [68Ga]Ga-PSMA-11 PET/CT and other baseline clinical characteristics in predicting prostate cancer (PCa) patients response to [177Lu]Lu-PSMA (PSMA-I&T), as well as patient survival. Procedures: In this retrospective study, 81 patients who received [177Lu]Lu-PSMA-I&T between October 2018 and January 2023 were reviewed. Eligible patients had metastatic castration-resistant PCa, underwent pre-treatment [68Ga]Ga-PSMA-11 PET/CT, and had serum prostate-specific antigen (PSA) levels available. On PET/CT images, SUVmax, SULmax, SUVpeak, and SULpeak of the most-avid tumoral lesion, as well as SUVmean of the parotid gland (P-SUVmean) and liver (L-SUVmean), were measured. Also, whole-body PSMA tumour volume (PSMA-TV) and total lesion PSMA (TL-PSMA) were calculated. To interpret treatment response after [177Lu]Lu-PSMA-I&T, a composite of PSA values and [68Ga]Ga-PSMA-11 PET/CT findings were considered. The outcomes were dichotomised into progressive versus controlled (stable disease or partial response) disease. Then, the association of baseline parameters with patient response was evaluated. Also, survival analyses were performed to assess baseline parameters in predicting overall survival. Results: Sixty patients (age:73 ± 8, PSA:185 ± 371) were included. Patients received at least one cycle of [177Lu]Lu-PSMA therapy (median = 4). Overall, half of the patients showed disease progression. In the progressive versus controlled disease evaluation, the highest SULmax, as well as SUVmax and SULmax to both backgrounds (L-SUVmean and P-SUVmean), were significantly correlated with the outcome (p-values < 0.05). In the multivariate analysis, only SULmax to the L-SUVmean remained significant (p-value = 0.038). The best cut-off was 8 (AUC = 0.71). With a median follow-up of 360 days, 11 mortal events were documented. In the multivariate survival analysis, only SULmax to P-SUVmean (cut-off = 2.4; p-value = 0.043) retained significance (hazard ratio = 4.0). Conclusions: A greater level of PSMA uptake, specifically higher tumour-to-background uptake in the hottest lesion, may hold substantial prognostic significance, considering both [177Lu]Lu-PSMA-I&T response and patient survival. These ratios may have the potential to be used for PCa patient selection for radioligand therapy. [ABSTRACT FROM AUTHOR]

Background: C-X-C motif chemokine receptor 4 (CXCR4) is overexpressed in various solid cancers and can be targeted by CXCR4-directed molecular imaging. We aimed to characterize the in-vivo CXCR4 expression in patients affected with solid tumors, along with a comparison to ex-vivo findings. Methods: A total 142 patients with 23 different histologically proven solid tumors were imaged with CXCR4-directed PET/CT using [68 Ga]Ga-pentixafor (total number of scans, 152). A semi-quantitative analysis of the CXCR4-positive tumor burden including maximum standardized uptake values (SUVmax) and target-to-background ratios (TBR) using blood pool was conducted. In addition, we performed histopathological staining to determine the immuno-reactive score (IRS) from patients' tumor tissue and investigated possible correlations with SUVmax (by providing Spearman's rho ρ). Based on imaging, we also assessed the eligibility for CXCR4-targeted radioligand therapy or non-radioactive CXCR4 inhibitory treatment (defined as more than five CXCR4-avid target lesions [TL] with SUVmax above 10). Results: One hundred three of 152 (67.8%) scans showed discernible uptake above blood pool (TBR > 1) in 462 lesions (52 primary tumors and 410 metastases). Median TBR was 4.4 (1.05–24.98), thereby indicating high image contrast. The highest SUVmax was observed in ovarian cancer, followed by small cell lung cancer, desmoplastic small round cell tumor, and adrenocortical carcinoma. When comparing radiotracer accumulation between primary tumors and metastases for the entire cohort, comparable SUVmax was recorded (P > 0.999), except for pulmonal findings (P = 0.013), indicative for uniform CXCR4 expression among TL. For higher IRS, a weak, but statistically significant correlation with increased SUVmax was observed (ρ = 0.328; P = 0.018). In 42/103 (40.8%) scans, more than five TL were recorded, with 12/42 (28.6%) exhibiting SUVmax above 10, suggesting eligibility for CXCR4-targeted treatment in this subcohort. Conclusions: In a whole-body tumor read-out, a substantial portion of prevalent solid tumors demonstrated increased and uniform [68 Ga]Ga-pentixafor uptake, along with high image contrast. We also observed a respective link between in- and ex-vivo CXCR4 expression, suggesting high specificity of the PET agent. Last, a fraction of patients with [68 Ga]Ga-pentixafor-positive tumor burden were rendered potentially suitable for CXCR4-directed therapy. [ABSTRACT FROM AUTHOR]

We show that longer exposure to 177Lu-PSMA-617 treatment for up to six cycles was not associated with greater toxicity risk. Safety analyses support a favourable benefit-risk profile for six cycles of 177Lu-PSMA-617 in patients with progressive, prostate-specific membrane antigen–positive, metastatic castration-resistant prostate cancer. [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) plus the standard of care (SoC) significantly improved overall survival and radiographic progression-free survival versus SoC alone in patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer in the VISION trial. We evaluated the safety of additional cycles of 177Lu-PSMA-617 and the impact of longer observation time for patients receiving 177Lu-PSMA-617 plus SoC. VISION was an international, open-label study. Patients were randomised 2:1 to receive 177Lu-PSMA-617 plus SoC or SoC alone. The incidence of treatment-emergent adverse events (TEAEs) was assessed in prespecified subgroups of patients who received ≤4 cycles versus 5–6 cycles of treatment and during each cycle of treatment. The TEAE incidence was also adjusted for treatment exposure to calculate the incidence per 100 patient-treatment years of observation. This analysis was performed for the first occurrence of TEAEs. The any-grade TEAE incidence was similar in cycles 1–4 and cycles 5–6. TEAE frequency was similar across all cycles of 177Lu-PSMA-617 treatment. No additional safety concerns were reported for patients who received >4 cycles. The exposure-adjusted safety analysis revealed that the overall TEAE incidence was similar between arms, but distinct trends for different TEAE types were noted and the incidence of events associated with 177Lu-PSMA-617 remained higher in the 177Lu-PSMA-617 arm. Longer exposure to 177Lu-PSMA-617 plus SoC was not associated with a higher toxicity risk, and the extended time for safety observation could account for the higher TEAE incidence in comparison to SoC alone. The findings support a favourable benefit-risk profile for 6 cycles of 177Lu-PSMA-617 in this setting and the use of up to 6 cycles of 177Lu-PSMA-617 in patients who are clinically benefiting from and tolerating this therapy. For patients with metastatic prostate cancer no longer responding to hormone therapy, an increase in the number of cycles of treatment with a radioactive compound called 177Lu-PSMA-617 from four to six had no additional adverse side effects. [ABSTRACT FROM AUTHOR]

Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer and a therapeutic target. Lutetium-177 (177Lu)-PSMA-617 is the first radioligand therapy to be approved in Canada for use in patients with metastatic castration-resistant prostate cancer (mCRPC). As this treatment represents a new therapeutic class, guidance regarding how to integrate it into clinical practice is needed. This article aims to review the evidence from prospective phase 2 and 3 clinical trials and meta-analyses of observational studies on the use of 177Lu-PSMA-617 in prostate cancer and discuss how Canadian clinicians might best apply these data in practice. The selection of appropriate patients, the practicalities of treatment administration, including necessary facilities for treatment procedures, the assessment of treatment response, and the management of adverse events are considered. Survival benefits were observed in clinical trials of 177Lu-PSMA-617 in patients with progressive, PSMA-positive mCRPC who were pretreated with androgen receptor pathway inhibitors and taxanes, as well as in taxane-naïve patients. However, the results of ongoing trials are awaited to clarify questions regarding the optimal sequencing of 177Lu-PSMA-617 with other therapies, as well as the implications of predictive biomarkers, personalized dosimetry, and combinations with other therapies. [ABSTRACT FROM AUTHOR]

Prostate-specific membrane antigen (PSMA) is an important target for drug delivery in prostate cancer. Heterogeneous PSMA expression impairs the efficacy of targeted therapies thereof. Combination therapies of PSMA-targeted radioligands with conventional therapies or new drugs aimed at upregulating PSMA in prostate cancer cells may improve therapy outcomes. Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein overexpressed in most prostate cancers and exploited as a target for PSMA-targeted therapies. Different approaches to target PSMA-expressing cancer cells have been developed, showing promising results in clinical trials. To discuss the regulation of PSMA expression and the main PSMA-targeted therapeutic concepts illustrating their clinical development and rationalizing combination approaches with examples. We performed a detailed literature search using PubMed and reviewed the American Society of Clinical Oncology and European Society of Medical Oncology annual meeting abstracts up to September 2023. We present an overarching description of the different strategies to target PSMA. The outcomes of PSMA-targeted therapies strongly rely on surface-bound PSMA expression. However, PSMA heterogeneity at different levels (interpatient and inter/intratumoral) limits the efficacy of PSMA-targeted therapies. We highlight the molecular mechanisms governing PSMA regulation, the understanding of which is crucial to designing therapeutic strategies aimed at upregulating PSMA expression. Thus far, homeobox B13 (HOXB13) and androgen receptor (AR) have emerged as critical transcription factors positively and negatively regulating PSMA expression, respectively. Furthermore, epigenetic regulation of PSMA has been also reported recently. In addition, many established therapeutic approaches harbor the potential to upregulate PSMA levels as well as potentiate DNA damage mediated by current radioligands. PSMA-targeted therapies are rapidly advancing, but their efficacy is strongly limited by the heterogeneous expression of the target. A thorough comprehension of how PSMA is regulated will help improve the outcomes through increasing PSMA expression and will provide the basis for synergistic combination therapies. Prostate-specific membrane antigen (PSMA) is overexpressed in most prostate cancers. PSMA-targeted therapies have shown promising results, but the heterogeneous expression of PSMA limits their efficacy. We propose to better elucidate the regulation of PSMA expression to increase the levels of the target and improve the therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Abstract Background Radiohybrid PSMA-targeted ligands (rhPSMA) have been introduced as a novel platform for theranostic applications. Among a variety of rhPSMA-ligands developed for radioligand therapy, two stereoisomers [177Lu]Lu-rhPSMA-10.1 and -10.2 have been synthesized and initially characterized in preclinical experiments with the aim to provide an optimized binding profile to human serum albumin, a reduction of charge, and thus accelerated kidney excretion, and unaffected or even improved tumor uptake. As both isomers showed similar in vitro characteristics and tumor uptake at 24 h post injection in tumor bearing mice and in order to identify the isomer with the most favorable pharmacokinetics for radioligand therapy, we carried out in-depth biodistribution and dosimetry studies in tumor-bearing and healthy mice. Results rhPSMA-10.1 and -10.2 were radiolabeled with lutetium-177 according to the established procedures of other DOTA-based PSMA ligands and displayed a high and comparable stability in all buffers and human serum (> 97%, 24 h). Biodistribution studies revealed fast clearance from the blood pool (0.3–0.6%ID/g at 1 h) and other background tissues within 48 h. Distinctive differences were found in the kidneys, where [177Lu]Lu-rhPSMA-10.1 displayed lower initial uptake and faster excretion kinetics compared to [177Lu]Lu-rhPSMA-10.2 expressed by a 1.5-fold and ninefold lower uptake value at 1 h and 24 h in healthy animals, respectively. Tumor uptake was comparable and in the range of 8.6–11.6%ID/g for both isomers over 24 h and was maintained up to 168 h at a level of 2.2 ± 0.8 and 4.1 ± 1.4%ID/g for [177Lu]Lu-rhPSMA-10.1 and [177Lu]Lu-rhPSMA-10.2, respectively. Conclusion Our preclinical data on biodistribution and dosimetry indicate a more favorable profile of [177Lu]Lu-rhPSMA-10.1 compared to [177Lu]Lu-rhPSMA-10.2 for PSMA-targeted radioligand therapy. [177Lu]Lu-rhPSMA-10.1 shows fast kidney clearance kinetics resulting in excellent tumor-to-organ ratios over a therapy relevant time course. Meanwhile, [177Lu]Lu-rhPSMA-10.1 is currently being investigated in clinical phase I/II studies in patients with mCRPC (NCT05413850), in patients with high-risk localized PC (NCT06066437, Nautilus Trial) and after external beam radiotherapy (NCT06105918).

Background: Radiohybrid PSMA-targeted ligands (rhPSMA) have been introduced as a novel platform for theranostic applications. Among a variety of rhPSMA-ligands developed for radioligand therapy, two stereoisomers [177Lu]Lu-rhPSMA-10.1 and -10.2 have been synthesized and initially characterized in preclinical experiments with the aim to provide an optimized binding profile to human serum albumin, a reduction of charge, and thus accelerated kidney excretion, and unaffected or even improved tumor uptake. As both isomers showed similar in vitro characteristics and tumor uptake at 24 h post injection in tumor bearing mice and in order to identify the isomer with the most favorable pharmacokinetics for radioligand therapy, we carried out in-depth biodistribution and dosimetry studies in tumor-bearing and healthy mice. Results: rhPSMA-10.1 and -10.2 were radiolabeled with lutetium-177 according to the established procedures of other DOTA-based PSMA ligands and displayed a high and comparable stability in all buffers and human serum (> 97%, 24 h). Biodistribution studies revealed fast clearance from the blood pool (0.3–0.6%ID/g at 1 h) and other background tissues within 48 h. Distinctive differences were found in the kidneys, where [177Lu]Lu-rhPSMA-10.1 displayed lower initial uptake and faster excretion kinetics compared to [177Lu]Lu-rhPSMA-10.2 expressed by a 1.5-fold and ninefold lower uptake value at 1 h and 24 h in healthy animals, respectively. Tumor uptake was comparable and in the range of 8.6–11.6%ID/g for both isomers over 24 h and was maintained up to 168 h at a level of 2.2 ± 0.8 and 4.1 ± 1.4%ID/g for [177Lu]Lu-rhPSMA-10.1 and [177Lu]Lu-rhPSMA-10.2, respectively. Conclusion: Our preclinical data on biodistribution and dosimetry indicate a more favorable profile of [177Lu]Lu-rhPSMA-10.1 compared to [177Lu]Lu-rhPSMA-10.2 for PSMA-targeted radioligand therapy. [177Lu]Lu-rhPSMA-10.1 shows fast kidney clearance kinetics resulting in excellent tumor-to-organ ratios over a therapy relevant time course. Meanwhile, [177Lu]Lu-rhPSMA-10.1 is currently being investigated in clinical phase I/II studies in patients with mCRPC (NCT05413850), in patients with high-risk localized PC (NCT06066437, Nautilus Trial) and after external beam radiotherapy (NCT06105918). [ABSTRACT FROM AUTHOR]

Metastatic castration‐resistant prostate cancer (mCRPC) remains a challenging condition to treat despite recent advancements. This retrospective study aimed to assess the activity and tolerability of Lutetium‐177 (Lu‐177) PSMA‐617 radioligand therapy (RLT) in mCRPC patients across multiple cancer centers in Turkey. The study included 165 patients who received at least one cycle of Lu‐177 PSMA‐617 RLT, with the majority having bone metastases and undergone prior treatments. Prostate‐specific antigen (PSA) levels were assessed before each treatment cycle, and the biochemical response was evaluated in accordance with the Prostate Cancer Work Group 3 Criteria. The PSA decline of ≥50% was classified as a response, while an increase of ≥25% in PSA levels was indicative of progressive disease. Neither response nor progression was considered as stable disease. The Lu‐177 PSMA‐617 RLT led to a significant PSA response, with 50.6% of patients achieving a >50% decrease in PSA levels. Median overall survival (OS) and progression‐free survival were 13.5 and 8.2 months, respectively. Patients receiving Lu‐177 PSMA‐617 RLT in combination with androgen receptor pathway inhibitors (ARPIs) had a higher OS compared to those receiving Lu‐177 PSMA‐617 RLT alone (18.2 vs 12.3 months, P =.265). The treatment was generally well‐tolerated, with manageable side effects such as anemia and thrombocytopenia. This study provides real‐world evidence supporting the effectiveness and safety of Lu‐177 PSMA‐617 RLT in mCRPC patients, particularly when used in combination with ARPIs. These findings contribute to the growing body of evidence on the potential benefits of PSMA‐targeted therapies in advanced prostate cancer. [ABSTRACT FROM AUTHOR]

Purpose: This study investigates imaging response of [177Lu]Lu-PSMA-617 radioligand therapy (RLT) based on the whole-body parameter total lesion PSMA (TLP), derived by PSMA-PET/CT and reflecting the total tumor burden, in patients with metastatic castration-resistant prostate cancer (mCRPC) enrolled in a prospective registry (NCT 04833517). Methods: A total of n = 102 mCRPC patients received a [68Ga]Ga-PSMA-11 PET/CT at baseline and after two cycles of PSMA-RLT, in which TLP was measured by using a semi-automated tumor segmentation. TLP was defined as the summed products of volume and uptake (∑ Volume × SUVmean) of all tumor lesions. The Kaplan-Meier method was used to determine the most appropriate ∆TLP thresholds for classification into partial remission (PR), stable disease (SD), and progressive disease (PD) regarding overall survival (OS). Furthermore, we analyzed criteria that are also frequently used in established response frameworks, such as the occurrence of new metastases as independent criterion (I) or in combination with change in tumor burden (II), and the change in PSA serum value (III). Results: For the ∆TLP thresholds −30%/+30% (and also for higher thresholds, −40%/+40% or −50%/+50%), significant differences between all three response categories became apparent (PR/PD: p = 0.001; PR/SD: p = 0.001; SD/PD: p = 0.018). Including the development of new metastases as independent criterion of PD, there was no significant difference in OS between SD and PD (p = 0.455), neither when applied in combination with TLP (p = 0.191). Similarly, significant differentiation between SD and PD was not achieved by PSA serum value (p = 0.973). Conclusion: In the largest monocentric study to date, TLP is shown to be a qualified prognostic biomarker, applying ∆TLP thresholds of −30%/+30%. It significantly differentiated between PR, SD, and PD, whereas other response criteria did not differentiate SD vs. PD. Using TLP, the development of new metastases is not a required information for predicting OS. [ABSTRACT FROM AUTHOR]

Purpose: This translational study aimed to determine the maximum tolerated dose (MTD), safety, dosimetry, and therapeutic efficacy of 177Lu-PSMA-EB-01 (denoted as [177Lu]Lu-LNC1003) in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: A total of 13 patients with mCRPC were recruited in this study. A standard 3 + 3 dose escalation protocol was performed. The following dose levels were ultimately evaluated: 1.11, 1.85, and 2.59 GBq/cycle. Patients received [177Lu]Lu-LNC1003 therapy for up to two cycles at a 6-week interval. Results: Patients received fractionated doses of [177Lu]Lu-LNC1003 ranging from 1.11 to 2.59 GBq per cycle. Myelosuppression was dose-limiting at 2.59 GBq, and 1.85 GBq was determined to be the MTD. The total-body effective dose for 177Lu-LNC1003 was 0.35 ± 0.05 mSv/MBq. The salivary glands were found to receive the highest estimated radiation dose, which was calculated to be 3.61 ± 2.83 mSv/MBq. The effective doses of kidneys and red bone marrow were 1.88 ± 0.35 and 0.22 ± 0.04 mSv/MBq, respectively. The tumor mean absorbed doses for bone and lymph node metastases were 8.52 and 9.51 mSv/MBq. Following the first treatment cycle, PSA decline was observed in 1 (33.3%), 4 (66.7%), and 2 (50.0%) patients at dose levels 1 (1.11 GBq), 2 (1.85 GBq), and 3 (2.59 GBq), respectively. Compared with the baseline serum PSA value, 1 (33.3%) at dose level 1 and 4 (66.6%) patients at dose level 2, presented a PSA decline after the second treatment cycle. Conclusion: This phase 1 trial revealed that the MTD of [177Lu]Lu-LNC1003 is 1.85 GBq. The treatment with multiple cycles at the dose of 1.11 GBq /cycle and 1.85 GBq /cycle was well tolerated. [177Lu]Lu-LNC1003 has higher tumor effective doses in bone and lymph nodes metastases while the absorbed dose in the red bone marrow should be closely monitored in future treatment studies with higher doses and multiple cycles. The frequency of administration also needs to be further explored to assess the efficacy and side effects of [177Lu]Lu-LNC1003 treatment. Trial registration: 177Lu-PSMA-EB-01 in patients with metastatic castration-resistant prostate cancer (NCT05613738, Registered 14 November 2022). URL of registryhttps://classic.clinicaltrials.gov/ct2/show/NCT05613738 [ABSTRACT FROM AUTHOR]

Radioligand therapy (RLT) is a targeted approach to treating cancer that has been shown to be safe and effective in a variety of disease states, including gastroenteropancreatic neuroendocrine tumors, lymphoma, and most recently, advanced prostate cancer. In the United States, patient access to this therapy is currently variable. Implementation of new RLT programs and expansion of existing programs are needed to broaden patient access to and standardize the delivery of RLT, especially as new therapies are introduced into clinical practice. Drawing from experience in establishing RLT programs in different settings, we have developed practical recommendations for building and implementing a robust RLT program. In this review, we present our recommendations for minimal requirements and optimal requirements, as well as system considerations, and special issues associated with implementing an RLT program in North American centers. [ABSTRACT FROM AUTHOR]

[177Lu]Lu-PSMAI&T is widely used for the radioligand therapy of metastatic castration-resistant prostate cancer (mCRPC). Since this kind of therapy has gained a large momentum in recent years, an upscaled production process yielding multiple patient doses in one batch has been developed. During upscaling, the established production method as well as the HPLC quality control were challenged. A major finding was a correlation between the specific activity and the formation of a pre-peak, presumably caused by radiolysis. Hence, nonradioactive reference standards were irradiated with an X-ray source and the formed pre-peak was subsequently identified as a deiodination product by UPLC-MS. To confirm the occurrence of the same deiodinated side product in the routine batch, a customized deiodinated precursor was radiolabeled and analyzed with the same HPLC setup, revealing an identical retention time to the pre-peak in the formerly synthesized routine batches. Additionally, further cyclization products of [177Lu]Lu-PSMAI&T were identified as major contributors to radiochemical impurities. The comparison of two HPLC methods showed the likelihood of the overestimation of the radiochemical purity during the synthesis of [177Lu]Lu-PSMAI&T. Finally, a prospective cost reduction through an optimization of the production process was shown. [ABSTRACT FROM AUTHOR]

Most Prostate Specific Membrane Antigens (PSMAs) targeting small molecules accumulate in the salivary glands (SGs), raising concerns about SG toxicity, especially after repeated therapies or therapy with 225Ac-labeled ligands. SG toxicity is assessed clinically by the severity of patient-reported xerostomia, but this parameter can be challenging to objectively quantify. Therefore, we explored the feasibility of using SG volume as a biomarker for toxicity. In 21 patients with late-stage metastatic resistant prostate cancer (mCRPC), the PSMA volume and ligand uptake of SG were analyzed retrospectively before and after two cycles of 177Lu-PSMA (LuPSMA; cohort A) and before and after one cycle of 225Ac-PSMA-617 (AcPSMA, cohort B). Mean Volume-SG in cohort A was 59 ± 13 vs. 54 ± 16 mL (−10%, p = 0.4), and in cohort B, it was 50 ± 13 vs. 40 ± 11 mL (−20%, p = 0.007), respectively. A statistically significant decrease in the activity concentration in the SG was only observed in group B (SUVmean: 9.2 ± 2.8 vs. 5.3 ± 1.8, p < 0.0001; vs. A: SUVmean: 11.2 ± 3.3 vs. 11.1 ± 3.5, p = 0.8). SG volume and PSMA-ligand uptake are promising markers to monitor the SG toxicity after a PSMA RLT. [ABSTRACT FROM AUTHOR]

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The development of potent novel androgen receptor inhibitors (ARi) such as apalutamide have improved the life expectancy in men with castration-resistant prostate cancer (CRPCa). However, some serious toxicity can occur limiting the choice of treatment in CRPCa. In our case, the patient experienced severe toxicity after initiation of apalutamide. Diagnostic PSMA-PET/CT confirmed the recurrence and tailored the treatment with 177Lu-PSMA-617 (RLT), a beta emitter radionuclide. RLT resulted in prolonged progression-free survival, thus postponing the commonly seen additional toxicity of chemotherapy.The case highlights the possibility of early RLT in PSMA avid tumors, a treatment with minimal side-effects.

Introduction/Justification: We present a case of a 71-year-old male patient diagnosed with myoepithelial carcinoma of the pelvis and perineum, who underwent fibroblast activation protein (FAP)-directed radioligand therapy and presented long lasting tumor retention as detected by late whole-body scans. Report: The patient had been previously submitted to neoadjuvant radiation therapy and surgery, with tumoral relapse at the surgical margins in the gluteal region. Lesions displayed a slow and progressive sarcomatoid growth pattern, with sacral osteolytic involvement, accompanied with obturatory and left common iliac lymph node metastases. Immunotherapy was initiated but discontinued due to grade IV diarrhea. With progressive disease evident on FDG PET/CT and no other viable chemotherapy indicated, FAPI radioligand therapy was proposed, given significant tracer uptake observed in FAP-directed PET/CT. The patient received an intravenous injection of 200 mCi of [177Lu]Lu-FAP-RTX, which was well tolerated, with no acute side effects reported. Blood tests remained within normal range. Beyond partial hair loss,no other adverse events were observed. Imaging studies including whole-body planar and SPECT/CT scans revealed intense tracer retention in the sacral mass and mild to moderate retention in the lymph node metastases up to 15 days post-treatment. Notably, indicative of a response to FAP-directed radioligand therapy, there was a resolution of drainage from a fistula in the intergluteal region. Follow-up imaging is still pending at the moment. Conclusion: This case is the first report on favorably sustained tumor retention of the radiopharmaceutical in a carcinoma patient undergoing FAP-directed radioligand therapy. With tumor response assessment still pending, longer follow-up and detailed observation is still necessary for a better understanding of potential benefits and side effects of FAP-directed radioligand therapy, especially in patients undergoing subsequent treatment cycles.

Summary: Background: The aim of this study was to provide quantitative evidence for the potential of PSMA-targeting radioligand therapy (RLT) as treatment approach for malignant brain tumours, and to explore whether tumour uptake could be enhanced by super-selective intra-arterial (ssIA)-administration. Methods: Ten patients (n = 5 high-grade glioma, n = 5 brain metastasis) received 1.5 MBq/kg [68Ga]Ga-PSMA-11 intravenously and, within 7 days, intra-arterially (i.e., selectively in tumour-feeding arteries), followed twice by PET-MRI at 90, 165 and 240 min post-injection. Patient safety was monitored for each procedure. Standardised uptake values (SUVs) were obtained for tumour, healthy-brain, salivary glands and liver. Tumour-to-salivary-gland (T/SG) and tumour-to-liver (T/L) uptake-ratios were calculated. Findings: No adverse events requiring study termination occurred. All patients showed uptake of [68Ga]Ga-PSMA-11 at the tumour site. Uptake was a median 15-fold higher following ssIA-administration (SUVmax median: 142.8, IQR: 102.8–245.9) compared to IV-administration (10.5, IQR:7.5–13.0). According to the bootstrap analysis, mean SUVmax after ssIA (168.8, 95% CI: 110.6–227.0) was well beyond the 95% confidence-interval of IV administration (10.5, 95% CI: 8.4–12.7). Uptake in healthy-brain was negligible, independent of administration route (SUVmean

We aimed to systematically determine the impact of tumor burden on 68Ga-prostate-specific membrane antigen-11 (68Ga-PSMA) PET biodistribution by the use of quantitative measurements. Methods: This international multicenter, retrospective analysis included 406 men with prostate cancer who underwent 68Ga-PSMA PET/CT. Of these, 356 had positive findings and were stratified by quintiles into a very low (quintile 1, ≤25 cm3), low (quintile 2, 25-189 cm3), moderate (quintile 3, 189-532 cm3), high (quintile 4, 532-1,355 cm3), or very high (quintile 5, ≥1,355 cm3) total PSMA-positive tumor volume (PSMA-VOL). PSMA-VOL was obtained by semiautomatic segmentation of total tumor lesions using qPSMA software. Fifty prostate cancer patients with no PSMA-positive lesions (negative scan) served as a control group. Normal organs, which included salivary glands, liver, spleen, and kidneys, were semiautomatically segmented using 68Ga-PSMA PET images, and SUVmean was obtained. Correlations between the SUVmean of normal organs and PSMA-VOL as continuous and categoric variables by quintiles were evaluated. Results: The median PSMA-VOL was 302 cm3 (interquartile range [IQR], 47-1,076 cm3). The median SUVmean of salivary glands, kidneys, liver, and spleen was 10.0 (IQR, 7.7-11.8), 26.0 (IQR, 20.0-33.4), 3.7 (IQR, 3.0-4.7), and 5.3 (IQR, 4.0-7.2), respectively. PSMA-VOL showed a moderate negative correlation with the SUVmean of the salivary glands (r = -0.44, P

BackgroundPSMA-TO-1 ("Tumor-Optimized-1") is a novel PSMA ligand with longer circulation time than PSMA-617. We compared the biodistribution in subcutaneous tumor-bearing mice of PSMA-TO-1, PSMA-617 and PSMA-11 when labeled with 68Ga and 177Lu, and the survival after treatment with 225Ac-PSMA-TO-1/-617 in a murine model of disseminated prostate cancer. We also report dosimetry data of 177Lu-PSMA-TO1/-617 in prostate cancer patients.MethodsFirst, PET images of 68Ga-PSMA-TO-1/-617/-11 were acquired on consecutive days in three mice bearing subcutaneous C4-2 xenografts. Second, 50 subcutaneous tumor-bearing mice received either 30 MBq of 177Lu-PSMA-617 or 177Lu-PSMA-TO-1 and were sacrificed at 1, 4, 24, 48 and 168 h for ex vivo gamma counting and biodistribution. Third, mice bearing disseminated lesions via intracardiac inoculation were treated with either 40 kBq of 225Ac-PSMA-617, 225Ac-PSMA-TO-1, or remained untreated and followed for survival. Additionally, 3 metastatic castration-resistant prostate cancer patients received 500 MBq of 177Lu-PSMA-TO-1 under compassionate use for dosimetry purposes. Planar images with an additional SPECT/CT acquisition were acquired for dosimetry calculations.ResultsTumor uptake measured by PET imaging of 68Ga-labeled agents in mice was highest using PSMA-617, followed by PSMA-TO-1 and PSMA-11. 177Lu-PSMA tumor uptake measured by ex vivo gamma counting at subsequent time points tended to be greater for PSMA-TO-1 up to 1 week following treatment (p > 0.13 at all time points). This was, however, accompanied by increased kidney uptake and a 26-fold higher kidney dose of PSMA-TO-1 compared with PSMA-617 in mice. Mice treated with a single-cycle 225Ac-PSMA-TO-1 survived longer than those treated with 225Ac-PSMA-617 and untreated mice, respectively (17.8, 14.5 and 7.7 weeks, respectively; p