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Prostate-specific membrane antigen (PSMA) is expressed by the majority of clinically significant prostate adenocarcinomas, and patients with target-positive disease can easily be identified by PSMA PET imaging. Promising results with PSMA-targeted radiopharmaceutical therapy have already been obtained in early-phase studies using various combinations of targeting molecules and radiolabels. Definitive evidence of the safety and efficacy of [177Lu]Lu-PSMA-617 in combination with standard-of-care has been demonstrated in patients with metastatic castration-resistant prostate cancer, whose disease had progressed after or during at least one taxane regimen and at least one novel androgen-axis drug. Preliminary data suggest that 177Lu-PSMA-radioligand therapy (RLT) also has high potential in additional clinical situations. Hence, the radiopharmaceuticals [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T are currently being evaluated in ongoing phase 3 trials. The purpose of this guideline is to assist nuclear medicine personnel, to select patients with highest potential to benefit from 177Lu-PSMA-RLT, to perform the procedure in accordance with current best practice, and to prepare for possible side effects and their clinical management. We also provide expert advice, to identify those clinical situations which may justify the off-label use of [177Lu]Lu-PSMA-617 or other emerging ligands on an individual patient basis.

Background Trials of lutetium prostate specific membrane antigen (PSMA) in men with metastatic castration-resistant prostate cancer (mCRPC) have demonstrated good safety and efficacy, but combination strategies may improve outcomes. Idronoxil is a synthetic flavonoid derivative with radiosensitising properties. Objective To evaluate the safety and activity of 177Lu PSMA 617 (LuPSMA-617) in combination with idronoxil suppositories (NOX66) in patients with end-stage mCRPC. Design, setting, and participants Thirty-two men with progressive mCRPC previously treated with taxane-based chemotherapy (91% treated with both docetaxel and cabazitaxel) and abiraterone and/or enzalutamide were enrolled in this phase I dose escalation study with phase II dose expansion. Intervention Screening with 68Ga PSMA and 18F-fludeoxyglucose positron emission tomography (PET)/computed tomography (CT) was performed. Men received up to six cycles of LuPSMA-617 (7.5 GBq) on day 1, with escalating doses of NOX66 on days 1–10 of a 6-wk cycle. Cohort 1 (n = 8) received 400 mg and cohort 2 (n = 24) 800 mg of NOX66. Outcome measurements and statistical analysis Adverse events (AEs), pain inventory scores, prostate-specific antigen (PSA) response, progression-free survival, and overall survival were evaluated. Results and limitations Fifty-six men were screened and 32 (57%) were enrolled with a screen failure rate of 21% for PET imaging criteria. Dosing was as follows: 97% (31/32) received two or more doses and 47% (15/32) completed six doses. Common AEs included xerostomia, fatigue, and anaemia. Anal irritation attributable to NOX66 occurred in 28%. PSA responses were as follows: 91% (29/32) had any PSA response (median –74%; 95% confidence interval [CI] 76–97) and 62.5% (20/32) had a PSA fall of >50% (95% CI 45–77). The median PSA progression-free survival was 6.1 mo (95% CI 2.8–9.2) and median overall survival was 17.1 mo (95% CI 6.5–27.1). Conclusions NOX66 with LuPSMA-617 is a safe and feasible therapeutic strategy in men treated with third-line therapy and beyond for mCRPC. Patient summary Addition of NOX66 to 177Lu prostate-specific membrane antigen 617 is safe, and further studies are needed to assess its potential to augment the anticancer effects of LuPSMA-617.

Multiparametric magnetic resonance imaging (MRI) is validated for the detection of clinically significant prostate cancer (csPCa), although patients with negative/equivocal MRI undergo biopsy for false negative concerns. In addition,This trial aimed to determine whether the combination of PSMA + MRI was superior to MRI in diagnostic performance for detecting csPCa.A prospective multicentre phase II imaging trial was conducted. A total of 296 men were enrolled with suspected prostate cancer, with no prior biopsy or MRI, recent MRI (6 mo), and planned transperineal biopsy based on clinical risk and MRI. In all, 291 men underwent MRI, pelvic-only PSMA, and systematic ± targeted biopsy.Sensitivity, specificity, and predictive values (negative predictive value [NPV] and positive predictive value) for csPCa were determined for MRI, PSMA, and PSMA + MRI. PSMA + MRI was defined as negative for PSMA negative Prostate Imaging Reporting and Data System (PI-RADS) 2/3 and positive for either MRI PI-RADS 4/5 or PSMA positive PI-RADS 2/3; csPCa was any International Society of Urological Pathology (ISUP) grade group ≥2 malignancy.Of the patients, 56% (n = 162) had csPCa; 67% had PI-RADS 3-5, 73% were PSMA positive, and 81% were combined PSMA + MRI positive. Combined PSMA + MRI improved NPV compared with MRI alone (91% vs 72%, test ratio = 1.27 [1.11-1.39], p 0.001). Sensitivity also improved (97% vs 83%, p 0.001); however, specificity was reduced (40% vs 53%, p = 0.011). Five csPCa cases were missed with PSMA + MRI (four ISUP 2 and one ISUP 3). Of all men, 19% (56/291) were PSMA + MRI negative (38% of PI-RADS 2/3) and could potentially have avoided biopsy, risking delayed csPCa detection in 3.1% men with csPCa (5/162) or 1.7% (5/291) overall.PSMA + MRI improved NPV and sensitivity for csPCa in an MRI triaged population. Further randomised studies will determine whether biopsy can safely be omitted in men with a high clinical suspicion of csPCa but negative combined imaging.The combination of magnetic resonance imaging (MRI) + prostate-specific membrane antigen positron emission tomography reduces false negatives for clinically significant prostate cancer (csPCa) compared with MRI, potentially allowing a reduction in the number of prostate biopsies required to diagnose csPCa.

To identify whether synchronous reading of multiparametric magnetic resonance imaging (mpMRI) andThis was a retrospective analysis of 100 patients randomly selected from the PRIMARY trial, a prospective Phase II multicentre imaging trial. Three dual-trained radiologist/nuclear medicine physicians re-reported the mpMRI and PSMA-PET both independently and synchronously for the same patients in random order, blinded to previous results. Diagnostic performance was assessed for mpMRI/PSMA-PET images read synchronously or independently and then synthesized. Agreement between imaging results and histopathology was examined. 'Concordance' between imaging modalities was defined as overlapping lesions. Reporting certainty was evaluated by the individual reporters for each modality.International Society of Urological Pathology Grade Group ≥2 cancer was present in 60% of patients on biopsy. Synchronous reading of mpMRI/PSMA-PET increased sensitivity compared to mpMRI or PSMA-PET alone (93% vs 80% vs 88%, respectively), although specificity was not improved (63% vs 58% vs 78%, respectively). No significant difference in diagnostic performance was noted between mpMRI/PSMA-PET read synchronously and mpMRI or PSMA-PET reported independently and then synthesized. Most patients had concordant imaging (60%), while others had discordant lesions only (28%) or a mixture (concordant and discordant lesions; 12%). When mpMRI/PSMA-PET findings were concordant and positive, 95% of patients had clinically significant prostate cancer (csPCa). When PSMA-PET alone was compared to synchronous PSMA-PET/MRI reads, there was an improvement in reader certainty in 20% of scans.Synchronous mpMRI/PSMA-PET reading improves reader certainty and sensitivity for csPCa compared to mpMRI or PSMA-PET alone. However, synthesizing the results of independently read PSMA-PET and mpMRI reports provided similar diagnostic performance to synchronous PSMA-PET/MRI reads. This may provide greater flexibility for urologists in terms of referral patterns, reducing healthcare system costs and improving efficiencies in prostate cancer diagnosis.

Introduction 18 F-Fludeoxyglucose PET-CT (FDG) is increasingly used to stage breast cancer. Most breast cancers express the Oestrogen Receptor (ER) and Progesterone Receptor (PR), and this subtype demonstrates lower activity on FDG imaging. Somatostatin receptors (SSTR) offer a potentially improved radiotracer target for ER+ /PR+ breast cancer. We present the first in␣vivo clinical study comparing 68 Ga-DOTATATE PET-CT (DOTA) to FDG and conventional imaging (bone scan and diagnostic CT), in metastatic ER+ /PR+ human epidermal growth factor receptor 2 (HER2) negative breast cancer. Methods Patients with clinically progressive metastatic ER+ /PR+ HER2- breast cancer underwent restaging with DOTA, FDG and conventional imaging. Scans were analysed visually, and semi-quantitatively. Wilcoxon-Rank Scoring was used to assess significance. Results Ten women (mean age 57 years) underwent imaging. 8/10 demonstrated disease on both DOTA and FDG. 2/10 positive on conventional imaging, but DOTA- /FDG- , and had no disease progression at 1-year follow-up. Heterogeneity of uptake was seen between DOTA and FDG with 5 bone lesions DOTA+ /FDG- and 1 bone lesion FDG+ /DOTA- . Twenty-one visceral lesions were FDG+ /DOTA- (2 patients), with 10/21 identified on conventional imaging. Maximum standard uptake values (SUV max) of DOTA were greater than FDG (10.9 vs. 6.6, P = ns). Four sites were biopsied (3 patients). 3/4 had high ER/PR expression (mean DOTA SUV max 9.4) and 1/4 low ER/PR expression (DOTA SUV max 3.1). Conclusion Whilst we have not demonstrated DOTA to be superior to FDG in staging of ER+ /PR+ breast cancers, DOTA may have a role in assessing HR status and treatment decisions; further evaluation of this is warranted.

To assess European Association of Urology (EAU) risk groups for biochemical recurrence (BCR) of prostate cancer relative to prostate-specific membrane antigen-positron emission tomography (PSMA-PET) status and oncological outcomes.A retrospective analysis of a study that incorporated PSMA-PET for men with BCR after radical prostatectomy (RP) was undertaken. EAU risk groups were considered relative to clinical variables, PSMA-PET findings, and deployment of salvage radiotherapy (SRT). The primary oncological outcome was event-free survival (EFS) and this was analysed relative to clinical and imaging variables. An 'event' occurred if prostate-specific antigen (PSA) level rose0.2 ng/mL above nadir or additional therapies were introduced.A total of 137 patients were included, most of whom had EAU high-risk disease (76%) and/or low PSA levels (80%0.5 ng/mL) at the time of PSMA-PET. EAU risk group was not associated with regional nodal/distant metastasis on PSMA-PET. Regional nodal/distant metastasis on PSMA PET (compared to negative/local recurrence: hazard ratio [HR] 2.2; P = 0.002) and SRT use (vs no SRT: HR 0.44; P = 0.004) were associated with EFS. EAU high-risk status was not significantly associated with worse EFS (HR 1.7, P = 0.12) compared to EAU low-risk status. Among patients who received SRT, both regional/distant metastasis on PSMA-PET (HR 3.1; P 0.001) and EAU high-risk status (HR 2.9; P = 0.04) were independently associated with worse EFS, which was driven by patients in the EAU high-risk group with regional/distant metastases (38%; HR 3.1, P = 0.001).In patients with post-RP BCR, PSMA-PET findings and receipt of SRT predicted EFS. In patients receiving SRT, PSMA status combined with EAU risk grouping was most predictive of EFS. These findings suggest that the EAU risk groups could be improved with the addition of PSMA-PET.

Background: 177Lutetium PSMA-617 (Lu-PSMA-617) is an effective therapy for metastatic castrate-resistant prostate cancer (mCRPC). However, treatment resistance occurs frequently and combination therapies may improve outcomes. We report the final safety and efficacy results of a phase I/II study combining Lu-PSMA-617 with idronoxil (NOX66), a radiosensitiser, and examined potential clinical, blood-based and imaging biomarkers. Methods: 56 men with progressive mCRPC previously treated with taxane chemotherapy and novel androgen signaling inhibitor (ASI) were enrolled. Patients received up to six doses of Lu-PSMA-617 (7.5Gbq) day 1 in combination with NOX66 suppository days 1-10 each 6-week cycle. Cohort 1 (n = 8) received 400mg NOX66, cohort 2 (n = 24) received 800mg and cohort 3 (n = 24) received 1200mg. 68Ga-PSMA and FDG PET/CT were performed at study entry and semi-quantitative imaging analysis was undertaken. Blood samples were collected for blood-based biomarkers including androgen receptor splice variant 7 expression. The primary outcomes were safety and tolerability; secondary outcomes included efficacy, pain scores and xerostomia. Regression analyses were performed to explore the prognostic value of baseline clinical, blood-based and imaging parameters. Results: 56/100 men screened were enrolled (56%) with a screen failure rate of 26% (26/100) for PET imaging criteria. All men had received prior treatment with ASI and docetaxel, and 95% (53/56) had received cabazitaxel. 96% (54/56) patients received ≥2 cycles of combination NOX66 and Lu-PSMA-617, and 46% (26/56) completed six cycles. Common adverse events were anaemia, fatigue and xerostomia. Anal irritation attributable to NOX66 occurred in 38%. 48/56 had a reduction in prostate-specific antigen (PSA) (86%, 95% CI 74-94), 34/56 (61%, 95% CI 47-74) had a PSA reduction ≥50% (PSA50). Median PSA progression-free survival was 7.5 months (95% CI 5.9-9) and median overall survival 19.7 months (95% CI 9.5-30). Higher PSMA SUVmean correlated with treatment response, while higher PSMA tumour volume and prior treatment with ASI for less than 12 months were associated with worse overall survival. Conclusion: NOX66 with Lu-PSMA-617 is a safe and feasible therapeutic strategy in men treated 3rd line and beyond for mCRPC. PSMA SUVmean, PSMA avid tumour volume and duration of treatment with ASI were independently associated with outcome.

Objective To assess the activity and safety of sequential lutetium-177 (Lu-177)-PSMA-617 and docetaxel vs docetaxel on a background of androgen deprivation therapy (ADT) in men with de novo metastatic hormone-naive 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; 15; and absence of extensive discordant fluorodeoxyglcuose (FDG)-positive, PSMA-negative disease. Ga-68-PSMA-11 and F-18-FDG positron-emission tomography (PET)/CT undergo central review to determine eligibility. Patients are randomized 1:1 to experimental treatment, Arm A (Lu-177-PSMA-617 7.5GBq q6w x 2 cycles followed by docetaxel 75 mg/m(2) q3w x 6 cycles), or standard-of-care treatment, Arm B (docetaxel 75 mg/m(2) q3w x 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 (

[68Ga]-Ga-PSMA-PET/CT (PSMA-PET) is routinely performed in many patients who have received or are receiving Androgen Deprivation Therapy (ADT). However, potentially occurring interactions of ADT on PSMA expression in men with Prostate cancer (PCa) have not been yet fully investigated nor understood. Since an influence of ADT on the expression of PSMA was observed in both in vitro and in vivo studies, relevant implications for image interpretation and PSMA-radioligand therapy (RLT) timing may arise from a better understanding of such a phenomenon. In this mini review, we analyzed the most relevant clinical literature on this topic (PubMed). We also presented a case series of two patients who underwent sequential PSMA-PET during ADT. We found a total of five studies which investigated the effect of ADT on PSMA expression on 43 patients at different stages of the natural history of the disease. Four studies investigated the effect of short-term ADT and detected an increase of PSMA expression (more or less heterogeneous). The remaining study investigated the long-term ADT effect, demonstrating a decrease in most lesions. In our case series, despite a complete PSA response, we observed a rapid up-regulation of PSMA expression in our PSMA-PET imaging immediately after ADT administration. Although clinical evidence remains inconclusive, a short-term ADT administration may seem to increase PSMA expression in some selected cases, while long-term ADT might have the opposite effect at least in castrate sensitive prostate cancer (CSPC) patients, even if potentially leading to an early selection of those lesions most at risk of becoming castrate resistant.

Summary Background Lutetium-177 [177Lu]Lu-PSMA-617 is a radiolabelled small molecule that delivers β radiation to cells expressing prostate-specific membrane antigen (PSMA), with activity and safety in patients with metastatic castration-resistant prostate cancer. We aimed to compare [177Lu]Lu-PSMA-617 with cabazitaxel in patients with metastatic castration-resistant prostate cancer. Methods We did this multicentre, unblinded, randomised phase 2 trial at 11 centres in Australia. We recruited men with metastatic castration-resistant prostate cancer for whom cabazitaxel was considered the next appropriate standard treatment. Participants were required to have adequate renal, haematological, and liver function, and an Eastern Cooperative Oncology Group performance status of 0–2. Previous treatment with androgen receptor-directed therapy was allowed. Men underwent gallium-68 [68Ga]Ga-PSMA-11 and 2-flourine-18[18F]fluoro-2-deoxy-D-glucose (FDG) PET-CT scans. PET eligibility criteria for the trial were PSMA-positive disease, and no sites of metastatic disease with discordant FDG-positive and PSMA-negative findings. Men were randomly assigned (1:1) to [177Lu]Lu-PSMA-617 (6·0–8·5 GBq intravenously every 6 weeks for up to six cycles) or cabazitaxel (20 mg/m2 intravenously every 3 weeks for up to ten cycles). The primary endpoint was prostate-specific antigen (PSA) response defined by a reduction of at least 50% from baseline. This trial is registered with ClinicalTrials.gov, NCT03392428. Findings Between Feb 6, 2018, and Sept 3, 2019, we screened 291 men, of whom 200 were eligible on PET imaging. Study treatment was received by 98 (99%) of 99 men randomly assigned to [177Lu]Lu-PSMA-617 versus 85 (84%) of 101 randomly assigned to cabazitaxel. PSA responses were more frequent among men in the [177Lu]Lu-PSMA-617 group than in the cabazitaxel group (65 vs 37 PSA responses; 66% vs 37% by intention to treat; difference 29% (95% CI 16–42; p Interpretation [177Lu]Lu-PSMA-617 compared with cabazitaxel in men with metastatic castration-resistant prostate cancer led to a higher PSA response and fewer grade 3 or 4 adverse events. [177Lu]Lu-PSMA-617 is a new effective class of therapy and a potential alternative to cabazitaxel. Funding Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, The Distinguished Gentleman's Ride, It's a Bloke Thing, and CAN4CANCER.

Previously, results from the TheraP trial showed that treatment with lutetium-177 [TheraP was a multicentre, open-label, randomised phase 2 trial that recruited men with metastatic castration-resistant prostate cancer after treatment with docetaxel who were suitable for cabazitaxel from 11 hospitals in Australia. Participants were required to be 18 years old or older; have adequate haematological, renal, and liver function; and an Eastern Cooperative Oncology Group performance status of 0-2. Participants were randomly assigned (1:1) using a centralised system using minimisation with a random component and that stratified patients by disease burden, previous treatment with enzalutamide or abiraterone, and study site. Patients were either given cabazitaxel (20 mg/m200 patients were randomly assigned between Feb 6, 2018, and Sept 3, 2019. 101 men were assigned to the cabazitaxel group and 99 were assigned to the [In men with metastatic castration-resistant prostate cancer, PSMA-PET SUVmean was predictive of higher likelihood of favourable response to [Prostate Cancer Foundation of Australia, Endocyte (a Novartis Company), Australian Nuclear Science and Technology Organisation, Movember Foundation, It's a Bloke Thing, CAN4CANCER, The Distinguished Gentleman's Ride.

Background Follow-up for patients with resected stage IIIA–D melanoma may include computed tomography (CT) or positron emission tomography (PET)/CT imaging to identify distant metastases. The aim of this study was to evaluate the test performance over follow-up time, of structured 6- and 12-monthly follow-up imaging schedules in these patients. Methods We conducted a retrospective analysis of consecutive resected stage IIIA–D melanoma patients from Melanoma Institute Australia (2000–2017). Patients were followed until a confirmed diagnosis of distant metastasis, end of follow-up schedule, or death. Test accuracy was evaluated by cross-classifying the results of the test against a composite reference standard of histopathology, cytology, radiologic imaging, and/or clinical follow-up, and then quantified longitudinally using logistic regression models with random effects. Results In total, 1373 imaging tests were performed among 332 patients. Distant metastases were detected in 110 (33%) patients during a median follow-up of 61 months (interquartile range 38–86), and first detected by imaging in 86 (78%) patients. 152 (68%) patients had at least one false-positive result. Sensitivity of the schedule over 5 years was 79% [95% confidence interval (CI) 70–86%] and specificity was 88% (95% CI 86–90%). There was no evidence of a significant difference in test performance over follow-up time or by American Joint Committee on Cancer (AJCC) substage. The positive predictive value ranged between 33 and 48% over follow-up time, reflecting a ratio of 1:2 false-positives per true-positive finding. Conclusions Regular 6- or 12-monthly surveillance imaging using CT or PET/CT has reasonable and consistent sensitivity and specificity over 5-year follow-up for resected stage IIIA–D melanoma patients. These data are useful when discussing the risks and benefits of long-term follow-up.

BACKGROUND Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is well validated in the staging of pre-treatment head and neck squamous cell carcinoma (HNSCC), although the impact of human papilloma virus (HPV) status and node size on accuracy remains unclear. The aim of this study was to assess the diagnostic accuracy of PET/CT based on HPV status and node size and determine the effects of maximum standardized uptake value thresholds on sensitivity, specificity and positive predictive value. METHODS A total of 38 patients with primary HNSCC were recruited. All patients underwent primary tumour resection and cervical node dissection following FDG-PET/CT. RESULTS A total of 38 patients including 68 dissected necks, representing 353 nodal levels and a total of 2701 lymph nodes were included. Histopathological analysis revealed lymph node metastases in 4.3% (116/2701) of dissected lymph nodes. Forty-four percent of patients had HPV-positive tumours. Sixty-four percent of involved lymph nodes were

Whole-body positron emission tomography/computed tomography (PET/CT) and brain magnetic resonance imaging (MRI) are commonly used to stage patients with palpable lymph node metastases from melanoma, but their role in patients with satellite and/or in-transit metastasis (S&ITM) is unclear. The aim of this study was to establish the diagnostic value of PET/CT and brain MRI in these patients, and to assess their influence on subsequent management decisions. In this prospective study, 25 melanoma patients with a first presentation of S&ITM who had no clinical evidence of palpable nodal or distant metastasis underwent whole-body(18)F-FDG PET/CT and brain MRI after a tentative pre-scan treatment plan had been made. Sensitivity and specificity of imaging were determined by pathological confirmation, clinical outcome and repeat PET/CT and MRI at 6 months. PET/CT led to a modification of the initial treatment plan in four patients (16%). All four were upstaged (AJCC stage eighth edition). PET/CT was false-positive in one patient, who had a Schwannoma in his trapezius muscle. A thyroid carcinoma was an incidental finding in another patient. The sensitivity of PET/CT was 58% and specificity 83%. In 6 months following the baseline PET/CT, further sites of in-transit or systemic disease were identified in 10 patients (40%). Brain MRI did not alter the treatment plan or change the disease stage in any patient. Whole-body PET/CT improved staging in melanoma patients with S&ITM and changed the originally-contemplated treatment plan in 16%. MRI of the brain appeared not to be useful.

Prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) is useful for selected clinical indications in patients with prostate cancer (PCa) but it may have broader clinical utility owing to the emergence of lutetium-177-PSMA-617 ([To assess expert opinion on the use of PSMA-based imaging and therapy to develop interim guidance.A panel of 21 PCa experts from various disciplines received thematic topics and relevant literature. A questionnaire to assess proposed guidance statements regarding PSMA PET/CT and [Panellists voted anonymously on statements using a nine-point Likert scale from 1 = strongly disagree to 9 = strongly agree. Median scores were calculated and consensus was assessed using methods proposed by the Research and Development (RAND) corporation.Statements were developed to cover the following topics: PSMA PET/CT utility, clinical use, and choice of tracer; patient selection; and management of patients receiving [Adoption of PSMA PET/CT as an imaging tool to guide [A panel of experts in prostate cancer reached a consensus for the majority of statements proposed regarding the role of prostate-specific membrane antigen (PSMA)-based imaging and therapy, particularly the use of PSMA-based imaging in patients suitable for [

256 Background: PSMA-targeted radioligand therapy has dramatically improved clinical outcomes in men with mCRPC. A blood-based liquid biopsy assay to detect PSMA expression on circulating tumor cells (CTCs) could be helpful to optimize therapeutic decisions and identify patients most likely to benefit from PSMA-targeted therapies. Here we describe the development of this PSMA blood-based assay and the application of the single cell sequencing (SCS) pipeline to identify copy number alterations and further characterize heterogeneity in late-stage disease. Methods: A 4-color immunofluorescence (IF) assay was developed to detect PSMA expression on CTCs on the Epic Sciences liquid biopsy platform. CTCs were identified as DAPI+, cytokeratin (CK)+, and CD45- with appropriate cell morphology. Cells were plated onto glass slides and subjected to IF staining followed by CTC identification using a high throughput scanning platform with digital pathology machine learning algorithms. Cell line cells (LNCaP, PC3s, 22Rv1) of varying PSMA expression levels were spiked into normal blood (CLC/WBC; 1:10000) to create laboratory derived slides. Assay specificity, sensitivity, limit of detection (LOD), precision, and overall accuracy, as well as subcellular localization of biomarker expression were reported. Clinical validation was performed in a cohort of high-risk mCRPC patients (N=24) with previously demonstrated PSMA expression by tissue biopsy, utilizing 3ml of blood. Additionally, a subset of CTCs (36 cells from 11 patients) underwent single-cell low-pass whole genome sequencing to identify copy number alterations. Results: The PSMA CTC assay (Epic Sciences) achieved analytical specificity, sensitivity, and overall accuracy of over 99%. Precision was evaluated using intra-class correlation (ICC) (0.98). The assay showed an LOD of 1 CLC/technical replicate. PSMA expression was specific to staining outside the nucleus and distinguished from CK cytoplasmic staining. Analysis of 24 mCRPC samples revealed that 21/24 (88%) had at least one conventional CTC/mL (range: 0-30 CTCs/mL), of which 16/21 (76%) were PSMA positive (range: 0-27 CTCs/mL) with considerable tumor heterogeneity. 36 sequenced CTCs (N=11 pts) exhibited genomic heterogeneity and frequent AR (3/11), MYC (7/11), and MYCN (5/11) gains or losses of PTEN (4/11), TP53 (7/11), BRCA2 (5/11), CHD1 (6/11), and/or RB1(5/11 pts). Conclusions: The PSMA CTC assay analytical results firmly support its feasibility to detect PSMA expression in CTCs from mCRPC patient samples. The assay demonstrates high sensitivity, specificity, and overall accuracy. Many ongoing trials are designed to target PSMA-positive tumors, positioning this assay as a robust research tool to identify and longitudinally monitor PSMA expression and explore heterogeneity, response, and resistance in these patient populations.

318 Background: Prostate cancer (PC) is the second most frequent malignancy in men worldwide. 68Ga-PSMA-11 is one of the most widely used radiotracers for positron emission tomography (PET) of prostate-specific membrane antigen (PSMA) positive lesions in men with PC and is part of standard clinical practice at many centres. Due to the longer half-life and shorter positron range of copper-64 (t1/2=12.7 hours; mean positron range=0.56 mm), a novel PSMA-targeting radiotracer labelled with this radionuclide, 64Cu-SAR-bisPSMA, has the potential to provide advantages over 68Ga-PSMA-11 (t1/2=68 minutes; mean positron range=3.5 mm). The 12.7 hour half-life of Cu-64 allows the central manufacturing of 64Cu-SAR-bisPSMA with a product shelf-life of up to 2 days. The longer half-life enables PET imaging from 1 to 72 hours after administration which offers greater flexibility in terms of scheduling of patients and may translate into detection of additional lesions due to increased Standardized Uptake Values (SUV) in the lesions relative to background following biological clearance of the tracer from organs over time. The shorter positron range may lead to improved resolution on the scan and thus, better detection of small lesions, including those that are in close proximity to each other, or to organs involved in clearance of the product such as the bladder and kidneys. In addition to the potential imaging and supply benefits of Cu-64, current generation PSMA targeting agents such as 68Ga-PSMA-11 have only a single targeting functional group. 64Cu-SAR-bisPSMA has two PSMA-targeting functional groups, which can lead to improved tumor uptake and retention. This was shown in a preclinical study, where 64Cu-SAR-bisPSMA outperformed the monomeric 64Cu-SAR-PSMA with respect to both tumor uptake and retention (Zia et al, 2019). Methods: Patients with untreated, histopathology-proven, intermediate- to high-risk PC, planned for radical prostatectomy underwent 68Ga-PSMA-11 PET/CT per institutional practice and were subsequently allocated to 1 out of 3 dose cohorts (1:1:3) to receive either 100 MBq, 150 MBq or 200 MBq of 64Cu-SAR-bisPSMA, respectively. A PET/CT was acquired at 3-hours (±1 hour) post-injection of 64Cu-SAR-bisPSMA. Two independent, blinded, central readers assessed the detection of primary PC on the 200 MBq 64Cu-SAR-bisPSMA PET/CTs as the primary endpoint. To compare the intensity of lesions on 68Ga-PSMA-11 and 64Cu-SAR-bisPSMA PET, both readers determined the SUVs (SUVmax, SUVmean) and tumour-to-background ratio (ratio of lesion SUVmax and background SUVmean) in up to 5 concordant lesions between 68Ga-PSMA-11 and 64Cu-SAR-bisPSMA PET/CT as an exploratory endpoint. Clinical trial information: NCT04839367 .

355 Background: We aimed to develop and to validate a multi-institutional nomogram of outcomes for PSMA-PET based salvage radiotherapy (sRT) following radical prostatectomy (RP) for patients with recurrent or persistent prostate cancer (PCa). Methods: Data from patients with a detectable post-RP prostate-specific antigen (PSA) treated with sRT with or without concurrent androgen-deprivation therapy (ADT) were obtained from 11 academic institutions from 5 countries. All patients had a PSMA-PET scan prior sRT and patients with distant metastases on PET were excluded from this analysis. The freedom from biochemical failure (FFBF) rate was estimated, and a predictive nomogram was generated and validated. Biochemical relapse (BR) was defined as PSA nadir +0.2 ng/ml after sRT. Results: Overall, 1029 patients (training set n=821, external validation set n=208) with a median follow-up of 33 months were included. On PSMA-PET, 427 (42%) and 313 (30%) patients had local and nodal recurrences, respectively. Elective pelvic lymphatics were irradiated in 368 (36%) patients. All patients received sRT to the prostatic fossa receiving a dose of 70 Gy in 103 (10%), 551 (54%) and 375 (36%) patients, respectively. Androgen deprivation therapy (ADT) was given in 325 (32%) patients. On multivariable Cox regression analysis, pre-SRT PSA, ISUP grade, pT stage, surgical margins, ADT use, sRT dose and nodal recurrence on PSMA PET were associated with FFBF. The nomogram concordance index was 0.7 for FFBF in external validation. Conclusions: We present an externally validated contemporary nomogram which can estimate individual patient outcomes after PSMA-PET guided sRT. Positive lymph nodes on PSMA-PET seem to be a new risk factor for BR after sRT.

TPS397 Background: Multi-parametric magnetic resonance imaging (MRI) has an established role for the diagnosis of clinically significant prostate cancer (sPCa), with superior diagnostic accuracy compared with transrectal ultrasound guided prostate biopsy alone. PRIMARY demonstrated significant improvement in sensitivity (97% vs 83%) and negative predictive value (91% vs 72%) with the addition of [68Ga]Ga-PSMA-11 PET/CT (PSMA PET/CT) vs MRI alone. Furthermore, 38% of patients with PI-RADS 2 or 3 were true negative on PSMA PET/CT, a population which may potentially benefit from avoiding transperineal prostate biopsy (TPPB). We hypothesize that the addition of PSMA PET/CT is non-inferior to MRI for the detection of sPCa in men with PI-RADS 2-3 disease, while providing the advantages of reducing unnecessary biopsies and limiting to targeted-only TPPB. Methods: This multi-centre, two-arm, randomized controlled, phase III trial will recruit 660 men with high clinical suspicion of sPC. Participants will be randomized in a 1:1 ratio in permuted blocks, stratified by center. In the experimental arm, participants will undergo a pelvic PSMA PET/CT. Local and central reviewers will interpret independently, based on the PRIMARY Score. Participants with a positive result will undergo targeted-TPPB, whereas those with negative PSMA PET/CT will avoid biopsy. In the control arm, all participants undergo template-TPPB. Patients will continue follow-up for subsequent clinical care for up to two years post-randomization. Key eligibility criteria include an MRI result of PI-RADS 2 with at least one red flag [PSA density >0.1, abnormal digital rectal examination (DRE), strong family history, BRCA mutation, PSA >10, PSA doubling time 0.75/year], or PI-RADS 3, having never undergone a prostate biopsy

5043 Background: PSMA-targeted radioligand therapy can improve the outcome of patients with advanced mCRPC. However, patients do not respond uniformly and a PSA decline of ≥50% (PSA50) was achieved only in 46% of the patients in the VISION trial. We hypothesized that using the parotid glands instead of the liver as the reference organ enables more selective stratification. The aim of this study was to test PSMA PET tumor-to-Salivary Glands ratio (PSG score) to predict outcomes after Lu-177 PSMA. Methods: This was an international multicenter retrospective study using the established dataset consisting of 270 men with mCRPC treated with Lu-177 PSMA (Gafita A, Lancet Oncol 2021). First, we assessed baseline PSMA PET quantitatively (qPSG score) to calculate the tumor-to-salivary gland ratio (qPSG = SUVmean whole-body-tumor / SUVmean parotid glands) using a semi-automatic segmentation software (qPSMA). Patients were divided into three groups: high (qPSG > 1.5), intermediate (qPSG = 0.5 - 1.5), and low (qPSG < 0.5). Second, we assessed the reproducibility and the predictive value of the PSG score visually (vPSG score) graded by ten nuclear medicine physicians. Each reader read the baseline PSMA PET 3D maximum intensity projection (MIP) images, and classified the patients into three groups: (high) most of the lesions (> 80%) show higher uptake than parotid glands; (intermediate) neither “low” nor “high”; (low) most of the lesions (> 80%) show lower uptake than parotid glands. In case of disagreement, a majority vote was used. Outcome measures were PSA-progression free-survival (PSA-PFS), overall survival (OS), and PSA50. Results: 237 men were analyzed after excluding 33 men whose parotid glands were out of the scan range. The number of the patients in the high, intermediate, and low groups were 56/237 (23.6%), 163 (68.8%), and 18 (7.6%) for qPSG score, and 106/237 (44.7%), 96 (40.5%), and 35 (14.8%) for vPSG score, respectively. The inter- and intra-readers reproducibility of the vPSG score showed substantial (Fleiss’ weighted Kappa: 0.68) and almost perfect (Cohen's weighted Kappa (mean): 0.83) agreement, respectively. The median PSA-PFS of high, intermediate, and low groups were 7.2, 4.0, and 1.9 months (p < 0.001) for qPSG score and 6.7, 3.8, and 1.9 months (p < 0.001) for vPSG score, respectively. Higher PSA50 rate was observed in the high group followed by the intermediate and low groups (high vs intermediate vs low: [qPSG] 69.6% vs 38.7% vs 16.7%; [vPSG] 63.2% vs 33.3% vs 16.1%). The median OS was longer in the high group than in the intermediate + low (i.e., non-high) group by qPSG (15.0 vs. 11.7 months (p = 0.013)) and vPSG score (14.3 vs.11.0 months (p = 0.038)). Conclusions: The PSG score is a valuable predictive biomarker for response to Lu-177 PSMA. The vPSG score yielded substantial reproducibility and comparable predictive value to the qPSG score.

Purpose The prognostic value of PSMA intensity on PSMA PET/CT due to underlying biology and subsequent clinical implications is an emerging topic of interest. We sought to investigate whether primary tumour PSMA PET intensity contributes to pre- and post-operative prediction of oncological outcomes following radical prostatectomy. Methods We performed a retrospective cohort study of 848 men who underwent all of multiparametric MRI (mpMRI), transperineal prostate biopsy, and 68 Ga-PSMA PET/CT prior to radical prostatectomy. PSMA intensity, quantified as maximum standard uptake value (SUVmax), and other clinical variables were considered relative to post-operative biochemical recurrence-free survival (BRFS) using Cox regression and Kaplan–Meier analysis. Results After a median follow-up of 41 months, 219 events occurred; the estimated 3-year BRFS was 79% and the 5-year BRFS was 70%. Increasing PSMA intensity was associated with less favourable BRFS overall (Log rank p p Conclusion These results in a large series of patients confirm PSMA intensity to be a novel, independent prognostic factor for BRFS.