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Objective: To assess the activity and safety of sequential lutetium-177 ( 177 Lu)-PSMA-617 and docetaxel vs docetaxel on a background of androgen deprivation therapy (ADT) in men with de novo metastatic hormone-naïve prostate cancer (mHNPC)., Patients and Methods: UpFrontPSMA (NCT04343885) is an open-label, randomized, multicentre, phase 2 trial, recruiting 140 patients at 12 Australian centres. Key eligibility criteria include: prostate cancer with a histological diagnosis within 12 weeks of screening commencement; prostate-specific antigen (PSA) >10 ng/mL at diagnosis; ≤4 weeks on ADT; evidence of metastatic disease on computed tomography (CT) and/or bone scan; high-volume prostate-specific membrane antigen (PSMA)-avid disease with a maximum standardized uptake value >15; and absence of extensive discordant fluorodeoxyglcuose (FDG)-positive, PSMA-negative disease. 68 Ga-PSMA-11 and 18 F-FDG positron-emission tomography (PET)/CT undergo central review to determine eligibility. Patients are randomized 1:1 to experimental treatment, Arm A ( 177 Lu-PSMA-617 7.5GBq q6w × 2 cycles followed by docetaxel 75 mg/m 2 q3w × 6 cycles), or standard-of-care treatment, Arm B (docetaxel 75 mg/m 2 q3w × 6 cycles). All patients receive continuous ADT. Patients are stratified based on disease volume on conventional imaging and duration of ADT at time of registration. The primary endpoint is the proportion of patients with undetectable PSA (≤0.2 ng/L) at 12 months after study treatment commencement. Secondary endpoints include safety, time to castration resistance, overall survival, PSA and radiographic progression-free survival, objective tumour response rate, early PSMA PET response, health-related quality of life, and frequency and severity of adverse events. Enrolment commenced in April 2020., Results and Conclusions: The results of this trial will generate data on the activity and safety of 177 Lu-PSMA-617 in men with de novo mHNPC in a randomized phase 2 design., (© 2021 The Authors BJU International © 2021 BJU International Published by John Wiley & Sons Ltd.)

177 Lu-PSMA-617 is a radioligand with high affinity for prostate-specific membrane antigen (PSMA), enabling targeted β-irradiation of prostate cancer. We have previously reported favorable activity with low toxicity in a prospective phase II trial involving 30 men with metastatic castration-resistant prostate cancer. We now report their longer-term outcomes, including a 20-patient extension cohort and outcomes of subsequent systemic treatments after completion of trial therapy. Methods: Fifty patients with PSMA-avid metastatic castration-resistant prostate cancer who had progressed after standard therapies received up to 4 cycles of 177 Lu-PSMA every 6 wk. Endpoints included prostate-specific antigen (PSA) response (Prostate Cancer Working Group 2), toxicity (Common Terminology Criteria for Adverse Events, version 4.03), imaging response, patient-reported health-related quality of life, progression-free survival, and overall survival. We also describe, as a novel finding, outcomes of men who subsequently progressed and had further systemic therapies, including 177 Lu-PSMA. Results: Seventy-five men were screened to identify 50 patients eligible for treatment. Adverse prognostic features of the cohort included short median PSA doubling time (2.3 mo) and extensive prior treatment, including prior docetaxel (84%), cabazitaxel (48%), and abiraterone or enzalutamide (92%). The mean administered radioactivity was 7.5 GBq/cycle. A PSA decline of at least 50% was achieved in 32 of 50 patients (64%; 95% confidence interval [CI], 50%-77%), including 22 patients (44%; 95% CI, 30%-59%) with at least an 80% decrease. Of 27 patients with measurable soft-tissue disease, 15 (56%) achieved an objective response by RECIST 1.1. The most common toxicities attributed to 177 Lu-PSMA were self-limiting G1-G2 dry mouth (66%), transient G1-G2 nausea (48%), G3-G4 thrombocytopenia (10%), and G3 anemia (10%). Brief Pain Inventory severity and interference scores decreased at all time points, including at the 3-mo follow-up, with a decrease of -1.2 (95% CI, -0.5 to -1.9; P = 0.001) and -1.0 (95% CI, -0.2 to -0.18; P = 0.013), respectively. At a median follow-up of 31.4 mo, median overall survival was 13.3 mo (95% CI, 10.5-18.7 mo), with a significantly longer survival of 18.4 mo (95% CI, 13.8-23.8 mo) in patients achieving a PSA decline of at least 50%. At progression after prior response, further 177 Lu-PSMA was administered to 15 (30%) patients (median of 2 cycles commencing 359 d from enrollment), with a PSA decline of at least 50% in 11 patients (73%). Four of 21 patients (19%) receiving other systemic therapies on progression experienced a PSA decline of at least 50%. There were no unexpected adverse events with 177 Lu-PSMA retreatment. Conclusion: This expanded 50-patient cohort of men with extensive prior therapy confirms our earlier report of high response rates, low toxicity, and improved quality of life with 177 Lu-PSMA radioligand therapy. On progression, rechallenge 177 Lu-PSMA demonstrated higher response rates than other systemic therapies., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Imaging of somatostatin receptor expression is an established technique for staging of neuroendocrine neoplasia and determining the suitability of patients for peptide receptor radionuclide therapy. PET/CT using 68 Ga-labeled somatostatin analogs is superior to earlier agents, but the rapid physical decay of the radionuclide poses logistic and regulatory challenges. 64 Cu has attractive physical characteristics for imaging and provides a diagnostic partner for the therapeutic radionuclide 67 Cu. Based on promising preclinical studies, we have performed a first-time-in-humans trial of 64 Cu-MeCOSar-Tyr 3 -octreotate ( 64 Cu-SARTATE) to assess its safety and ability to localize disease at early and late imaging time-points. Methods: In a prospective trial, 10 patients with known neuroendocrine neoplasia and positive for uptake on 68 Ga-DOTA-octreotate ( 68 Ga-DOTATATE) PET/CT underwent serial PET/CT imaging at 30 min, 1 h, 4 h, and 24 h after injection of 64 Cu-SARTATE. Adverse reactions were recorded, and laboratory testing was performed during infusion and at 1 and 7 d after imaging. Images were analyzed for lesion and normal-organ uptake and clearance to assess lesion contrast and perform dosimetry estimates. Results: 64 Cu-SARTATE was well tolerated during infusion and throughout the study, with 3 patients experiencing mild infusion-related events. High lesion uptake and retention were observed at all imaging time-points. There was progressive hepatic clearance over time, providing the highest lesion-to-liver contrast at 24 h. Image quality remained high at this time. Comparison of 64 Cu-SARTATE PET/CT obtained at 4 h to 68 Ga-DOTATATE PET/CT obtained at 1 h indicated comparable or superior lesion detection in all patients, especially in the liver. As expected, the highest early physiologic organ uptake was in the kidneys, liver, and spleen. Conclusion: 64 Cu-SARTATE is safe and has excellent imaging characteristics. High late-retention in tumor and clearance from the liver suggest suitability for diagnostic studies and for prospective dosimetry for 67 Cu-SARTATE peptide receptor radionuclide therapy, and the half-life of 64 Cu would also facilitate good-manufacturing-practice production and distribution to sites without access to 68 Ga., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Bulky disease is an adverse prognostic factor for 177 Lu-DOTA-octreotate ( 177 Lu-DOTATATE) peptide receptor radionuclide therapy (PRRT). 90 Y-DOTA-octreotate ( 90 Y-DOTATATE) has theoretical advantages in this setting but may less effectively treat co-existent smaller deposits and have higher toxicity than 177 Lu-DOTATATE. The aim of this study was to assess the efficacy and safety of using these agents sequentially., Methods: We reviewed patients (pts) with at least one lesion of a transaxial diameter >4 cm who completed 1-2 cycles of 90 Y-DOTATATE followed by 2-3 cycles of 177 Lu-DOTATATE, with treatment empirically adapted to disease size and burden in individual patients. Data collected included morphological and molecular imaging response, toxicity, and progression-free and overall survival., Results: Twenty-six pts (17 men; aged 27-74 years) received a median cumulative activity of 6.5 GBq 90 Y-DOTATATE, and 21 GBq 177 Lu-DOTATATE. All but one received radiosensitising chemotherapy. Adverse prognostic factors included ENETS grade 2 or 3 in 58 %, and FDG-avid disease in 73 %. Nineteen pts treated for progressive disease had stabilisation (37 %) or regression on CT (42 % partial response, 21 % minor response), with a mean 59 % (8-99 %) reduction in disease burden. All seven pts treated for uncontrolled symptoms reported improvement during PRRT with 4/7 having complete symptom resolution at 3 months. Eight patients had grade 3/4 lymphopaenia, and two patients grade 3/4 thrombocytopaenia without significant hepatic or renal toxicity. Median survival was not reached after a median follow-up of 35 months. Median progression-free survival was 33 months., Conclusion: PRCRT with 90 Y -DOTATATE followed by 177 Lu-DOTATATE in individualised regimens achieved high clinical and morphological response in patients with bulky tumours. Despite lack of a control arm, the efficacy of this treatment approach appears higher than reported results with either agent used alone or other approved treatments, particularly given the adverse prognostic features of this cohort.

Background: Pheochromocytomas (PCC) and paragangliomas (PGL) are neuroendocrine tumours arising from pluripotent neural crest stem cells and are associated with neurons of the autonomic nervous system. PCCs/PGLs are often hereditary and multifocal, and their biologic behaviour and metabolic activity vary making imaging of these tumours challenging. The imaging gold standard has been I-123 MIBG complemented by CT or MRI. PGLs being neuroendocrine tumours express somatostatin receptors enabling imaging with Ga-68 DOTA-coupled peptides such as DOTATATE. Imaging with F-18 FDG also provides additional information regarding metabolic activity and biologic aggressiveness of these tumours, or, in some situations, reflecting metabolic reprogramming of these tumours. We report our experience using both Ga-68 DOTATATE and F-18 FDG PET/CT imaging in patients with PGLs and PCCs., Methods: This was a retrospective review of 23 patients with proven PGL/PCC who underwent both DOTATATE and FDG PET/CT. Seven patients also had I-123 MIBG SPECT/CT and 1 patient had I-124 MIBG PET/CT. Lesional intensity and patterns of uptake were analysed., Results: DOTATATE and FDG were positive at most sites of disease (96.2 % vs 91.4 %), although uptake intensity was significantly higher on DOTATATE with a median SUV of 21 compared to 12.5 for FDG (p < 0.001). SUVmax on F-18 FDG was significantly higher (p < 0.001) in clinically aggressive cases. I-123/I-124 MIBG detected fewer lesions (30.4 %)., Conclusion: Overall, Ga-68 DOTATATE PET/CT detected similar number but has significantly greater lesion-to-background contrast compared to F-18 FDG PET/CT. Combined with high specificity, patient convenience and relatively low cost, DOTATATE PET/CT should be considered the ideal first line investigation for imaging PGL/PCC. Depending on DOTATATE findings and the clinical question, FDG and MIBG remain useful and, in selected cases, may provide more accurate staging, disease characterisation and guide treatment choices.

This review provides practical guidance for clinicians involved in the management of endocrine malignancies, including endocrinologists, medical oncologists, surgeons and nuclear medicine specialists regarding the indications and use of 2-fluoro-2-deoxy-d-glucose F-18 (FDG) PET/computed tomography (CT), particularly with respect to targeted radionuclide therapy. Key principles of FDG PET/CT for radionuclide therapy are explored in detail using gastroenteropancreatic neuroendocrine tumors as a prototype endocrine malignancy. The relevant literature is reviewed, and practical application in this new and emerging field is highlighted with the use of case examples., (Copyright © 2015 Elsevier Inc. All rights reserved.)