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In the past decade, a growing body of literature has reported promising results for prostate-specific membrane antigen (PSMA)-targeted radionuclide imaging and therapy in prostate cancer. First clinical studies evaluating the efficacy of [177Lu]Lu-PSMA radioligand therapy (PSMA-RLT) demonstrated favorable results in prostate cancer patients. [177Lu]Lu-PSMA is generally well tolerated due to its limited side effects. While PSMA is highly overexpressed in prostate cancer cells, varying degrees of PSMA expression have been reported in other malignancies as well, particularly in the tumor-associated neovasculature. Hence, it is anticipated that PSMA-RLT could be explored for other solid cancers. Here, we describe the current knowledge of PSMA expression in other solid cancers and define a perspective towards broader clinical implementation of PSMA-RLT. This review focuses specifically on salivary gland cancer, glioblastoma, thyroid cancer, renal cell carcinoma, hepatocellular carcinoma, lung cancer, and breast cancer. An overview of the (pre)clinical data on PSMA immunohistochemistry and PSMA PET/CT imaging is provided and summarized. Furthermore, the first clinical reports of non-prostate cancer patients treated with PSMA-RLT are described.

Background In recent years, there is increasing evidence showing a beneficial outcome (e.g. progression free survival; PFS) after metastases-directed therapy (MDT) with external beam radiotherapy (EBRT) or targeted surgery for oligometastatic hormone sensitive prostate cancer (oHSPC). However, many patients do not qualify for these treatments due to prior interventions or tumor location. Such oligometastatic patients could benefit from radioligand therapy (RLT) with 177 Lu-PSMA; a novel tumor targeting therapy for end-stage metastatic castration-resistant prostate cancer (mCRPC). Especially because RLT could be more effective in low volume disease, such as the oligometastatic status, due to high uptake of radioligands in smaller lesions. To test the hypothesis that 177 Lu-PSMA is an effective treatment in oHSPC to prolong PFS and postpone the need for androgen deprivation therapy (ADT), we initiated a multicenter randomized clinical trial. This is globally, the first prospective study using 177 Lu-PSMA-I&T in a randomized multicenter setting. Methods & design This study compares 177 Lu-PSMA-I&T MDT to the current standard of care (SOC); deferred ADT. Fifty-eight patients with oHSPC (≤5 metastases on PSMA PET) and high PSMA uptake (SUVmax > 15, partial volume corrected) on 18 F-PSMA PET after prior surgery and/or EBRT and a PSA doubling time of < 6 months, will be randomized in a 1:1 ratio. The patients randomized to the interventional arm will be eligible for two cycles of 7.4GBq 177 Lu-PSMA-I&T at a 6-week interval. After both cycles, patients are monitored every 3 weeks (including adverse events, QoL- and xerostomia questionnaires and laboratory testing) at the outpatient clinic. Twenty-four weeks after cycle two an end of study evaluation is planned together with another 18 F-PSMA PET and (whole body) MRI. Patients in the SOC arm are eligible to receive 177 Lu-PSMA-I&T after meeting the primary study objective, which is the fraction of patients who show disease progression during the study follow up. A second primary objective is the time to disease progression. Disease progression is defined as a 100% increase in PSA from baseline or clinical progression. Discussion This is the first prospective randomized clinical study assessing the therapeutic efficacy and toxicity of 177 Lu-PSMA-I&T for patients with oHSPC. Trial registration Clinicaltrials.gov identifier: NCT04443062 .

Background The BULLSEYE trial is a multicenter, open-label, randomized controlled trial to test the hypothesis if 177 Lu-PSMA is an effective treatment in oligometastatic hormone-sensitive prostate cancer (oHSPC) to prolong the progression-free survival (PFS) and postpone the need for androgen deprivation therapy (ADT). The original study protocol was published in 2020. Here, we report amendments that have been made to the study protocol since the commencement of the trial. Changes in methods and materials Two important changes were made to the original protocol: (1) the study will now use 177 Lu-PSMA-617 instead of 177 Lu-PSMA-I&T and (2) responding patients with residual disease on 18 F-PSMA PET after the first two cycles are eligible to receive additional two cycles of 7.4 GBq 177 Lu-PSMA in weeks 12 and 18, summing up to a maximum of 4 cycles if indicated. Therefore, patients receiving 177 Lu-PSMA-617 will also receive an interim 18 F-PSMA PET scan in week 4 after cycle 2. The title of this study was modified to; “Lutetium-177-PSMA in Oligo-metastatic Hormone Sensitive Prostate Cancer” and is now partly supported by Advanced Accelerator Applications, a Novartis Company. Conclusions We present an update of the original study protocol prior to the completion of the study. Treatment arm patients that were included and received 177 Lu-PSMA-I&T under the previous protocol will be replaced. Trial registration ClinicalTrials.gov NCT04443062 . First posted: June 23, 2020.

IntroductionFibroblast activation protein (FAP) is highly overexpressed in stromal tissue of various cancers. While FAP has been recognized as a potential diagnostic or therapeutic cancer target for decades, the surge of radiolabeled FAP-targeting molecules has the potential to revolutionize its perspective. It is presently hypothesized that FAP targeted radioligand therapy (TRT) may become a novel treatment for various types of cancer. To date, several preclinical and case series have been reported on FAP TRT using varying compounds and showing effective and tolerant results in advanced cancer patients. Here, we review the current (pre)clinical data on FAP TRT and discuss its perspective towards broader clinical implementation. MethodsA PubMed search was performed to identify all FAP tracers used for TRT. Both preclinical and clinical studies were included if they reported on dosimetry, treatment response or adverse events. The last search was performed on July 22 2022. In addition, a database search was performed on clinical trial registries (date 15th of July 2022) to search for prospective trials on FAP TRT.ResultsIn total, 35 papers were identified that were related to FAP TRT. This resulted in the inclusion of the following tracers for review: FAPI-04, FAPI-46, FAP-2286, SA.FAP, ND-bisFAPI, PNT6555, TEFAPI-06/07, FAPI-C12/C16, and FSDD.ConclusionTo date, data was reported on more than 100 patients that were treated with different FAP targeted radionuclide therapies such as [177Lu]Lu-FAPI-04, [90Y]Y-FAPI-46, [177Lu]Lu-FAP-2286, [177Lu]Lu-DOTA.SA.FAPI and [177Lu]Lu-DOTAGA.(SA.FAPi)2. In these studies, FAP targeted radionuclide therapy has resulted in objective responses in difficult to treat end stage cancer patients with manageable adverse events. Although no prospective data is yet available, these early data encourages further research.

Introduction While [ 177 Lu]Lu-PSMA radioligand therapy is currently only applied in end-stage metastatic castrate-resistant prostate cancer (mCRPC) patients, also low-volume hormone-sensitive metastatic prostate cancer (mHSPC) patients can benefit from it. However, there are toxicity concerns related to the sink effect in low-volume disease. This prospective study aims to determine the kinetics of [ 177 Lu]Lu-PSMA in mHSPC patients, analyzing the doses to organs at risk (salivary glands, kidneys, liver, and bone marrow) and tumor lesions < 1 cm diameter. Methods Ten mHSPC patients underwent two cycles of [ 177 Lu]Lu-PSMA therapy. Three-bed position SPECT/CT was performed at 5 time points after each therapy. Organ dosimetry and lesion dosimetry were performed using commercial software and a manual approach, respectively. Correlation between absorbed index lesion dose and treatment response (PSA drop of > 50% at the end of the study) was calculated and given as Spearman’s r and p-values. Results Kinetics of [ 177 Lu]Lu-PSMA in mHSPC patients are comparable to those in mCRPC patients. Lesion absorbed dose was high (3.25 ± 3.19 Gy/GBq) compared to organ absorbed dose (salivary glands: 0.39 ± 0.17 Gy/GBq, kidneys: 0.49 ± 0.11 Gy/GBq, liver: 0.09 ± 0.01 Gy/GBq, bone marrow: 0.017 ± 0.008 Gy/GBq). A statistically significant correlation was found between treatment response and absorbed index lesion dose ( p  = 0.047). Conclusions We successfully performed small lesion dosimetry and showed that the tumor sink effect in mHSPC patients is of less concern than was expected. Tumor-to-organ ratio of absorbed dose was high and tumor uptake correlates with PSA response. Additional treatment cycles are legitimate in terms of organ toxicity and could lead to better tumor response.

Rationale Prolonged in vivo evaluation of PSMA tracers could improve tumor imaging and patient selection for 177 Lu-PSMA-617 and 177 Lu-PSMA-I&T. In this study, we present the radiolabeling method of PSMA-617 and PSMA-I&T with the long-lived positron emitter 89 Zr to enable PET imaging up to 7 days post-injection. We compared the biodistribution of 89 Zr-PSMA-617 and 89 Zr-PSMA-I&T to those of 177 Lu-PSMA-617 and 177 Lu-PSMA-I&T, respectively, in a PSMA + xenograft model. Moreover, we provide the first human 89 Zr-PSMA-617 images. Materials and methods PSMA ligands were labeled with 50-55 MBq [ 89 Zr]ZrCl 4 using a two-step labeling protocol. For biodistribution, BALB/c nude mice bearing PSMA + and PSMA − xenografts received 0.6 µg (0.6–1 MBq) of 89 Zr-PSMA-617, 89 Zr-PSMA-I&T, 177 Lu-PSMA-617, or 177 Lu-PSMA-I&T intravenously. Ex vivo biodistribution and PET/SPECT imaging were performed up to 168 h post-injection. Dosimetry was performed from the biodistribution data. The patient received 90.5 MBq 89 Zr-PSMA-617 followed by PET/CT imaging. Results 89 Zr-labeled PSMA ligands showed a comparable ex vivo biodistribution to its respective 177 Lu-labeled counterparts with high tumor accumulation in the PSMA + xenografts. However, using a dose estimation model for 177 Lu, absorbed radiation dose in bone and kidneys differed among the 177 Lu-PSMA and 89 Zr-PSMA tracers. 89 Zr-PSMA-617 PET in the first human patient showed high contrast of PSMA expressing tissues up to 48 h post-injection. Conclusion PSMA-617 and PSMA-I&T were successfully labeled with 89 Zr and demonstrated high uptake in PSMA + xenografts, which enabled PET up to 168 h post-injection. The biodistribution of 89 Zr-PSMA-I&T and 89 Zr-PSMA-617 resembled that of 177 Lu-PSMA-I&T and 177 Lu-PSMA-617, respectively. The first patient 89 Zr-PSMA-617 PET images were of high quality warranting further clinical investigation.

BackgroundDosimetry in [177Lu]Lu-PSMA therapy is a valuable tool to assess treatment efficacy and toxicity. This study aims to develop a clinically implementable protocol to determine the absorbed dose in organs and tumor lesions after [177Lu]Lu-PSMA-617 therapy, by reducing the imaging time points and utilizing population-based kinetics with a single scan, with evaluation of its influence on the uncertainty in absorbed dose.MethodsTen patients with metastatic hormone-sensitive prostate cancer received two cycles of [177Lu]Lu-PSMA-617. Post-treatment imaging was performed at 1 h, 24 h, 48 h, 72 h and 168 h, consisting of three-bed positions SPECT/CT and a whole-body planar scan. Five-time point SPECT dosimetry was performed for lesions and organs with physiological uptake (kidneys, liver and salivary glands) and used as the reference standard. Absorbed dose values for various simplified protocols were compared to the reference standard.ResultsAccurate lesion dosimetry is possible using one-time point SPECT imaging at 168 h, with an increase in uncertainty (20% vs. 14% for the reference standard). By including a second time point, uncertainty was comparable to the reference standard (13%). Organ dosimetry can be performed using a single SPECT at 24 h or 48 h. Dosimetry based on planar scans did not provide accurate dose estimations.ConclusionAccurate lesion dosimetry in [177Lu]Lu-PSMA therapy can be performed using a one- or two-time point protocol, making dosimetry assessments more suitable for routine clinical implementation, although dosimetry based om multiple time points is more accurate.Clinical trial registration This study was approved by the Medical Review Ethics Committee Region Arnhem-Nijmegen on January 23, 2018 and was registered on clinicaltrials.gov (NCT03828838).

Introduction Patient eligibility for [ 177 Lu]Lu-PSMA therapy remains a challenge, with only 40–60% response rate when patient selection is done based on the lesion uptake (SUV) on [ 68 Ga]Ga-PSMA-PET/CT. Prediction of absorbed dose based on this pre-treatment scan could improve patient selection and help to individualize treatment by maximizing the absorbed dose to target lesions while adhering to the threshold doses for the organs at risk (kidneys, salivary glands, and liver). Methods Ten patients with low-volume hormone-sensitive prostate cancer received a pre-therapeutic [ 68 Ga]Ga-PSMA-11 PET/CT, followed by 3 GBq [ 177 Lu]Lu-PSMA-617 therapy. Intra-therapeutically, SPECT/CT was acquired at 1, 24, 48, 72, and 168 h. Absorbed dose in organs and lesions ( n  = 22) was determined according to the MIRD scheme. Absorbed dose prediction based on [ 68 Ga]Ga-PSMA-PET/CT was performed using tracer uptake at 1 h post-injection and the mean tissue effective half-life on SPECT. Predicted PET/actual SPECT absorbed dose ratios were determined for each target volume. Results PET/SPECT absorbed dose ratio was 1.01 ± 0.21, 1.10 ± 0.15, 1.20 ± 0.34, and 1.11 ± 0.29 for kidneys (using a 2.2 scaling factor), liver, submandibular, and parotid glands, respectively. While a large inter-patient variation in lesion kinetics was observed, PET/SPECT absorbed dose ratio was 1.3 ± 0.7 (range: 0.4–2.7, correlation coefficient  r  = 0.69, p  < 0.01). Conclusion A single time point [ 68 Ga]Ga-PSMA-PET scan can be used to predict the absorbed dose of [ 177 Lu]Lu-PSMA therapy to organs, and (to a limited extent) to lesions. This strategy facilitates in treatment management and could increase the personalization of [ 177 Lu]Lu-PSMA therapy.

Proportional hazards models have been proposed to analyse time-to-event phenotypes in genome-wide association studies (GWAS). However, little is known about the ability of proportional hazards models to identify genetic associations under different generative models and when ascertainment is present. Here we propose the age-dependent liability threshold (ADuLT) model as an alternative to a Cox regression based GWAS, here represented by SPACox. We compare ADuLT, SPACox, and standard case-control GWAS in simulations under two generative models and with varying degrees of ascertainment as well as in the iPSYCH cohort. We find Cox regression GWAS to be underpowered when cases are strongly ascertained (cases are oversampled by a factor 5), regardless of the generative model used. ADuLT is robust to ascertainment in all simulated scenarios. Then, we analyse four psychiatric disorders in iPSYCH, ADHD, Autism, Depression, and Schizophrenia, with a strong case-ascertainment. Across these psychiatric disorders, ADuLT identifies 20 independent genome-wide significant associations, case-control GWAS finds 17, and SPACox finds 8, which is consistent with simulation results. As more genetic data are being linked to electronic health records, robust GWAS methods that can make use of age-of-onset information will help increase power in analyses for common health outcomes. Robust genome-wide association study (GWAS) methods that can utilise time-to-event information such as age-of-onset will help increase power in analyses for common health outcomes. Here, the authors propose a computationally efficient time-to-event model for GWAS.

Background The expression of prostate-specific membrane antigen (PSMA), a target for oncological imaging and treatment, is upregulated by androgen blockade in prostate cancer. Salivary duct carcinoma (SDC), an aggressive histological subtype of salivary gland cancer, resembles prostate cancer in terms of PSMA and androgen receptor (AR) expression. A similar upregulation of PSMA in SDC would have implications for future studies with PSMA-targeted imaging and therapy. Additionally, FDG PET/CT scans are frequently used for SDC imaging, but the effect of androgen blockade on FDG uptake is unknown. This study investigated the effect of combined androgen blockade (CAB) on tumour PSMA and FDG uptake in patients with SDC. Results Eight patients with recurrent and/or metastatic AR-positive SDC who started CAB (goserelin plus bicalutamide) as standard of care were prospectively enrolled. [ 68  Ga]Ga-PSMA-11 and [ 18 F]FDG PET/CT scans were performed within 21 days before and 21 ± 7 days after CAB initiation. PET parameters, including SUV max , were obtained for PSMA and FDG positive lesions. A total of 80 metastatic lesions were analysed on a per-lesion basis. SUV max changes after CAB initiation were categorised as increased (≥ + 20%), stable (between -20% and + 20%), or decreased (≤ -20%). The PSMA SUV max increased in 20 lesions (25%), remained stable in 46 lesions (58%), and decreased in 14 lesions (18%), with no significant overall change (Wilcoxon signed rank test, p = 0.74). The FDG SUV max increased in 35 lesions (44%), remained stable in 39 lesions (49%), and decreased in 6 lesions (8%), with a significant overall median increase of + 0.97 (Wilcoxon signed rank test, p < 0.001). The median PFS was 2.2 months (95% confidence interval 1.7–2.7 months). Conclusions Androgen blockade in patients with recurrent and/or metastatic SDC did not induce a significant increase in tumour PSMA uptake after three weeks. In contrast, tumour FDG uptake increased significantly after three weeks of CAB, which may reflect the poor tumour response in this cohort and/or a transient treatment-related effect. Trial registration : ClinicalTrials.gov, NCT04214353. Registered 13 December 2019.