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[ 177 Lu]Lu-prostate-specific membrane antigen (PSMA) is an effective treatment for metastatic castration-resistant prostate cancer (mCRPC). [ 177 Lu]Lu-PSMA SPECT/CT 24 h after injection has shown potential as a response biomarker for [ 177 Lu]Lu-PSMA therapy but is not convenient for patients. This study investigated 4-h [ 177 Lu]Lu-PSMA SPECT/CT as an alternative to 24-h [ 177 Lu]Lu-PSMA SPECT/CT for evaluation of treatment response. Methods: This prospective analysis enrolled 23 patients diagnosed with mCRPC commencing [ 177 Lu]Lu-PSMA-I&T therapy. Two patients were excluded because of incomplete imaging data. Posttherapy SPECT/CT was performed at 4 and 24 h after the first dose and 4 h after the second dose. Baseline [ 68 Ga]Ga-PSMA-11 PET/CT and 4- and 24-h [ 177 Lu]Lu-PSMA SPECT/CT were analyzed both visually and semiquantitatively. Bland-Altman plots assessed agreement of semiquantitative parameters from the 4- and 24-h scans. Quantitative assessment of the change in the total tumor volume (TTV) on the 4-h [ 177 Lu]Lu-PSMA SPECT/CT after the first and second doses was correlated to patient outcomes. Results: All patients had mCRPC previously treated with an androgen receptor pathway inhibitor, and 11 (52%) received prior taxane chemotherapy. Median age was 78 y, and median prostate-specific antigen level was 54 ng/mL. On visual analysis, disease distribution was unchanged among the 3 imaging methods. Eleven patients (52%) had a median of 1 lesion not identified on 4-h [ 177 Lu]Lu-PSMA SPECT/CT compared with 24-h [ 177 Lu]Lu-PSMA SPECT/CT. All missed lesions on the 4-h [ 177 Lu]Lu SPECT/CT were smaller than 2 cm. Mean differences and agreement between 4- and 24-h SPECT/CT quantitative parameters were within acceptable bounds for lesion number, SUV max , and SUV mean , with higher variation observed for TTV. The change in TTV between dose 1 and 2 [ 177 Lu]Lu-PSMA SPECT/CT predicted prostate-specific antigen progression-free survival. Conclusion: [ 177 Lu]Lu-PSMA SPECT/CT at 4 h after injection appears a promising alternative to 24-h [ 177 Lu]Lu-PSMA SPECT/CT for treatment response assessment, with improved patient convenience., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background and Objective: This review aims to provide an overview of novel diagnostic and therapeutic radiopharmaceuticals tested recently or used currently in genitourinary cancers within prospective phase 1-2 clinical trials, summarizing progresses and future directions., Methods: A systematic search was conducted using the PubMed/MEDLINE and ClinicalTrials.gov databases for original prospective research studies following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines., Key Findings and Limitations: Forty-six papers were systematically reviewed; 74 ongoing clinical trials were identified. The results of 27 novel radiopharmaceuticals (ie, not approved by the Food and Drug Administration/European Medicines Agency and not listed in the Pharmacopeia) prospectively investigated in genitourinary cancers, mostly prostate, for diagnostic, theranostic, or therapeutic purposes (21, one, and five of the 27 radiopharmaceuticals, respectively) over the past 5 yr were presented. Most were prostate-specific membrane antigen-targeting agents (17/27); other targets included gastrin-releasing peptide receptor, carbonic anhydrase IX, Cu, six transmembrane epithelial antigen of the prostate 1, tumor-associated glycoprotein 42, and urokinase-type plasminogen activator receptor. Ongoing research confirms the same trend. Fibroblast activation protein inhibitor, PD-L1, CD8, nectin-4, and HER2 are other targets under investigation. Among the 22 ongoing therapeutic trials (out of the 74 ongoing clinical trials), targeted alpha therapy is being explored in 12, and five are evaluating combinations of radioligand therapy with other treatments. We confirmed the safety of radiopharmaceuticals (regardless of the diagnostic/therapeutic purpose) and showed promising results in terms of diagnostic accuracy and therapeutic efficacy in genitourinary cancers., Conclusions and Clinical Implications: There continues to be expansion in radiopharmaceutical approaches to genitourinary cancers, reflecting a strong emphasis on improving tumor detection and treatment, which will likely impact future management across the disease spectrum, with the potential for improved patient care and outcomes., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background and Objective: Innovations have improved outcomes in advanced prostate cancer (PC). Nonetheless, we continue to lack high-level evidence on a variety of topics that greatly impact daily practice. The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) surveyed experts on key questions in clinical management in order to supplement evidence-based guidelines. Here we present voting results for questions from APCCC 2024., Methods: Before the conference, a panel of 120 international PC experts used a modified Delphi process to develop 183 multiple-choice consensus questions on eight different topics. Before the conference, these questions were administered via a web-based survey to the voting panel members ("panellists")., Key Findings and Limitations: Consensus was a priori defined as ≥75% agreement, with strong consensus defined as ≥90% agreement. The voting results show varying degrees of consensus, as discussed in this article and detailed in the Supplementary material. These findings do not include a formal literature review or meta-analysis., Conclusions and Clinical Implications: The voting results can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers in prioritising areas for future research. Diagnostic and treatment decisions should always be individualised on the basis of patient and cancer characteristics, and should incorporate current and emerging clinical evidence, guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2024 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Lutetium-177 [ 177 Lu]Lu-prostate-specific membrane antigen (PSMA)-617 improves survival and quality of life in patients with metastatic castration-resistant prostate cancer, but whether it confers a benefit in hormone-sensitive disease is unknown. We aimed to evaluate [ 177 Lu]Lu-PSMA-617 before docetaxel treatment in patients with de-novo high-volume metastatic hormone-sensitive prostate cancer., Methods: UpFrontPSMA was an investigator-initiated, multicentre, open-label, randomised, phase 2 trial done at 11 Australian hospitals. Eligible patients had prostate adenocarcinoma without clinically significant neuroendocrine differentiation or small-cell histology, were aged 18 years or older, had less than 4 weeks on androgen deprivation therapy, had an Eastern Cooperative Oncology Group performance status of 0-2, and had high-volume PSMA-avid disease on [ 68 Ga]Ga-PSMA-11 PET-CT with no major discordance on 2-[ 18 F] fluorodeoxyglucose-PET-CT. Patients were randomly assigned (1:1) to the experimental treatment ([ 177 Lu]Lu-PSMA-617 followed 6 weeks later by docetaxel) or standard-of-care treatment (docetaxel alone) using computer-based block randomisation with random block sizes, stratified by disease volume by conventional imaging and duration of androgen deprivation therapy at the time of registration. Neither patients nor investigators were masked to treatment assignment. Patients in the experimental group received two cycles of [ 177 Lu]Lu-PSMA-617 7·5 GBq every 6 weeks intravenously, followed 6 weeks later by six cycles of docetaxel 75 mg/m 2 every 3 weeks intravenously, whereas patients in the standard-of-care treatment group received six cycles of docetaxel 75 mg/m 2 every 3 weeks intravenously. All patients received continuous androgen deprivation therapy. The primary endpoint was undetectable prostate-specific antigen (≤0·2 ng/mL) at 48 weeks, assessed using a modified intention-to-treat analysis. The trial is registered with ClinicalTrials.gov, NCT04343885., Findings: Between May 5, 2020, and April 18, 2023, 130 patients were randomly assigned, 63 (48%) to [ 177 Lu]Lu-PSMA-617 plus docetaxel and 67 (52%) to docetaxel alone. All patients were male and no race or ethnicity data were collected. Median follow-up was 2·5 years (IQR 1·8-3·0). Four patients in the docetaxel alone group withdrew consent after randomisation and no data beyond screening were collected. An additional four patients were not evaluable for the primary endpoint at 48 weeks (two in each group). 25 (41%) of 61 patients (95% CI 30-54) in the [ 177 Lu]Lu-PSMA-617 plus docetaxel group had undetectable PSA at 48 weeks compared with ten (16%) of 61 patients (9-28) in the docetaxel alone group (OR 3·88, 95% CI 1·61-9·38; p=0·0020). The most common grade 3 or 4 treatment-related adverse events were febrile neutropenia (seven [11%] of 63 patients in the [ 177 Lu]Lu-PSMA-617 plus docetaxel group vs six [10%] of 63 patients in the docetaxel alone group) and diarrhoea (four [6%] of 63 patients vs none). Serious adverse events occurred in 16 (25%) patients in the [ 177 Lu]Lu-PSMA-617 plus docetaxel group (none were definitely related to [ 177 Lu]Lu-PSMA-617) and 16 (25%) patients in the docetaxel alone group. No treatment-related deaths occurred., Interpretation: [ 177 Lu]Lu-PSMA-617 followed by docetaxel improved antitumour activity in patients with de-novo high-volume metastatic hormone-sensitive prostate cancer compared with docetaxel alone, without increased toxic effects. Our data potentially support a role for [ 177 Lu]Lu-PSMA-617 in metastatic hormone-sensitive prostate cancer., Funding: Prostate Cancer Research Alliance (Movember Foundation and Australian Government Medical Research Future Fund), US Department of Defence Impact Award-Clinical Trials, Endocyte/Advanced Accelerator Applications (a Novartis company), Australian Nuclear Science and Technology Organization, Victorian Cancer Agency, University of Melbourne, and Peter MacCallum Cancer Foundation., Competing Interests: Declaration of interests AAA reports grants from Aptevo Therapeutics (institutional), Astellas (investigator), Astellas (institutional), AstraZeneca (institutional), AstraZeneca (investigator), Bionomics (institutional), Bristol Myers Squibb (institutional), Eli Lilly (institutional), Exelixis (institutional), Gilead Sciences (institutional), GlaxoSmithKline (institutional), Hinova (institutional), Ipsen (institutional), Janssen (institutional), MedImmune (institutional), Merck Serono (investigator), Merck Serono (institutional), Merck Sharpe & Dohme (institutional), Novartis (institutional), Pfizer (institutional), Sanofi Aventis (institutional), and SYNthorx (institutional); consulting fees from Astellas, Novartis, Janssen, Sanofi, AstraZeneca, Bristol Myers Squibb, Tolmar, Telix Pharma, Merck, Bayer, Ipsen, Merck Serono, Amgen, and Noxopharm; honoraria from Janssen, Astellas, Novartis, Tolmar, Amgen, Pfizer, Bayer, Telix Pharma, Bristol Myers Squibb, Merck Serono, AstraZeneca, Sanofi, Ipsen, Merck Sharp & Dohme, Noxopharm, Daiichi Sankyo, and Arvinas; speakers' bureau fees from Astellas, Novartis, Amgen, Bayer, Janssen, Ipsen, Bristol Myers Squibb, and Merck Serono; support for attending meetings from Amgen, Astellas, Bayer, Hinova, Janssen, Merck Serono, Novartis, Pfizer, and Tolmar; participation on data safety monitoring or advisory boards for Arvinas, Astellas, Novartis, Janssen, Sanofi, AstraZeneca, Bristol Myers Squibb, Tolmar, Telix Pharma, Merck Sharpe & Dohme, Bayer, Ipsen, Merck Serono, Amgen, Noxopharm, and Daiichi Sankyo. MV reports personal fees from AstraZeneca and Merck Sharpe & Dohme and grants (to their institution) from AstraZeneca, Merck Sharpe & Dohme, Alpine Immune Sciences, Virocure, Hinova, Atridia/Hengrui, Antengene, and Biogene. AJW declares grants to their institution from Merck Sharpe & Dohme; consulting fees from Merck Sharpe & Dohme, Bayer, Bristol Myers Squibb, Pfizer, Ipsen, and Astellas; honoraria from Astellas and Bristol Myers Squibb; and support for attending meetings from Bayer. AG reports grants from Sun Pharma; consulting fees from Regeneron and Bayer; support to attend meetings from Sun Pharma and Bristol Myers Squibb; and participation in a data safety monitoring or advisory board for Regeneron and Bayer. RJF reports committee involvement in the Australasian Radiopharmaceutical Trials Network (unpaid). LE reports research grant support (to their institution) from Novartis and Clarity Pharma; consulting fees for lectures or advisory boards from Astellas, Janssen, AstraZeneca, Clarity, Novartis, and Telix in the past 5 years; and philanthropic grant support from the Prostate Cancer Foundation, St Vincent's Clinic Research Foundation, and the Curran Foundation. DGM has received reimbursement for advisory board or speaker bureau activity from the following companies (in the past 36 months): Janssen, Astellas, Bayer, AstraZeneca, Mundipharma, Novartis, and Ipsen. AR has received reimbursement for advisory board or speaker bureau activity from the following companies: AstraZeneca, Daiichi Sankyo, Lily, Pfizer, Merck Sharpe & Dohme, Roche, and Novartis. DAP reports personal fees from Eisai. MSH reports grants and receipt of equipment, materials, drugs, medical writing, gifts, or other services from the Prostate Cancer Foundation, NHRMC, Movember, US Department of Defense, Medical Research Future Fund, Bayer, Peter MacCallum Foundation, Isotopia, and the Australian Nuclear Science and Technology Organisation; consulting fees from Merck Sharp & Dohme and Novartis; honoraria from Janssen, Novartis, and AstraZeneca; and support for meetings from Merck Sharp & Dohme, Novartis, Janssen, AstraZeneca, and Astellas. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Purpose: Despite growing evidence for bilateral pelvic radiotherapy (whole pelvis RT, WPRT) there is almost no data on unilateral RT (hemi pelvis RT, HPRT) in patients with nodal recurrent prostate cancer after prostatectomy. Nevertheless, in clinical practice HPRT is sometimes used with the intention to reduce side effects compared to WPRT. Prostate-specific membrane antigen positron emission tomography / computed tomography (PSMA-PET/CT) is currently the best imaging modality in this clinical situation. This analysis compares PSMA-PET/CT based WPRT and HPRT., Methods: A propensity score matching was performed in a multi-institutional retrospective dataset of 273 patients treated with pelvic RT due to nodal recurrence (214 WPRT, 59 HPRT). In total, 102 patients (51 in each group) were included in the final analysis. Biochemical recurrence-free survival (BRFS) defined as prostate specific antigen (PSA) < post-RT nadir + 0.2ng/ml, metastasis-free survival (MFS) and nodal recurrence-free survival (NRFS) were calculated using the Kaplan-Meier method and compared using the log rank test., Results: Median follow-up was 29 months. After propensity matching, both groups were mostly well balanced. However, in the WPRT group there were still significantly more patients with additional local recurrences and biochemical persistence after prostatectomy. There were no significant differences between both groups in BRFS (p = .97), MFS (p = .43) and NRFS (p = .43). After two years, BRFS, MFS and NRFS were 61%, 86% and 88% in the WPRT group and 57%, 90% and 82% in the HPRT group, respectively. Application of a boost to lymph node metastases, a higher RT dose to the lymphatic pathways (> 50 Gy EQD2 α/β=1.5 Gy ) and concomitant androgen deprivation therapy (ADT) were significantly associated with longer BRFS in uni- and multivariate analysis., Conclusions: Overall, this analysis presents the outcome of HPRT in nodal recurrent prostate cancer patients and shows that it can result in a similar oncologic outcome compared to WPRT. Nevertheless, patients in the WPRT may have been at a higher risk for progression due to some persistent imbalances between the groups. Therefore, further research should prospectively evaluate which subgroups of patients are suitable for HPRT and if HPRT leads to a clinically significant reduction in toxicity., (© 2024. The Author(s).)

Background: Salvage radiation therapy (sRT) is often the sole curative option in patients with biochemical recurrence after radical prostatectomy. After sRT, we developed and validated a nomogram to predict freedom from biochemical failure., Objective: This study aims to evaluate prostate-specific membrane antigen-positron emission tomography (PSMA-PET)-based sRT efficacy for postprostatectomy prostate-specific antigen (PSA) persistence or recurrence. Objectives include developing a random survival forest (RSF) model for predicting biochemical failure, comparing it with a Cox model, and assessing predictive accuracy over time. Multinational cohort data will validate the model's performance, aiming to improve clinical management of recurrent prostate cancer., Methods: This multicenter retrospective study collected data from 13 medical facilities across 5 countries: Germany, Cyprus, Australia, Italy, and Switzerland. A total of 1029 patients who underwent sRT following PSMA-PET-based assessment for PSA persistence or recurrence were included. Patients were treated between July 2013 and June 2020, with clinical decisions guided by PSMA-PET results and contemporary standards. The primary end point was freedom from biochemical failure, defined as 2 consecutive PSA rises >0.2 ng/mL after treatment. Data were divided into training (708 patients), testing (271 patients), and external validation (50 patients) sets for machine learning algorithm development and validation. RSF models were used, with 1000 trees per model, optimizing predictive performance using the Harrell concordance index and Brier score. Statistical analysis used R Statistical Software (R Foundation for Statistical Computing), and ethical approval was obtained from participating institutions., Results: Baseline characteristics of 1029 patients undergoing sRT PSMA-PET-based assessment were analyzed. The median age at sRT was 70 (IQR 64-74) years. PSMA-PET scans revealed local recurrences in 43.9% (430/979) and nodal recurrences in 27.2% (266/979) of patients. Treatment included dose-escalated sRT to pelvic lymphatics in 35.6% (349/979) of cases. The external outlier validation set showed distinct features, including higher rates of positive lymph nodes (47/50, 94% vs 266/979, 27.2% in the learning cohort) and lower delivered sRT doses (<66 Gy in 57/979, 5.8% vs 46/50, 92% of patients; P<.001). The RSF model, validated internally and externally, demonstrated robust predictive performance (Harrell C-index range: 0.54-0.91) across training and validation datasets, outperforming a previously published nomogram., Conclusions: The developed RSF model demonstrates enhanced predictive accuracy, potentially improving patient outcomes and assisting clinicians in making treatment decisions., (©Ali Janbain, Andrea Farolfi, Armelle Guenegou-Arnoux, Louis Romengas, Sophia Scharl, Stefano Fanti, Francesca Serani, Jan C Peeken, Sandrine Katsahian, Iosif Strouthos, Konstantinos Ferentinos, Stefan A Koerber, Marco E Vogel, Stephanie E Combs, Alexis Vrachimis, Alessio Giuseppe Morganti, Simon KB Spohn, Anca-Ligia Grosu, Francesco Ceci, Christoph Henkenberens, Stephanie GC Kroeze, Matthias Guckenberger, Claus Belka, Peter Bartenstein, George Hruby, Louise Emmett, Ali Afshar Omerieh, Nina-Sophie Schmidt-Hegemann, Lucas Mose, Daniel M Aebersold, Constantinos Zamboglou, Thomas Wiegel, Mohamed Shelan. Originally published in JMIR Cancer (https://cancer.jmir.org), 20.09.2024.)

Objectives: To construct and externally calibrate a predictive model for early biochemical recurrence (BCR) after radical prostatectomy (RP) incorporating clinical and modern imaging characteristics of the primary tumour., Patients and Methods: Patients who underwent RP following multiparametric magnetic resonance imaging, prostate biopsy and prostate-specific membrane antigen-positron emission tomography/computed tomography (PSMA-PET/CT), from two centres in Australia and the Netherlands. The primary outcome was biochemical recurrence-free survival (BRFS), where BCR was defined as a rising PSA level of ≥0.2 ng/mL or initiation of postoperative treatment per clinician discretion. Proportional hazards models to predict time to event were developed in the Australian sample using relevant pre- and post-surgical parameters and primary tumour maximum standardised uptake value (SUV max ) on diagnostic PSMA-PET/CT. Calibration was assessed in an external dataset from the Netherlands with the same inclusion criteria., Results: Data from 846 patients were used to develop the models. Tumour SUV max was associated with worse predicted 3-year BRFS for both pre- and post-surgical models. SUV max change from 4 to 16 lessened the predicted 3-year BRFS from 66% to 42% for a patient aged 65 years with typical pre-surgical parameters (PSA level 8 ng/mL, Prostate Imaging-Reporting and Data System score 4/5 and biopsy Gleason score ≥4 + 5). Considering post-surgical variables, a patient with the same age and PSA level but pathological stage pT3a, RP Gleason score ≥4 + 5 and negative margins, SUV max change from 4 to 16 lessened the predicted 3-year BRFS from 76% to 61%. Calibration on an external sample (n = 464) showed reasonable performance; however, a tendency to overestimate survival in patients with good prognostic factors was observed., Conclusion: Tumour SUV max on diagnostic PSMA-PET/CT has utility additional to commonly recognised variables for prediction of BRFS after RP., (© 2024 The Author(s). BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Importance: Observed treatment effects on overall survival (OS) differed substantially in the first 2 randomized clinical trials of lutetium Lu 177 vipivotide tetraxetan (Lu-177) prostate-specific membrane antigen (PSMA) in metastatic castration-resistant prostate cancer., Objective: To investigate factors associated with the observed difference in treatment effects on OS, including differences in the risk of crossover from randomized treatment after disease progression., Design, Setting, and Participants: This comparative effectiveness study used individual participant data from 2 randomized clinical trials, TheraP (A Randomised Phase 2 Trial of 177Lu-PSMA617 Theranostic Versus Cabazitaxel in Progressive Metastatic Castration Resistant Prostate Cancer [ANZUP Protocol 1603]) (n = 200), recruited from February 2018 to September 2019 in Australia, and published data from VISION (An International, Prospective, Open Label, Multicenter, Randomized Phase 3 Study of 177Lu-PSMA-617 in the Treatment of Patients With Progressive PSMA-Positive Metastatic Castration-Resistant Prostate Cancer) (n = 831), recruited from June 2018 to October 2019 in North America and Europe. Individual participant data for OS were reconstructed from VISION using the published survival curves. Data were analyzed February 6, 2018, to December 31, 2021, for TheraP and June 4, 2018, to January 27, 2021, for VISION., Interventions: TheraP randomized participants to receive treatment with Lu-177 PSMA or cabazitaxel. VISION randomized participants to receive treatment with or without Lu-177 PSMA in addition to physicians' choice of protocol-permitted treatments (PPT; approved hormonal treatments [such as abiraterone and enzalutamide], bisphosphonates, radiotherapy, denosumab, or glucocorticoids), excluding cabazitaxel., Main Outcomes and Measures: Patient characteristics, treatment protocols, and OS outcomes of the 2 trials were compared. Estimates of the effect on OS from TheraP were adjusted for crossover from randomly assigned treatment using a rank-preserving structural failure time model (RPSFTM) and inverse probability of censoring weights (IPCW) methods., Results: The 200 participants in TheraP and 831 participants in VISION were similar in age (median [range], 72 [49-86] vs 71 [40-94] years). Improved OS was observed in the comparator treatment group (cabazitaxel) in TheraP compared with VISION (PPT) (hazard ratio [HR], 0.53 [95% CI, 0.39-0.71]). The Lu-177 PSMA treatment groups in TheraP and VISION had similar OS (HR, 0.92 [95% CI, 0.70-1.19]). In TheraP, 20 of 101 participants in the cabazitaxel group crossed over to Lu-177 PSMA, while 32 of 99 participants in the Lu-177 PSMA arm crossed over to cabazitaxel. No statistically significant differences in OS between the Lu-177 PSMA and cabazitaxel groups of TheraP were observed after controlling for crossover to cabazitaxel: RPSFTM HR, 0.97 (95% CI, 0.60-1.58); IPCW HR, 0.92 (95% CI, 0.65-1.32); RPSFTM HR, 0.97 (95% CI, 0.60-1.58) and IPCW HR, 0.82 (95% CI, 0.54-1.24) for crossover to Lu-177 PSMA; RPSFTM HR, 0.96 (95% CI, 0.53-1.74) and IPCW HR, 0.82 (95% CI, 0.53-1.27) for crossover to either Lu-177 PSMA or cabazitaxel., Conclusions and Relevance: Findings of this secondary analysis of the TheraP and VISION randomized clinical trials suggest that the choice of comparator treatments (ie, cabazitaxel vs PPT) may explain the difference in the observed effect of Lu-177 PSMA on OS between the 2 trials. Causal inference methods such as RPSFTM and IPCW may help rule out crossover as a plausible explanation.

Purpose: The Prostate Imaging Reporting and Data System (PI-RADS) score is standard of care for clinically significant prostate cancer (csPCa) diagnosis. The PRIMARY score (prostate-specific membrane antigen [PSMA]-positron emission tomography [PET]/CT) also has high diagnostic accuracy for csPCa. This study aimed to develop an easily calculated combined (P) score for csPCa detection (International Society of Urological Pathology [ISUP] ≥2) incorporating separately read PI-RADS and PRIMARY scores, with external validation., Materials and Methods: Two datasets of men with suspected PCa, no prior biopsy, recent MRI and 68 Ga-PSMA-11-PET/CT, and subsequent transperineal biopsy were evaluated. These included the development sample (n = 291, 56% csPCa) a prospective trial and the validation sample (n = 227, 67% csPCa) a multicenter retrospective database. Primary outcome was detection of csPCa (ISUP ≥2), with ISUP ≥ 3 cancer detection a secondary outcome. Score performance was evaluated by area under the curve, sensitivity, specificity, and decision curve analysis., Results: The 5-point combined (P) score was developed in a prospective dataset. In the validation dataset, csPCa was identified in 0%, 20%, 52%, 96%, and 100% for P score 1 to 5. The area under the curve was 0.93 (95% CI: 0.90-0.96), higher than PI-RADS 0.89 (95% CI: 0.85-0.93, P = .039) and PRIMARY score alone 0.84 (95% CI: 0.79-0.89, P < .001). Splitting scores at 1/2 (negative) vs 3/4/5 (positive), P score sensitivity was 94% (95% CI: 89-97) compared to PI-RADS 89% (95% CI: 83-93) and PRIMARY score 86% (95% CI: 79-91). For ISUP ≥ 3, P score sensitivity was 99% (95% CI: 95-100) vs 94% (95% CI: 88-98) and 92% (95% CI: 85-97) for PI-RADS and PRIMARY scores respectively. A maximum standardized uptake value > 12 (P score 5) was ISUP ≥ 2 in all cases with 93% ISUP ≥ 3., Conclusions: The P score is easily calculated and improves accuracy for csPCa over both PI-RADS and PRIMARY scores. It should be considered when PSMA-PET is undertaken for diagnosis.

Background: Neoadjuvant dabrafenib plus trametinib has a high pathological response rate and impressive short-term survival in patients with resectable stage III melanoma. We report 5-year outcomes from the phase II NeoCombi trial., Patients and Methods: NeoCombi (NCT01972347) was a single-arm, open-label, single-centre, phase II trial. Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, American Joint Committee on Cancer seventh edition clinical stage IIIB-C BRAF V600E/K-mutant melanoma and Eastern Cooperative Oncology Group performance status ≤1. Patients received 52 weeks of treatment with dabrafenib 150 mg (orally twice per day) plus trametinib 2 mg (orally once per day), with complete resection of the pre-therapy tumour bed at week 12., Results: Between 20 August 2014 and 19 April 2017, 35 patients were enrolled. At data cut-off (17 August 2021), the median follow-up was 60 months [95% confidence interval (CI) 56-72 months]. Overall, 21 of 35 (60%) patients recurred, including 12 (57%) with first recurrence in locoregional sites (followed by later distant recurrence in 6) and 9 (43%) with first recurrence in distant sites, including 3 in the brain. Most recurrences occurred within 2 years, with no recurrences beyond 3 years. At 5 years, recurrence-free survival (RFS) was 40% (95% CI 27% to 60%), distant metastasis-free survival (DMFS) was 57% (95% CI 42% to 76%), and overall survival was 80% (95% CI 67% to 94%). Five-year survival outcomes were stratified by pathological response: RFS was 53% with pathological complete response (pCR) versus 28% with non-pCR (P = 0.087), DMFS was 59% versus 55% (P = 0.647), and overall survival was 88% versus 71% (P = 0.205), respectively., Conclusions: Neoadjuvant dabrafenib plus trametinib has high pathological response rates in clinical stage III melanoma, but low rates of RFS, similar to those achieved with adjuvant targeted therapy alone. Patients with a pCR to dabrafenib plus trametinib still had a high risk of recurrence, unlike that seen with immunotherapy where recurrences are rare., Competing Interests: Disclosure AMM—advisory boards BMS, MSD, Novartis, Roche, Pierre-Fabre, QBiotics. RAS—advisory boards MetaOptima Technology Inc., F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN Inc., Bristol-Myers Squibb, Myriad Genetics, GlaxoSmithKline. RPMS—advisory boards MSD, Novartis, and Qbiotics and speaking honoraria from BMS and Novartis. GVL—consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Immunocore, Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, PHMR Ltd, Pierre Fabre, Provectus, Regeneron. All other authors have declared no conflicts of interest., (Copyright © 2024 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Novel prostate-specific membrane antigen (PSMA) ligands labeled with α-emitting radionuclides are sparking a growing interest in prostate cancer treatment. These targeted alpha therapies (TATs) have attractive physical properties that deem them effective in progressive metastatic castrate-resistant prostate cancer (mCRPC). Among the PSMA TAT radiopharmaceuticals, [225Ac]Ac-PSMA has been used extensively on a compassionate basis and is currently undergoing phase I trials. Notably, TAT has the potential to improve quality of life and has favorable antitumor activity and outcomes in multiple scenarios other than in mCRPC. In addition, resistance mechanisms to TAT may be amenable to combination therapies., Competing Interests: Disclosure Ethical approval and consent to participate: Although this is a review article, ethics approval and informed consent for the images used are available. Competing interests: The authors declare that they have no competing interests. Consent for publication: Informed patient consent for publication of [(68) Ga] Ga-DOTATATE PET/CT and [(68) Ga]Ga-PSMA-PET/CT images and other relevant information was obtained. Availability of data and materials: The articles quoted and referenced are available online as referenced. The images used for the review are available from the corresponding author on request. Funding: The authors declare that the review was conducted in the absence of any commercial or financial relationships., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective criteria for measuring treatment response in prostate cancer are critical to clinical research and practice. The Prostate Cancer Working Group 3 criteria are widely accepted relying only on conventional imaging for radiographic treatment response. Prostate-specific membrane antigen PET/computed tomography was proven to be superior to conventional imaging in initial diagnosis and biochemical recurrence of prostate cancer. Moreover, there is growing evidence of its role in treatment response assessment in prostate cancer. This study will review the different criteria for imaging treatment response on conventional and advanced molecular imaging for different therapies, and the future perspective in posttherapy imaging., Competing Interests: Disclosure No conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

177 Lu-PSMA therapy is an effective treatment in patients with metastatic castration-resistant prostate cancer. SUV mean is a valuable screening biomarker to assess the suitability for 177 Lu-PSMA therapy but requires quantitative software. This study aims to develop a simple, clinically applicable prostate-specific membrane antigen PET/CT score that encompasses the elements of SUV mean without requiring additional quantification. Methods: Datasets from ethics-approved trials of patients with metastatic castration-resistant prostate cancer after androgen receptor signaling inhibition and taxane chemotherapy (or unfit for taxane), who were treated with 177 Lu-PSMA-617 and 177 Lu-PSMA I&T with a pretreatment screening with 68 Ga-PSMA-11 PET/CT, and clinical outcome data, including a prostate-specific antigen (PSA) 50% response rate (PSA50), PSA progression-free survival (PSA-PFS), and overall survival (OS), were included. The screening 68 Ga-PSMA-11 PET/CT of all participants was analyzed both semiquantitatively and visually. Semiquantitative analysis was used to derive the SUV mean Visual analysis of the 68 Ga-PSMA-11 PET/CT images involved a binary visual heterogeneity assessment (homogeneous or heterogeneous), allocating a tumor SUV max range (<15, 15-29, 30-49, 50-79, or ≥80). A 4-category score incorporating both heterogeneity and intensity of tumors (HIT) was then developed as a combination of heterogeneity and intensity (SUV max range). The SUV max was less than 15 for score 1, 15-79 with heterogeneous intensity for score 2, 15-79 with homogeneous intensity for score 3, and 80 or greater for score 4. This score was evaluated according to clinical outcomes (PSA50, PSA-PFS, and OS) and compared with SUV mean Results: Data from 139 participants were analyzed. In total, 75 (54%) patients achieved a PSA50 with a median PSA-PFS of 5.5 mo (95% CI, 4.1-6.0 mo) and an OS of 13.5 mo (95% CI, 11.1-17.9 mo). SUV mean was associated with PSA50 and survival outcomes when analyzed as a continuous variable or as quartiles. The PSA50 for HIT scores 1-4 was 0%, 39%, 65%, and 76%, respectively. The HIT score was strongly related to PSA-PFS and OS (log-rank test, P < 0.001 and P = 0.002). The median PSA-PFS for HIT scores 1-4 was 1.0, 4.1, 6.0, and 8.5, respectively, and the median OS was 7.6, 12.0, 18.5, and 16.9 mo, respectively. Cohen κ between readers for the HIT score was 0.71. Conclusion: A prostate-specific membrane antigen PET/CT score incorporating HIT derived from tools on a standard PET workstation is comparable with quantitative SUV mean as a prognostic tool following 177 Lu-PSMA therapy., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Multiparametric magnetic resonance imaging (mpMRI) has an established role for the diagnosis of clinically significant prostate cancer (sPCa). The PRIMARY trial demonstrated that [ 68 Ga]Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT) was associated with a significant improvement in sensitivity and negative predictive value for sPCa detection., Objective: To demonstrate that addition of prostate-specific membrane antigen (PSMA) radioligand PET/CT will enable some men to avoid transperineal prostate biopsy without missing sPCa, and will facilitate biopsy targeting of PSMA-avid sites., Design, Setting, and Participants: This multicentre, two-arm, phase 3, randomised controlled trial will recruit 660 participants scheduled to undergo biopsy. Eligible participants will have clinical suspicion of sPCa with a Prostate Imaging-Reporting and Data System (PI-RADS) score of 2 and red flags, or a PI-RADS score of 3 on mpMRI (PI-RADS v2). Participants will be randomised at a 1:1 ratio in permuted blocks stratified by centre. The trial is registered on ClinicalTrials.gov as NCT05154162., Intervention: In the experimental arm, participants will undergo pelvic PSMA PET/CT. Local and central reviewers will interpret scans independently using the PRIMARY score. Participants with a positive result will undergo targeted transperineal prostate biopsies, whereas those with a negative result will undergo prostate-specific antigen monitoring alone. In the control arm, all participants undergo template transperineal prostate biopsies. Participants will be followed for subsequent clinical care for up to 2 yr after randomisation., Outcome Measurements and Statistical Analysis: sPCa is defined as Gleason score 3 + 4 (≥10%) = 7 disease (grade group 2) or higher on transperineal prostate biopsy. Avoidance of transperineal prostate biopsy will be measured at 6 mo from randomisation. The primary endpoints will be analysed on an intention-to-treat basis., Conclusions: Patient enrolment began in March 2022, with recruitment expected to take 36 mo., Patient Summary: For patients with suspected prostate cancer who have nonsuspicious or unclear MRI (magnetic resonance imaging) scan findings, a different type of scan (called PSMA PET/CT; prostate-specific membrane antigen positron emission tomography/computed tomography) may identify men who could avoid an invasive prostate biopsy. This type of scan could also help urologists in better targeting of samples from suspicious lesions during prostate biopsies., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

We report a cluster of serogroup B invasive meningococcal disease identified via genomic surveillance in older adults in England and describe the public health responses. Genomic surveillance is critical for supporting public health investigations and detecting the growing threat of serogroup B Neisseria meningitidis infections in older adults.

Purpose: The European Association of Urology (EAU) proposed a risk stratification (high vs. low risk) for patients with biochemical recurrence (BR) following radical prostatectomy (RP). Here we investigated whether this stratification accurately predicts outcome, particularly in patients staged with PSMA-PET., Methods: For this study, we used a retrospective database including 1222 PSMA-PET-staged prostate cancer patients who were treated with salvage radiotherapy (SRT) for BR, at 11 centers in 5 countries. Patients with lymph node metastases (pN1 or cN1) or unclear EAU risk group were excluded. The remaining cohort comprised 526 patients, including 132 low-risk and 394 high-risk patients., Results: The median follow-up time after SRT was 31.0 months. The 3-year biochemical progression-free survival (BPFS) was 85.7 % in EAU low-risk versus 69.4 % in high-risk patients (p = 0.002). The 3-year metastasis-free survival (MFS) was 94.4 % in low-risk versus 87.6 % in high-risk patients (p = 0.005). The 3-year overall survival (OS) was 99.0 % in low-risk versus 99.6 % in high-risk patients (p = 0.925). In multivariate analysis, EAU risk group remained a statistically significant predictor of BPFS (p = 0.003, HR 2.022, 95 % CI 1.262-3.239) and MFS (p = 0.013, HR 2.986, 95 % CI 1.262-7.058)., Conclusion: Our data support the EAU risk group definition. EAU risk grouping for BCR reliably predicted outcome in patients staged lymph node-negative after RP and with PSMA-PET before SRT. To our knowledge, this is the first study validating the EAU risk grouping in patients treated with PSMA-PET-planned SRT., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Enzalutamide and lutetium-177 [ 177 Lu]Lu-prostate-specific membrane antigen (PSMA)-617 both improve overall survival in patients with metastatic castration-resistant prostate cancer. Androgen and PSMA receptors have a close intracellular relationship, with data suggesting complementary benefit if targeted concurrently. In this study, we assessed the activity and safety of enzalutamide plus adaptive-dosed [ 177 Lu]Lu-PSMA-617 versus enzalutamide alone as first-line treatment for metastatic castration-resistant prostate cancer., Methods: ENZA-p was an open-label, randomised, controlled phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older with metastatic castration-resistant prostate cancer not previously treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [ 68 Ga]Ga-PSMA-PET-CT (PSMA-PET-CT) positive disease, Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for study site, disease burden, use of early docetaxel, and previous treatment with abiraterone acetate. Patients were either given oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq [ 177 Lu]Lu-PSMA-617 every 6-8 weeks dependent on an interim PSMA-PET-CT (week 12). The primary endpoint was prostate-specific antigen (PSA) progression-free survival, defined as the interval from the date of randomisation to the date of first evidence of PSA progression, commencement of non-protocol anticancer therapy, or death. The analysis was done in the intention-to-treat population, using stratified Cox proportional hazards regression. This trial is registered with ClinicalTrials.gov, NCT04419402, and participant follow-up is ongoing., Findings: 162 participants were randomly assigned between Aug 17, 2020, and July 26, 2022. 83 men were assigned to the enzalutamide plus [ 177 Lu]Lu-PSMA-617 group, and 79 were assigned to the enzalutamide group. Median follow-up in this interim analysis was 20 months (IQR 18-21), with 32 (39%) of 83 patients in the enzalutamide plus [ 177 Lu]Lu-PSMA-617 group and 16 (20%) of 79 patients in the enzalutamide group remaining on treatment at the data cutoff date. Median age was 71 years (IQR 64-76). Median PSA progression-free survival was 13·0 months (95% CI 11·0-17·0) in the enzalutamide plus [ 177 Lu]Lu-PSMA-617 group and 7·8 months (95% CI 4·3-11·0) in the enzalutamide group (hazard ratio 0·43, 95% CI 0·29-0·63, p<0·0001). The most common adverse events (all grades) were fatigue (61 [75%] of 81 patients), nausea (38 [47%]), and dry mouth (32 [40%]) in the enzalutamide plus [ 177 Lu]Lu-PSMA-617 group and fatigue (55 [70%] of 79), nausea (21 [27%]), and constipation (18 [23%]) in the enzalutamide group. Grade 3-5 adverse events occurred in 32 (40%) of 81 patients in the enzalutamide plus [ 177 Lu]Lu-PSMA-617 group and 32 (41%) of 79 patients in the enzalutamide group. Grade 3 events that occurred only in the enzalutamide plus [ 177 Lu]Lu-PSMA-617 group included anaemia (three [4%] of 81 participants) and decreased platelet count (one [1%] participant). No grade 4 or 5 events were attributed to treatment on central review in either group., Interpretation: The addition of [ 177 Lu]Lu-PSMA-617 to enzalutamide improved PSA progression-free survival providing evidence of enhanced anticancer activity in patients with metastatic castration-resistant prostate cancer with risk factors for early progression on enzalutamide and warrants further evaluation of the combination more broadly in metastatic prostate cancer., Funding: Prostate Cancer Research Alliance (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, Roy Morgan Research, and Endocyte (a Novartis company)., Competing Interests: Declaration of interests LE reports research grant support (to their institution) from Novartis and Clarity Pharma; consulting fees for lectures or advisory boards from Astellas, Janssen, AstraZeneca, Clarity, Novartis, and Telix in the past 5 years; and philanthropic grant support from the Prostate Cancer Foundation, St Vincent's Clinic Research Foundation, and Curran Foundation. SSa reports grants from Novartis/AAA, AstraZeneca, Merck Sharp & Dohme, Genentech, Pfizer, Amgen, and Senhwa to their institution; and personal fees from AstraZeneca, Merck Sharp & Dohme, Bristol Myers Squibb, and AstraZeneca to their institution, outside the submitted work. CG donated personal fees from Astellas, Janssen, AstraZeneca, Bristol Myers Squibb, Pfizer/EMD Serono, Ipsen, Astellas, and MSD, direct and complete, to a third party not-for-profit. CG declares consulting fees (unrelated to this work) from Novotech, Cadex Geonomics, and BCAL Diagnostics; and participation on an advisory board for Alloplex. MSH reports grants and receipt of equipment, materials, drugs, medical writing, gifts, or other services from the Prostate Cancer Foundation, National Health and Medical Research Council (NHRMC), Movember, US Department of Defense, Medical Research Future Fund, Bayer, Peter MacCallum Foundation, Isotopia, and the Australian Nuclear Science and Technology Organisation; consulting fees from Merck Sharp & Dohme and Novartis; honoraria from Janssen, Novartis, AstraZeneca, and Astellas; support for meetings from Merck Sharp & Dohme, Novartis, Janssen, AstraZeneca, and Astellas; leadership or fiduciary role in other board from Australian Friends of Sheba; and other financial or non-financial interests from Peter MacCallum Cancer Centre and the University of Melbourne. DAP reports personal fees from Ipsen and Eisai, all outside the submitted work. RJF reports institution funding and consulting fees from AIQ Solutions, outside the submitted work; and committee involvement in the Australasian Radiopharmaceutical Trials Network (unpaid). MRS reports grants to his institution from the Australian NHMRC, Cancer Australia, Astellas, Amgen, AstraZeneca, Bayer, Bionomics, Bristol Myers Squibb, Celgene, Medivation, Merck Sharp & Dohme, Pfizer, Roche, Sanofi, and Tilray, all outside the submitted work. IDD reports grants from the NHMRC, during the conduct of the study; and institutional payments to support prostate cancer trials from Pfizer, ANZUP Cancer Trials Group, Bayer, Astellas, Janssen, Movember Foundation, and Merck Sharp & Dohme, outside the submitted work. IDD is unremunerated Chair of the ANZUP Cancer Trials Group and is supported in part by an Australian NHMRC Investigator Grant (grant number 2016274). AMJ reports consulting or advisory roles (to their institution) from Janssen Oncology, Pfizer, and Astellas Pharma; and research funding (to their institution) from Bristol Myers Squibb, Janssen Oncology, Merck Sharp & Dohme, Mayne Pharma, Roche/Genentech, Bayer, Lilly, Pfizer, and AstraZeneca. AW declares consulting fees from MSD, Eisai, Bristol Myers Squibb, and Astellas; honoraria from Eisai and MSD; and participation on an advisory board from Loxo-Lilly, MSD, and Astellas. DP declares support for travel from Astellas and participation on an advisory board from Astellas. MC reports advisory board fees from Astellas. MV reports personal fees from AstraZeneca and MSD. AYZ reports grants or contracts from Astellas, Amgen, AstraZeneca, Bionomics, Bristol Myers Squibb, Celgene, Medivation, Merck Sharp & Dohme, Pfizer, Roche, Sanofi, and Tilray; consulting fees from Merck Sharpe & Dohme; honoraria from Merck Sharpe & Dohme, Astellas, Bayer, Pfizer, Merck, Mundipharma, Janssen, and AstraZeneca; and participation on a data safety monitoring board or advisory board from Merck, Merck Sharpe & Dohme, Astellas, and Bayer. JCG reports consulting fees from Bristol Myers Squibb, GlaxoSmithKline, and MSD; honoraria from Bayer, Ipsen, Eisai, Janssen, GlaxoSmithKline, and MSD; support to attend meetings from Bayer and BeiGene; and participation on a data safety monitoring board or advisory board from AstraZeneca. LH reports support for the present manuscript from Astellas; research funding from Astellas, Bayer, and Imagion; participation on advisory boards from Astellas, Bayer, Janssen, and MSD; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas, Bayer, Janssen, and MSD; support for attending meetings from Bayer; a provisional patent (Australian number 2022902527, Prognostic Markers [plasma lipid prognostic signature in metastatic prostate cancer]; patent owned by the Chris O'Brien Lifehouse [their institution]); participation on a data safety monitoring board or advisory board from Astellas, Bayer, and Imagion; advisory board leadership role for ANZUP; and stock or stock options from Connected Medical Solutions. SY reports grants or contracts from NHMRC, Cancer Australia, Astellas, Amgen, AstraZeneca, Bionomics, Bristol Myers Squibb, Celgene, Medivation, Merck Sharp & Dohme, Pfizer, Roche, Sanofi, and Tilray; and support for attending meetings from Bayer. All other authors declare no competing interests., (Copyright © 2024. Published by Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Prognostic models have been developed using data from a multicentre noncomparative study to forecast the likelihood of a 50% reduction in prostate-specific antigen (PSA50), longer prostate-specific antigen (PSA) progression-free survival (PFS), and longer overall survival (OS) in patients with metastatic castration-resistant prostate cancer receiving [ 177 Lu]Lu-PSMA radioligand therapy. The predictive utility of the models to identify patients likely to benefit most from [ 177 Lu]Lu-PSMA compared with standard chemotherapy has not been established., Objective: To determine the predictive value of the models using data from the randomised, open-label, phase 2, TheraP trial (primary objective) and to evaluate the clinical net benefit of the PSA50 model (secondary objective)., Design, Setting, and Participants: All 200 patients were randomised in the TheraP trial to receive [ 177 Lu]Lu-PSMA-617 (n = 99) or cabazitaxel (n = 101) between February 2018 and September 2019., Outcome Measurements and Statistical Analysis: Predictive performance was investigated by testing whether the association between the modelled outcome classifications (favourable vs unfavourable outcome) was different for patients randomised to [ 177 Lu]Lu-PSMA versus cabazitaxel. The clinical benefit of the PSA50 model was evaluated using a decision curve analysis., Results and Limitations: The probability of PSA50 in patients classified as having a favourable outcome was greater in the [ 177 Lu]Lu-PSMA-617 group than in the cabazitaxel group (odds ratio 6.36 [95% confidence interval {CI} 1.69-30.80] vs 0.96 [95% CI 0.32-3.05]; p = 0.038 for treatment-by-model interaction). The PSA50 rate in patients with a favourable outcome for [ 177 Lu]Lu-PSMA-617 versus cabazitaxel was 62/88 (70%) versus 31/85 (36%). The decision curve analysis indicated that the use of the PSA50 model had a clinical net benefit when the probability of a PSA response was ≥30%. The predictive performance of the models for PSA PFS and OS was not established (treatment-by-model interaction: p = 0.36 and p = 0.41, respectively)., Conclusions: A previously developed outcome classification model for PSA50 was demonstrated to be both predictive and prognostic for the outcome after [ 177 Lu]Lu-PSMA-617 versus cabazitaxel, while the PSA PFS and OS models had purely prognostic value. The models may aid clinicians in defining strategies for patients with metastatic castration-resistant prostate cancer who failed first-line chemotherapy and are eligible for [ 177 Lu]Lu-PSMA-617 and cabazitaxel., Patient Summary: In this report, we validated previously developed statistical models that can predict a response to Lu-PSMA radioligand therapy in patients with advanced prostate cancer. We found that the statistical models can predict patient survival, and aid in determining whether Lu-PSMA therapy or cabazitaxel yields a higher probability to achieve a serum prostate-specific antigen response., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate the additional value of prostate-specific membrane antigen positron emission tomography (PSMA-PET) to conventional diagnostic tools to select patients for hemi-ablative focal therapy (FT)., Patients and Methods: We performed a retrospective analysis on a multicentre cohort (private and institutional) of 138 patients who underwent multiparametric magnetic resonance imaging (mpMRI), PSMA-PET, and systematic biopsies prior to radical prostatectomy between January 2011 and July 2021. Patients were eligible when they met the consensus criteria for FT: PSA <15 ng/mL, clinical/radiological T stage ≤T2b, and International Society of Urological Pathology (ISUP) grade 2-3. Clinically significant prostate cancer (csPCa) was defined as ISUP grade ≥2, extracapsular extension >0.5 mm or seminal vesicle involvement at final histopathology. The diagnostic accuracy of mpMRI, systematic biopsies and PSMA-PET for csPCa (separate and combined) was calculated within a four-quadrant prostate model by receiver-operating characteristic and 2 × 2 contingency analysis. Additionally, we assessed whether the diagnostic tools correctly identified patients suitable for hemi-ablative FT., Results: In total 552 prostate quadrants were analysed and 272 (49%) contained csPCa on final histopathology. The area under the curve, sensitivity, specificity, positive predictive value and negative predictive value for csPCa were 0.79, 75%, 83%, 81% and 77%, respectively, for combined mpMRI and systematic biopsies, and improved after addition of PSMA-PET to 0.84, 87%, 80%, 81% and 86%, respectively (P < 0.001). On final histopathology 46/138 patients (33%) were not suitable for hemi-ablative FT. Addition of PSMA-PET correctly identified 26/46 (57%) non-suitable patients and resulted in 4/138 (3%) false-positive exclusions., Conclusions: Addition of PSMA-PET to the conventional work-up by mpMRI and systematic biopsies could improve selection for hemi-ablative FT and guide exclusion of patients for whom whole-gland treatments might be a more suitable treatment option., (© 2023 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Background: Salvage radiation therapy (SRT) and surveillance for low-risk prostate-specific antigen (PSA) recurrence have competing risks and benefits. The efficacy of early SRT to the prostate bed with or without pelvic lymph nodes compared to surveillance in patients with PSA recurrence after radical prostatectomy and no identifiable recurrent disease evident on prostate specific membrane antigen-positron emission tomography/computer tomography (PSMA-PET/CT) is unknown., Study Design: The Dedicated Imaging Post-Prostatectomy for Enhanced Radiotherapy outcomes (DIPPER) is an open-label, multicentre, randomised Phase II trial., Endpoints: The primary endpoint is 3-year event-free survival, with events comprising one of PSA recurrence (PSA ≥0.2 ng/mL higher than baseline), radiological evidence of metastatic disease, or initiation of systemic or other salvage treatments. Secondary endpoints include patient-reported outcomes, treatment patterns, participant perceptions, and cost-effectiveness., Eligibility Criteria: Eligible participants have PSA recurrence of prostate cancer after radical prostatectomy, defined by serum PSA level of 0.2-0.5 ng/mL, deemed low risk according to modified European Association of Urology biochemical recurrence risk criteria (International Society for Urological Pathology Grade Group ≤2, PSA doubling time >12 months), with no definite/probable recurrent prostate cancer on PSMA-PET/CT., Patients and Methods: A total of 100 participants will be recruited from five Australian centres and randomised 1:1 to SRT or surveillance. Participants will undergo 6-monthly clinical evaluation for up to 36 months. Androgen-deprivation therapy is not permissible. Enrolment commenced May 2023., Trial Registration: This trial has been registered with the Australian New Zealand Clinical Trials Registry (ACTRN: ACTRN12622001478707)., (© 2023 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

The PRIMARY score is a 5-category scale developed to identify clinically significant intraprostate malignancy (csPCa) on 68 Ga-prostate-specific membrane antigen (PSMA)-11 PET/CT ( 68 Ga-PSMA PET) using a combination of anatomic site, pattern, and intensity. Developed within the PRIMARY trial, the score requires evaluation in external datasets. This study aimed to assess the reproducibility and diagnostic accuracy of the PRIMARY score in a cohort of patients who underwent multiparametric MRI (mpMRI) and 68 Ga-PSMA PET before prostate biopsy for the diagnosis of prostate cancer. Methods: In total, data from 242 men who had undergone 68 Ga-PSMA PET and mpMRI before transperineal prostate biopsy were available for this ethics-approved retrospective study. 68 Ga-PSMA PET and mpMRI data were centrally collated in a cloud-based deidentified image database. Six experienced prostate-focused nuclear medicine specialists were trained (1 h) in applying the PRIMARY score with 30 sample images. Six radiologists experienced in prostate mpMRI read images as per the Prostate Imaging-Reporting and Data System (PI-RADS), version 2.1. All images were read (with masking of clinical information) at least twice, with discordant findings sent to a masked third (or fourth) reader as necessary. Cohen κ was determined for both imaging scales as 5 categories and then collapsed to binary (negative and positive) categories (score 1 or 2 vs. 3, 4, or 5). Diagnostic performance parameters were calculated, with an International Society of Urological Pathology grade group of at least 2 (csPCa) on biopsy defined as the gold standard. Combined-imaging-positive results were defined as any PI-RADS score of 4 or 5 or as a PI-RADS score of 1-3 with a PRIMARY score of 3-5. Results: In total, 227 patients with histopathology, 68 Ga-PSMA PET, and mpMRI imaging before prostate biopsy were included; 33% had no csPCa, and 67% had csPCa. Overall interrater reliability was higher for the PRIMARY scale (κ = 0.70) than for PI-RADS (κ = 0.58) when assessed as a binary category (benign vs. malignant). This was similar for all 5 categories (κ = 0.65 vs. 0.48). Diagnostic performance to detect csPCa was comparable between PSMA PET and mpMRI (sensitivity, 86% vs. 89%; specificity, 76% vs. 74%; positive predictive value, 88% vs. 88%; negative predictive value, 72% vs. 76%). Using combined imaging, sensitivity was 94%, specificity was 68%, positive predictive value was 86%, and negative predictive value was 85%. Conclusion: The PRIMARY score applied by first-user nuclear medicine specialists showed substantial interrater reproducibility, exceeding that of PI-RADS applied by mpMRI-experienced radiologists. Diagnostic performance was similar between the 2 modalities. The PRIMARY score should be considered when interpreting intraprostatic PSMA PET images., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: The TheraP study reported improved prostate-specific antigen responses with lutetium-177 [ 177 Lu]Lu-PSMA-617 versus cabazitaxel in men with metastatic castration-resistant prostate cancer progressing after docetaxel. In this Article, we report the secondary outcome of overall survival with mature follow-up, and an updated imaging biomarker analysis. We also report the outcomes of participants excluded due to ineligibility on gallium-68 [ 68 Ga]Ga-PSMA-11 and 2-[ 18 F]fluoro-2-deoxy-D-glucose (2-[ 18 F]FDG) PET-CT., Methods: TheraP was an open-label, randomised phase 2 trial at 11 centres in Australia. Eligible participants had metastatic castration-resistant prostate cancer progressing after docetaxel, and PET imaging with [ 68 Ga]Ga-PSMA-11 and 2-[ 18 F]FDG that showed prostate-specific membrane antigen (PSMA)-positive disease and no sites of metastatic disease with discordant 2-[ 18 F]FDG-positive and PSMA-negative findings. Participants were randomly assigned (1:1) to treatment with [ 177 Lu]Lu-PSMA-617 (every 6 weeks for a maximum of six cycles; starting at 8·5 GBq, decreasing by 0.5 GBq to 6·0 GBq for the sixth cycle) versus cabazitaxel (20 mg/m 2 every 3 weeks, maximum of ten cycles). Overall survival was analysed by intention-to-treat and summarised as restricted mean survival time (RMST) to account for non-proportional hazards, with a 36-month restriction time corresponding to median follow-up. This trial is registered with ClinicalTrials.gov, NCT03392428, and is complete., Findings: 291 men were registered from Feb 6, 2018, to Sept 3, 2019; after study imaging, 200 were eligible and randomly assigned to treatment with [ 177 Lu]Lu-PSMA-617 (n=99) or cabazitaxel (n=101). After completing study treatment, 20 (20%) participants assigned to cabazitaxel and 32 (32%) assigned to [ 177 Lu]Lu-PSMA-617 were subsequently treated with the alternative regimen. After a median follow-up of 35·7 months (IQR 31·1 to 39·2), 77 (78%) participants had died in the [ 177 Lu]Lu-PSMA-617 group and 70 (69%) participants had died in the cabazitaxel group. Overall survival was similar among those assigned to [ 177 Lu]Lu-PSMA-617 versus those assigned to cabazitaxel (RMST 19·1 months [95% CI 16·9 to 21·4] vs 19·6 months [17·4 to 21·8]; difference -0·5 months [95% CI -3·7 to 2·7]; p=0·77). No additional safety signals were identified with the longer follow-up in this analysis. 80 (27%) of 291 men who were registered after initial eligibility screening were excluded after [ 68 Ga]Ga-PSMA-11 and 2-[ 18 F]FDG PET. In the 61 of these men with follow-up available, RMST was 11·0 months (95% CI 9·0 to 13·1)., Interpretation: These results support the use of [ 177 Lu]Lu-PSMA-617 as an alternative to cabazitaxel for PSMA-positive metastatic castration-resistant prostate cancer progressing after docetaxel. We did not find evidence that overall survival differed between the randomised groups. Median overall survival was shorter for men who were excluded because of low PSMA expression or 2-[ 18 F]FDG-discordant disease., Funding: Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, It's a Bloke Thing, CAN4CANCER, and The Distinguished Gentleman's Ride., Competing Interests: Declaration of interests MSH reports research grant support (to their institution) from Novartis (including AAA and Endocyte), Australian Nuclear Science and Technology Organization (ANSTO), Bayer, Isotopia, and MIM; and consulting fees for lectures or advisory boards from Astellas and AstraZeneca in the past 2 years, and from Janssen, MSD, and Mundipharma in the past 5 years. LE reports personal fees from AstraZenca, Janssen, and Astellas, outside the submitted work. SS reports grants from AAA, AstraZeneca, MSD, and Genetech to their institution; and personal fees from AstraZeneca, MSD, Bristol Myers Squibb, and AstraZeneca to their institution, outside the submitted work. DAP reports personal fees from Ipsen and Eisai, outside the submitted work. RJF reports institution funding and consulting fees from AIQ Solutions, outside of the submitted work; and committee involvement in the Australasian Radiopharmaceutical Trials Network (unpaid). CG donated personal fees from Astellas, Janssen, AstraZeneca, Bristol Myers Squibb, EMD Serono, Ipsen, Astellas, and MSD, direct and complete, to a third party not-for-profit. AMS reports trial or research funding from EMD Serono, ITM, AVID, Medimmune, Telix, Adalta, Fusion, Antengene, Earli, Curis, and Cyclotek; grants from the Australian National Health and Medical Research Council (NHMRC) and Medical Research Future Fund (MRFF), including an NHMRC Investigator Grant; and board and advisory committee involvement for the Australian and New Zealand Society of Nuclear Medicine and Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group (unpaid); all outside the submitted work. EMK reports personal fees from Astellas Pharma, Janssen, Pfizer, Ipsen, and Roche, all outside the submitted work; and is supported by a Prostate Cancer Foundation Young Investigator Award and University of British Columbia Killam Postdoctoral Fellowship. AAA reports grants or personal fees from Janssen, Astellas, Novartis, Merck Serono, Tolmar, Amgen, Pfizer, Bayer, Telix Pharmaceuticals, Bristol Myers Squibb, Sanofi, Noxopharm, AstraZeneca, Ipsen, MSD, Aculeus Therapeutics, and Daiichi Sankyo; and grants from Astellas (investigator), Merck Serono (investigator), AstraZeneca (investigator), Bristol Myers Squibb (institutional), AstraZeneca (institutional), Aptevo Therapeutics (institutional), GlaxoSmithKline (institutional), Pfizer (institutional), MedImmune (institutional), Astellas (institutional), Synthorx (institutional), Bionomics (institutional), Sanofi Aventis (institutional), Novartis (institutional), Ipsen (institutional), Exelixis (institutional), MSD (institutional), Janssen (institutional), Eli Lilly (institutional), Gilead Sciences (institutional), Merck Serono (institutional), and Hinova (institutional), all outside the submitted work. MRS reports grants to his institution from the NHMRC, Cancer Australia, Astellas, Amgen, AstraZeneca, Bayer, Bionomics, Bristol Myers Squibb, Celgene, Medivation, MSD, Pfizer, Roche, Sanofi, and Tilray, all outside the submitted work. IDD reports grants from the NHMRC, during the conduct of the study; and institutional payments to support prostate cancer trials from Pfizer, the ANZUP Cancer Trials Group, Bayer, Astellas, Janssen, Movember Foundation, and MSD, outside the submitted work. IDD is also unremunerated Chair of the ANZUP Cancer Trials Group, and is supported in part by an NHMRC Investigator Grant (grant number 2016274). AMJ reports consulting or advisory roles (to their institution) from Janssen Oncology, Ipsen, AstraZeneca, Sanofi, Pfizer, Novartis, Bristol Myers Squibb, Merck Serono, Eisai, Bayer, and Astellas Pharma; and research funding (to their institution) from Bristol Myers Squibb, Janssen Oncology, MSD, Mayne Pharma, Genentech, Bayer, Lilly, Pfizer, and AstraZeneca. AI reports personal fees for a consulting role for Curium Pharma and payment to their institution for a consulting role from Ambrx Pharma, all outside the submitted work. AJW reports a consulting role for and travel support from Bayer. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: In prostate cancer (PCa), questions remain on indications for prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging and PSMA radioligand therapy, integration of advanced imaging in nomogram-based decision-making, dosimetry, and development of new theranostic applications., Objective: We aimed to critically review developments in molecular hybrid imaging and systemic radioligand therapy, to reach a multidisciplinary consensus on the current state of the art in PCa., Design, Setting, and Participants: The results of a systematic literature search informed a two-round Delphi process with a panel of 28 PCa experts in medical or radiation oncology, urology, radiology, medical physics, and nuclear medicine. The results were discussed and ratified in a consensus meeting., Outcome Measurements and Statistical Analysis: Forty-eight statements were scored on a Likert agreement scale and six as ranking options. Agreement statements were analysed using the RAND appropriateness method. Ranking statements were analysed using weighted summed scores., Results and Limitations: After two Delphi rounds, there was consensus on 42/48 (87.5%) of the statements. The expert panel recommends PSMA PET to be used for staging the majority of patients with unfavourable intermediate and high risk, and for restaging of suspected recurrent PCa. There was consensus that oligometastatic disease should be defined as up to five metastases, even using advanced imaging modalities. The group agreed that [ 177 Lu]Lu-PSMA should not be administered only after progression to cabazitaxel and that [ 223 Ra]RaCl 2 remains a valid therapeutic option in bone-only metastatic castration-resistant PCa. Uncertainty remains on various topics, including the need for concordant findings on both [ 18F ]FDG and PSMA PET prior to [ 177 Lu]Lu-PSMA therapy., Conclusions: There was a high proportion of agreement among a panel of experts on the use of molecular imaging and theranostics in PCa. Although consensus statements cannot replace high-certainty evidence, these can aid in the interpretation and dissemination of best practice from centres of excellence to the wider clinical community., Patient Summary: There are situations when dealing with prostate cancer (PCa) where both the doctors who diagnose and track the disease development and response to treatment, and those who give treatments are unsure about what the best course of action is. Examples include what methods they should use to obtain images of the cancer and what to do when the cancer has returned or spread. We reviewed published research studies and provided a summary to a panel of experts in imaging and treating PCa. We also used the research summary to develop a questionnaire whereby we asked the experts to state whether or not they agreed with a list of statements. We used these results to provide guidance to other health care professionals on how best to image men with PCa and what treatments to give, when, and in what order, based on the information the images provide., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aim: The optimal management for early recurrent prostate cancer following radical prostatectomy (RP) in patients with negative prostate-specific membrane antigen positron-emission tomography (PSMA-PET) scan is an ongoing subject of debate. The aim of this study was to evaluate the outcome of salvage radiotherapy (SRT) in patients with biochemical recurrence with negative PSMA PET finding., Methods: This retrospective, multicenter (11 centers, 5 countries) analysis included patients who underwent SRT following biochemical recurrence (BR) of PC after RP without evidence of disease on PSMA-PET staging. Biochemical recurrence-free survival (bRFS), metastatic-free survival (MFS) and overall survival (OS) were assessed using Kaplan-Meier method. Multivariable Cox proportional hazards regression assessed predefined predictors of survival outcomes., Results: Three hundred patients were included, 253 (84.3%) received SRT to the prostate bed only, 46 (15.3%) additional elective pelvic nodal irradiation, respectively. Only 41 patients (13.7%) received concomitant androgen deprivation therapy (ADT). Median follow-up after SRT was 33 months (IQR: 20-46 months). Three-year bRFS, MFS, and OS following SRT were 73.9%, 87.8%, and 99.1%, respectively. Three-year bRFS was 77.5% and 48.3% for patients with PSA levels before PSMA-PET ≤ 0.5 ng/ml and > 0.5 ng/ml, respectively. Using univariate analysis, the International Society of Urological Pathology (ISUP) grade > 2 (p = 0.006), metastatic pelvic lymph nodes at surgery (p = 0.032), seminal vesicle involvement (p < 0.001), pre-SRT PSA level of > 0.5 ng/ml (p = 0.004), and lack of concomitant ADT (p = 0.023) were significantly associated with worse bRFS. On multivariate Cox proportional hazards, seminal vesicle infiltration (p = 0.007), ISUP score >2 (p = 0.048), and pre SRT PSA level > 0.5 ng/ml (p = 0.013) remained significantly associated with worse bRFS., Conclusion: Favorable bRFS after SRT in patients with BR and negative PSMA-PET following RP was achieved. These data support the usage of early SRT for patients with negative PSMA-PET findings., (© 2023. The Author(s).)

Prostate cancer (PCa) is the most common cancer diagnosed in men in most developed countries and a leading cause of cancer-related morbidity and mortality. Prostate-specific membrane antigen positron emission tomography (PSMA-PET) has become a valuable tool in the staging and assessment of disease recurrence in PCa, and more recently for assessment for treatment eligibility to PSMA radioligand therapy (RLT). Harmonization of PSMA-PET interpretation and synoptic reports are needed to communicate concisely and reproducibly PSMA-PET/CT to referring physicians and to support clinician therapeutic management decisions in various stages of the disease. Uniform image interpretation is also important to provide comparable data between clinical trials and to translate such data from research to daily practice. This review provides an overview of the value of PSMA-PET across the different clinical stages of PCa, discusses published reporting criteria for PSMA-PET, identifies pitfalls in reporting PSMA, and provides recommendations for synoptic reports., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Preoperative assessment of the probability of pelvic lymph-node metastatic disease (pN1) is required to identify patients with prostate cancer (PCa) who are candidates for extended pelvic lymph-node dissection (ePLND)., Objective: To develop a novel intuitive prognostic nomogram for predicting pathological lymph-node (pN) status in contemporary patients with primary diagnosed localized PCa, using preoperative clinical and histopathological parameters, magnetic resonance imaging (MRI), and prostate-specific membrane antigen (PSMA) positron emission tomography (PET)., Design, Setting, and Participants: In total, 700 eligible patients who underwent robot-assisted radical prostatectomy and ePLND were included in the model-building cohort. The external validation cohort consisted of 305 surgically treated patients. Logistic regression with backward elimination was used to select variables for the Amsterdam-Brisbane-Sydney nomogram., Outcome Measurements and Statistical Analysis: Performance of the final model was evaluated using the area under the receiver operating characteristic curve (AUC), calibration plots, and decision-curve analyses. Models were subsequently validated in an external population., Results and Limitations: The Amsterdam-Brisbane-Sydney nomogram included initial prostate-specific antigen value, MRI T stage, highest biopsy grade group (GG), biopsy technique, percentage of systematic cores with clinically significant PCa (GG ≥2), and lymph-node status on PSMA-PET. The AUC for predicting pN status was 0.81 (95% confidence interval [CI] 0.78-0.85) for the final model. On external validation, the Amsterdam-Brisbane-Sydney nomogram showed superior discriminative ability to the Briganti-2017 and Memorial Sloan Kettering Cancer Center (MSKCC) nomograms (AUC 0.75 [95% CI 0.69-0.81] vs 0.67 [95% CI 0.61-0.74] and 0.65 [95% CI 0.58-0.72], respectively; p < 0.05), and similar discriminative ability to the Briganti-2019 nomogram (AUC 0.78 [95% CI 0.71-0.86] vs 0.80 [95% CI 0.73-0.86]; p = 0.76). The Amsterdam-Brisbane-Sydney nomogram showed excellent calibration on external validation, with an increased net benefit at a threshold probability of ≥4%., Conclusions: The validated Amsterdam-Brisbane-Sydney nomogram performs superior to the Briganti-2017 and MSKCC nomograms, and similar to the Briganti-2019 nomogram. Furthermore, it is applicable in all patients with newly diagnosed unfavorable intermediate- and high-risk PCa., Patient Summary: We developed and validated the Amsterdam-Brisbane-Sydney nomogram for the prediction of prostate cancer spread to lymph nodes before surgery. This nomogram performs similar or superior to all presently available nomograms., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: In active surveillance there is significant interest in whether imaging modalities such as multiparametric magnetic resonance imaging (mpMRI) or 68 Gallium prostate-specific membrane antigen positron emission tomography/computerized tomography ( 68 Ga-PSMA-PET/CT) can improve the detection of progression to clinically significant prostate cancer (csPCa) and thus reduce the frequency of prostate biopsies and associated morbidity. Recent studies have demonstrated the value of mpMRI in active surveillance; however, mpMRI does miss a proportion of disease progression and thus alone cannot replace biopsy. To date, prostate-specific membrane antigen positron emission tomography (PSMA-PET) has shown additive value to mpMRI in its ability to detect prostate cancer (PCa) in the primary diagnostic setting. Our objective is to evaluate the diagnostic utility of PSMA-PET to detect progression to csPCa in active surveillance patients., Methods: We will perform a prospective, cross-sectional, partially blinded, multicentre clinical trial evaluating the additive value of PSMA-PET with mpMRI against saturation transperineal template prostate biopsy. Two hundred and twenty-five men will be recruited who have newly diagnosed PCa which is suitable for active surveillance. Following enrolment, patients will undergo a PSMA-PET and mpMRI within 3 months of a repeat 12-month confirmatory biopsy. Patients who remain on active surveillance after confirmatory biopsy will then be planned to have a further mpMRI and PSMA-PET prior to a repeat biopsy in 3-4 years. The primary outcome is to assess the ability of PSMA-PET to detect or exclude significant malignancy on repeat biopsy. Secondary outcomes include (I) assess the comparative diagnostic accuracies of mpMRI and PSMA-PET alone [sensitivity/specificity/negative predictive value (NPV)/positive predictive value (PPV)] to detect progression on biopsy based on predefined histologic criteria for progression; (II) comparison of index lesion identification by template biopsies vs. MRI targeted lesions vs. PSMA targeted lesions; (III) evaluation of concordance of lesions identified on final histopathology and each imaging modality (PSMA-PET and/or mpMRI) in the subset of patients proceeding to RP., Discussion: The results of this trial will define the role of PSMA-PET in active surveillance and potentially reduce the number of biopsies needed to detect progression to csPCa., Trial Registration: The current trial was registered with the ANZCTR on the 3/2/2022 with the trial ID ACTRN12622000188730, it is accessible at https://www.anzctr.org.au/., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-22-708/coif). MJR reports the consulting fees (proctoring, prostate biopsy technique) from BXTAccelyon, and the participation on DSMB (PSMA-PET related) in Peter MacCallum Cancer Centre, Melbourne. DW and RS report the employment with I-MED Radiology. WD reports the employment with Douglass Hanly Moir pathology. The other authors have no conflicts of interest to declare., (2023 Translational Andrology and Urology. All rights reserved.)

Background: Lutetium-177-prostate-specific membrane antigen- 617 (Lu-PSMA) is an effective therapy for metastatic castration-resistant prostate cancer (mCRPC). However, treatment responses are heterogeneous despite stringent positron emission tomography (PET)-based imaging selection criteria. Molecularly based biomarkers have potential to refine patient selection and optimise outcomes., Objective: To identify circulating tumour DNA (ctDNA) features associated with treatment outcomes for men treated with Lu-PSMA., Design Setting and Participants: ctDNA from men treated with Lu-PSMA in combination with idronoxil for progressive mCRPC were analysed using an 85-gene customised sequencing assay. ctDNA fractions, molecular profiles, and the presence of alterations in aggressive-variant prostate cancer (AVPC) genes were analysed at baseline, cycle 3 and at disease progression., Intervention: Men received Lu-PSMA with idronoxil every 6 wk for up to six cycles., Outcome Measurements and Statistical Analysis: Baseline and exit PSMA and fluorodeoxyglucose PET/computed tomography (CT) imaging was conducted at baseline and study exit. Single-photon emission CT (SPECT) scans were performed 24 h after Lu-PSMA. Blood samples were collected at baseline,cycle 3 and at disease progression. Cox proportional-hazards models were used to assess associations and derive hazard ratios (HRs) and confidence intervals (CIs) for associations between molecular factors, imaging features, and clinical outcomes., Results and Limitations: Sixty samples from 32 men were sequenced (32 at baseline, 24 at cycle 3, four from patients with disease progression); two samples (baseline, on-treatment) from one individual were excluded from analysis owing to poor quality of the baseline sequencing data. Alterations in AVPC genes were associated with shorter prostate-specific antigen (PSA) progression-free survival (PFS) and overall survival (OS) in univariate (HR 3.4, 95% CI 1.5-7.7; p  = 0.0036; and HR 3.3, 95% CI 1.4-7.7; p  = 0.0063, respectively) and multivariate analyses (HR 4.8, 95% CI 1.8-13; p  = 0.0014; and HR 4.1, 95% CI 1.6-11; p  = 0.004)., Conclusions: ctDNA alterations in AVPC genes were associated with shorter PSA PFS and OS among men treated with Lu-PSMA and intermittent idronoxil. These candidate molecular biomarkers warrant further study to determine whether they have predictive value and potential to guide synergistic combination strategies to enhance outcomes for men treated with Lu-PSMA for mCRPC., Patient Summary: Certain DNA/gene changes detected in the blood of men with advanced prostate cancer were associated with shorter benefit from lutetium PSMA, a targeted radioactive therapy. This information may be useful in determining which men may benefit most from this treatment, but additional research is needed., (© 2023 The Author(s).)

177 Lu-prostate-specific membrane antigen (PSMA) is an effective treatment for metastatic castration-resistant prostate cancer. Rarer treatment-related adverse events have not yet been described. Methods: We present case reviews of 2 men with a marked hypocalcemic osteosclerotic response to 177 Lu-PSMA-I&T therapy. A clinical dataset of 177 Lu-PSMA-I&T therapy was evaluated to estimate the incidence and clinical association with hypocalcemia. Results: Forty-one of the 127 men (32%) had a serum calcium drop, and 6 (5%) developed clinical hypocalcemia during 177 Lu-PSMA therapy. The baseline total tumor volume was significantly higher in those who developed hypocalcemia (median, 3,249 cm 3 [interquartile range, 1,856-3,852] vs. 465 [interquartile range 135-1,172]; P = 0.002). The mean prostate-specific antigen response in those with hypocalcemia was 78% (SD, 24%). Conclusion: Hypocalcemia may occur in response to 177 Lu-PSMA-I&T, particularly with both high-volume bone metastases and a significant prostate-specific antigen response, and may be severe, requiring corticosteroids. Further evaluation of 177 Lu-PSMA-induced hypocalcemia is required to better understand mechanisms, optimal treatments, and repercussions from any subsequent osteosclerotic response., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Oligometastatic disease in prostate cancer (PCa) is a challenging clinical scenario encountered more frequently with the widespread adoption of PSMA-PET. SBRT aims to defer androgen deprivation and may deliver sustained biochemical failure (BF) free survival in selected patients. Little long-term data is currently available regarding the effectiveness of this approach., Methods: A retrospective single institution study of PSMA-PET directed SBRT without initial ADT for oligo-metachronous PCa. Median dose/fractionation was 24 Gy in 2# to bones and 30 Gy in 3# to lymph nodes. The primary endpoint was time to BF (PSA + 0.2 ug/L above nadir). Secondary endpoints included time to ADT for relapse (i.e. palliative ADT), BF defined as PSA nadir + 2 ug/L, toxicity, patterns of failure and survival. Patients were excluded if they received ADT with their SBRT, had short disease-free interval, or > 3 metastases on PSMA-PET., Results: 103 patients treated from November-2014 to December-2019 were analysed from our prospective database. Median follow-up was 5 years. 64 patients were treated for nodal only disease, 35 bone only and 4 mixed. 15% were free of any BF at 5 years with median time to BF of 1.1 years. 32% (33/103) of patients had further curative-intent radiation treatment following their first BF after SBRT, including subsequent SBRT. Eight patients underwent potentially curative treatment for their second or third relapse. Allowing for salvage treatment, 29/103 (28%) were biochemically disease free at last follow up. At 5 years, 39% of patients had never received any ADT and 55% had not started ADT for relapse with a median time to ADT for relapse of 5.5 years. There were 2 grade 3 toxicities (rib fracture and lymphoedema), and no local failures., Conclusion: PSMA-PET guided SBRT for oligo-metachronous PCa recurrence in appropriately triaged patients results in excellent local control, low toxicity and over 50% ADT free at 5 years., (© 2023. The Author(s).)

Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy can improve the outcome of patients with advanced metastatic castration-resistant prostate cancer, but patients do not respond uniformly. We hypothesized that using the salivary glands as a reference organ can enable selective patient stratification. We aimed to establish a PSMA PET tumor-to-salivary gland ratio (PSG score) to predict outcomes after [ 177 Lu]PSMA. Methods: In total, 237 men with metastatic castration-resistant prostate cancer treated with [ 177 Lu]PSMA were included. A quantitative PSG (qPSG) score (SUV mean ratio of whole-body tumor to parotid glands) was semiautomatically calculated on baseline [ 68 Ga]PSMA-11 PET images. Patients were divided into 3 groups: high (qPSG > 1.5), intermediate (qPSG = 0.5-1.5), and low (qPSG < 0.5) scores. Ten readers interpreted the 3-dimensional maximum-intensity-projection baseline [ 68 Ga]PSMA-11 PET images and classified patients into 3 groups based on visual PSG (vPSG) score: high (most of the lesions showed higher uptake than the parotid glands) intermediate (neither low nor high), and low (most of the lesions showed lower uptake than the parotid glands). Outcome data included a more than 50% prostate-specific antigen decline, prostate-specific antigen (PSA) progression-free survival, and overall survival (OS). Results: Of the 237 patients, the numbers in the high, intermediate, and low groups were 56 (23.6%), 163 (68.8%), and 18 (7.6%), respectively, for qPSG score and 106 (44.7%), 96 (40.5%), and 35 (14.8%), respectively, for vPSG score. The interreader reproducibility of the vPSG score was substantial (Fleiss weighted κ, 0.68). The more than 50% prostate-specific antigen decline was better in patients with a higher PSG score (high vs. intermediate vs. low, 69.6% vs. 38.7% vs. 16.7%, respectively, for qPSG [ P < 0.001] and 63.2% vs 33.3% vs 16.1%, respectively, for vPSG [ P < 0.001]). The median PSA progression-free survival of the high, intermediate, and low groups by qPSG score was 7.2, 4.0, and 1.9 mo ( P < 0.001), respectively, by qPSG score and 6.7, 3.8, and 1.9 mo ( P < 0.001), respectively, by vPSG score. The median OS of the high, intermediate, and low groups was 15.0, 11.2, and 13.9 mo ( P = 0.017), respectively, by qPSG score and 14.3, 9.6, and 12.9 mo ( P = 0.018), respectively, by vPSG score. Conclusion: The PSG score was prognostic for PSA response and OS after [ 177 Lu]PSMA. The visual PSG score assessed on 3-dimensional maximum-intensity-projection PET images yielded substantial reproducibility and comparable prognostic value to the quantitative score., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

68 Ga-fibroblast activation protein inhibitors (FAPIs) are promising radiotracers for cancer imaging, with emerging data in the recent years. Nonetheless, the interobserver agreement on 68 Ga-FAPI PET/CT study interpretations in cancer patients remains poorly understood. Methods: 68 Ga-FAPI PET/CT was performed on 50 patients with various tumor entities (sarcoma [ n = 10], colorectal cancer [ n = 10], pancreatic adenocarcinoma [ n = 10], genitourinary cancer [ n = 10], and other types of cancer [ n = 10]). Fifteen masked observers reviewed and interpreted the images using a standardized approach for local, local nodal, and metastatic involvement. Observers were grouped by experience as having a low (<30 prior 68 Ga-FAPI PET/CT studies; n = 5), intermediate (30-300 studies; n = 5), or high level of experience (>300 studies; n = 5). Two independent readers with a high level of experience and unmasked to clinical information, histopathology, tumor markers, and follow-up imaging (CT/MRI or PET/CT) served as the standard of reference (SOR). Observer groups were compared by overall agreement (percentage of patients matching SOR) and Fleiss κ with mean and corresponding 95% CI. We defined acceptable agreement as a κ value of at least 0.6 (substantial or higher) and acceptable accuracy as at least 80%. Results: Highly experienced observers agreed substantially on all categories (primary tumor: κ = 0.71; 95% CI, 0.71-0.71; local nodal involvement: κ = 0.62; 95% CI, 0.61-0.62; distant metastasis: κ = 0.75; 95% CI, 0.75-0.75), whereas observers with intermediate experience showed substantial agreement on primary tumor (κ = 0.73; 95% CI, 0.73-0.73) and distant metastasis (κ = 0.65; 95% CI, 0.65-0.65) but moderate agreement on local nodal stages (κ = 0.55; 95% CI, 0.55-0.55). Observers with low experience had moderate agreement on all categories (primary tumor: κ = 0.57; 95% CI, 0.57-0.58; local nodal involvement: κ = 0.51; 95% CI, 0.51-0.52; distant metastasis: κ = 0.54; 95% CI, 0.53-0.54). Compared with SOR, the accuracy for readers with high, intermediate, and low experience was 85%, 83%, and 78%, respectively. In summary, only highly experienced readers showed substantial agreement and a diagnostic accuracy of at least 80% in all categories. Conclusion: The interpretation of 68 Ga-FAPI PET/CT for cancer imaging had substantial reproducibility and accuracy among highly experienced observers only, especially for local nodal and metastatic assessments. Therefore, for accurate interpretation of different tumor entities and pitfalls, we recommend training or experience with at least 300 representative scans for future clinical readers., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: The purpose of this retrospective, multicenter study was to assess efficacy of PSMA-PET/CT-guided salvage radiotherapy (sRT) in patients with recurrent or persistent PSA after primary surgery and PSA levels < 0.2 ng/ml., Methods: The study included patients from a pooled cohort (n = 1223) of 11 centers from 6 countries. Patients with PSA levels > 0.2 ng/ml prior to sRT or without sRT to the prostatic fossa were excluded. The primary study endpoint was biochemical recurrence-free survival (BRFS) and BR was defined as PSA nadir after sRT + 0.2 ng/ml. Cox regression analysis was performed to assess the impact of clinical parameters on BRFS. Recurrence patterns after sRT were analyzed., Results: The final cohort consisted of 273 patients; 78/273 (28.6%) and 48/273 (17.6%) patients had local or nodal recurrence on PET/CT. The most frequently applied sRT dose to the prostatic fossa was 66-70 Gy (n = 143/273, 52.4%). SRT to pelvic lymphatics was delivered in 87/273 (31.9%) patients and androgen deprivation therapy was given to 36/273 (13.2%) patients. After a median follow-up time of 31.1 months (IQR: 20-44), 60/273 (22%) patients had biochemical recurrence. The 2- and 3-year BRFS was 90.1% and 79.2%, respectively. The presence of seminal vesicle invasion in surgery (p = 0.019) and local recurrences in PET/CT (p = 0.039) had a significant impact on BR in multivariate analysis. In 16 patients, information on recurrence patterns on PSMA-PET/CT after sRT was available and one had recurrent disease inside the RT field., Conclusion: This multicenter analysis suggests that implementation of PSMA-PET/CT imaging for sRT guidance might be of benefit for patients with very low PSA levels after surgery due to promising BRFS rates and a low number of relapses within the sRT field., (© 2023. The Author(s).)

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 [ 177 Lu]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 177 Lu-PSMA-radioligand therapy (RLT) also has high potential in additional clinical situations. Hence, the radiopharmaceuticals [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]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 177 Lu-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 [ 177 Lu]Lu-PSMA-617 or other emerging ligands on an individual patient basis., (© 2023. The Author(s).)

Background/purpose: The present study aimed to assess whether SRT to the prostatic fossa should be initiated in a timely manner after detecting biochemical recurrence (BR) in patients with prostate cancer, when no correlate was identified with prostate-specific membrane antigen positron emission tomography (PSMA-PET)., Materials and Methods: This retrospective, multicenter analysis included 1222 patients referred for PSMA-PET after a radical prostatectomy due to BR. Exclusion criteria were: pathological lymph node metastases, prostate-specific antigen (PSA) persistence, distant or lymph node metastases, nodal irradiation, and androgen deprivation therapy (ADT). This led to a cohort of 341 patients. Biochemical progression-free survival (BPFS) was the primary study endpoint., Results: The median follow-up was 28.0 months. The 3-year BPFS was 71.6% in PET-negative cases and 80.8% in locally PET-positive cases. This difference was significant in univariate (p = 0.019), but not multivariate analyses (p = 0.366, HR: 1.46, 95%CI: 0.64-3.32). The 3-year BPFS in PET-negative cases was significantly influenced by age (p = 0.005), initial pT3/4 (p < 0.001), pathology scores (ISUP) ≥ 3 (p = 0.026), and doses to fossa > 70 Gy (p = 0.027) in univariate analyses. In multivariate analyses, only age (HR: 1.096, 95%CI: 1.023-1.175, p = 0.009) and PSA-doubling time (HR: 0.339, 95%CI: 0.139-0.826, p = 0.017) remained significant., Conclusion: To our best knowledge, this study provided the largest SRT analysis in patients without ADT that were lymph node-negative on PSMA-PET. A multivariate analysis showed no significant difference in BPFS between locally PET-positive and PET-negative cases. These results supported the current EAU recommendation to initiate SRT in a timely manner after detecting BR in PET negative patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The impact of molecular imaging (MI) on patient management after biochemical recurrence (BCR) following radical prostatectomy has been described in many studies. However, it is not known if MI-induced management changes are appropriate. This study aimed to determine if androgen deprivation therapy (ADT) management plan is improved by MI in patients who are candidates for salvage radiation therapy., Methods: Data were analyzed from the multicenter prospective PROPS trial evaluating PSMA/Choline PET in patients being considered for salvage radiotherapy (sRT) with BCR after prostatectomy. We compared the pre- and post-MI ADT management plans for each patient and cancer outcomes as predicted by the MSKCC nomogram. A higher percentage of predicted BCR associated with ADT treatment intensification after MI was considered as an improvement in a patient's management., Results: Seventy-three patients with a median PSA of 0.38 ng/mL were included. In bivariate analysis, a positive finding on MI (local or metastatic) was associated with decision to use ADT with an odds ratio of 3.67 (95% CI, 1.25 to 10.71; p = 0.02). No factor included in the nomogram was associated with decision to use ADT. Also, MI improved selection of patients to receive ADT based on predicted BCR after sRT : the predicted nomogram 5-year biochemical-free survivals were 52.5% and 43.3%, (mean difference, 9.2%; 95% CI 0.8 to 17.6; p = 0.03) for sRT alone and ADT±sRT subgroups, while there was no statistically significant difference between subgroups before MI., Conclusions: PSMA and/or Choline PET/CT before sRT can potentially improve patient ADT management by directing clinicians towards more appropriate intensification., (© 2023. The Author(s).)

Background: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) can detect multiparametric magnetic resonance imaging (mpMRI)-invisible prostate tumours and improve the sensitivity of detection of prostate cancer (PCa) in comparison to mpMRI alone. Numerous risk calculators have been validated as tools for stratification of men at risk of being diagnosed with clinically significant (cs)PCa., Objective: To develop a novel risk calculator using clinical parameters and imaging parameters from mpMRI and PSMA PET/CT in a cohort of patients undergoing mpMRI and PSMA PET/CT before biopsy., Design Setting and Participants: A total of 291 men from the PRIMARY prospective trial underwent mpMRI and PSMA PET/CT before transperineal prostate biopsy with sampling of systematic and targeted cores., Outcome Measurements and Statistical Analysis: Novel risk calculators were developed using multivariable logistic regression analysis to predict detection of overall PCa (International Society of Urological Pathology grade group [GG] ≥1) and csPCa (GG ≥2). The risk calculators were then compared with the European Randomised Study of Screening for Prostate Cancer risk calculator incorporating mpMRI (ERSPC-MRI). Resampling methods were used to evaluate the discrimination and calibration of the risk calculators and to perform decision curve analysis., Results and Limitations: Age, prostate-specific antigen, prostate volume, and mpMRI Prostate Imaging-Reporting and Data System scores were included in the MRI risk calculator, resulting in area under the receiver operating characteristic curve (AUC) values of 0.791 for overall PCa (GG ≥1) and 0.812 for csPCa (GG ≥2). Addition of the maximum standardised uptake value (SUVmax) on PSMA PET/CT for the prostate lesion, and of SUVmax for the mpMRI lesions for the MRI-PSMA risk calculator resulted in AUCs of 0.831 for overall PCa and 0.876 for csPCa (≥ISUP2).The ERSPC-MRI risk calculator had AUCs of 0.758 ( p  = 0.02) for overall PCa and 0.805 ( p  = 0.001) for csPCa. Both the MRI and MRI-PSMA risk calculators were superior to the ERSPC-MRI for both overall PCa and csPCa., Conclusions: These novel risk calculators incorporate clinical and radiological parameters for stratification of men at risk of csPCa. The risk calculator including PSMA PET/CT data is superior to a calculator incorporating mpMRI data alone., Patient Summary: We evaluated a new risk calculator that uses clinical information and results from two types of scan to predict the risk of clinically significant prostate cancer on prostate biopsy. This risk model can guide patients and clinicians in shared decision-making and may help in avoiding unnecessary prostate biopsies., (© 2023 The Authors.)

Importance: Prostate-specific antigen membrane positron-emission tomography (PSMA-PET) is increasingly used to guide salvage radiotherapy (sRT) after radical prostatectomy for patients with recurrent or persistent prostate cancer., Objective: To develop and validate a nomogram for prediction of freedom from biochemical failure (FFBF) after PSMA-PET-based sRT., Design, Setting, and Participants: This retrospective cohort study included 1029 patients with prostate cancer treated between July 1, 2013, and June 30, 2020, at 11 centers from 5 countries. The initial database consisted of 1221 patients. All patients had a PSMA-PET scan prior to sRT. Data were analyzed in November 2022., Exposures: Patients with a detectable post-radical prostatectomy prostate-specific antigen (PSA) level treated with sRT to the prostatic fossa with or without additional sRT to pelvic lymphatics or concurrent androgen deprivation therapy (ADT) were eligible., Main Outcomes and Measures: The FFBF rate was estimated, and a predictive nomogram was generated and validated. Biochemical relapse was defined as a PSA nadir of 0.2 ng/mL after sRT., Results: In the nomogram creation and validation process, 1029 patients (median age at sRT, 70 years [IQR, 64-74 years]) were included and further divided into a training set (n = 708), internal validation set (n = 271), and external outlier validation set (n = 50). The median follow-up was 32 months (IQR, 21-45 months). Based on the PSMA-PET scan prior to sRT, 437 patients (42.5%) had local recurrences and 313 patients (30.4%) had nodal recurrences. Pelvic lymphatics were electively irradiated for 395 patients (38.4%). All patients received sRT to the prostatic fossa: 103 (10.0%) received a dose of less than 66 Gy, 551 (53.5%) received a dose of 66 to 70 Gy, and 375 (36.5%) received a dose of more than 70 Gy. Androgen deprivation therapy was given to 325 (31.6%) patients. On multivariable Cox proportional hazards regression analysis, pre-sRT PSA level (hazard ratio [HR], 1.80 [95% CI, 1.41-2.31]), International Society of Urological Pathology grade in surgery specimen (grade 5 vs 1+2: HR, 2.39 [95% CI, 1.63-3.50], pT stage (pT3b+pT4 vs pT2: HR, 1.91 [95% CI, 1.39-2.67]), surgical margins (R0 vs R1+R2+Rx: HR, 0.60 [95% CI, 0.48-0.78]), ADT use (HR, 0.49 [95% CI, 0.37-0.65]), sRT dose (>70 vs ≤66 Gy: HR, 0.44 [95% CI, 0.29-0.67]), and nodal recurrence detected on PSMA-PET scans (HR, 1.42 [95% CI, 1.09-1.85]) were associated with FFBF. The mean (SD) nomogram concordance index for FFBF was 0.72 (0.06) for the internal validation cohort and 0.67 (0.11) in the external outlier validation cohort., Conclusions and Relevance: This cohort study of patients with prostate cancer presents an internally and externally validated nomogram that estimated individual patient outcomes after PSMA-PET-guided sRT.

Context: Prostate-specific membrane antigen (PSMA) targeting positron emission tomography (PET) is emerging to become a reference imaging tool for the staging and restaging of patients with prostate cancer for both clinical routine and trials. The prostate cancer molecular imaging standardized evaluation (PROMISE) criteria have been proposed as a framework for whole-body staging (molecular imaging TNM staging, denoted miTNM staging) to describe the prostate cancer disease extent on PSMA-PET., Objective: To create a comprehensive and integrated framework for PSMA-PET image interpretation and reporting., Evidence Acquisition: We propose the PROMISE V2 framework, which integrates an updated miTNM system, improved assessment of local disease, and a slightly modified PSMA-expression score for clinical routine. We have added a response monitoring framework defining qualitative and quantitative parameters to be recorded for a longitudinal assessment in clinical trials., Evidence Synthesis: We provide a comprehensive literature review on the current use of the PROMISE framework in clinical research and prospective trials. PROMISE variables demonstrate a clear association with survival. PSMA expression assessed by the PSMA-expression score was used in several trials, and a low PSMA-expression score is a negative prognosticator of overall survival after 177 Lu-PSMA radioligand therapy. The proposed imaging parameters recorded for response assessment in clinical trials can be utilized to determine response according to PSMA-PET progression (PPP) or Response Evaluation Criteria in PSMA-PET/Computed Tomography (RECIP) frameworks, but also future response criteria., Conclusions: PROMISE V2 offers standardized reporting of disease extent for clinical routine and research. Parameters recorded within clinical trials facilitate objective response assessment., Patient Summary: Prostate-specific membrane antigen (PSMA) targeting positron emission tomography (PET) has become a standard imaging examination for prostate cancer. We propose a comprehensive framework for the analysis and reporting of PSMA-PET findings that will improve the communication between imaging experts and uro-oncologists., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: To identify whether synchronous reading of multiparametric magnetic resonance imaging (mpMRI) and 68 Ga-PSMA-11 positron emission tomography (PET)/computed tomography (prostate-specific membrane antigen [PSMA-PET]) images can improve diagnostic performance and certainty compared with mpMRI/PSMA-PET reported independently and synthesized, while also assessing concordance between imaging modalities and agreement with histopathology., Methods: This 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., Results: 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., Conclusion: 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., (© 2022 BJU International.)

Background: 177 LuPSMA is an effective treatment in metastatic castrate-resistant prostate cancer with trials adopting a standardised dose interval. Adjusting treatment intervals utilising early response biomarkers may improve patient outcomes., Objective: This study evaluated progression-free survival (PFS) and overall survival (OS) based on treatment interval adjustment utilising 177 LuPSMA 24-h SPECT/CT ( 177 Lu-SPECT) and early prostate-specific antigen (PSA) response., Design: Retrospective analysis of a clinical 177 Lu-PSMA-I&T treatment programme., Methods: In all, 125 men were treated with 6-weekly 177 LuPSMA-I&T [median 3 cycles, interquartile range (IQR): 2-4], median dose 8.0 GBq [95% confidence interval (CI): 7.5-8.0]. Imaging screening involved 68 GaPSMA-11 PET/diagnostic CT. 177 Lu-SPECT/diagnostic CT was acquired following each therapy, and clinical assessments 3-weekly. Following dose 2 (week 6), a composite PSA and 177 Lu-SPECT/CT imaging response [partial response (PR), stable disease (SD), and progressive disease (PD)] determined ongoing management. Response group (RG) 1 (marked reduction in PSA/imaging PR) break in treatment until subsequent PSA rise, then re-treatment. RG 2 (stable or reduced PSA and/or imaging SD) 6-weekly treatments until six doses, or no longer clinically benefitting. RG 3 (rise in PSA and/or imaging PD) recommended for an alternative treatment., Results: Overall PSA50% response rate (PSARR) was 60% (75/125), median PSA-PFS 6.1 months (95%CI: 5.5-6.7), and median OS 16.8 months (95%CI: 13.5-20.1). 35% (41/116) were classified as RG 1, 34% (39/116) RG 2, and 31% (36/116) RG 3. PSARRs by RG were 95% (38/41), 74% (29/39), and 8% (3/36); median PSA-PFS rates were 12.1 months (95%CI: 9.3-17.4), 6.1 months (95%CI: 5.8-9.0), and 2.6 months (95%CI: 1.6-3.1); and OS rates were 19.2 months (95%CI: 16.8-20.7), 13.2 months (95%CI: 12.0-18.8), and 11.2 months (95%CI: 8.7-15.6) for RG 1, 2, and 3, respectively. The median months of 'treatment holiday' for RG 1 was 6.1 months (IQR: 3.4-8.7). Nine men had received prior 177 LuPSMA-617 and were retreated with 177 LuPSMA-I&T, with a PSARR of 56% on re-treatment., Conclusion: Personalising dosing regimens using early response biomarkers with 177 LuPSMA has the potential to achieve similar treatment responses to continuous dosing while allowing treatment breaks or intensification. Further evaluation of early response biomarker-guided treatment regimens in prospective trials is warranted., Plain Language Summary: Lutetium-PSMA therapy is a new therapy for metastatic prostate cancer that is well tolerated and effective. However, not all men respond equally, with some responding very well and others progressing early. Personalising treatments require tools that can accurately measure treatment responses, preferably early in the treatment course, so adjustments to treatment can be made. Lutetium-PSMA can measure tumour sites after each therapy by taking whole body 3D images at 24 h using a small radiation wave from the treatment itself. This is called a SPECT scan. Previous work has shown that both prostate-specific antigen (PSA) response and changes in tumour volume on a SPECT scan can predict how patients will respond to treatment as early as dose 2. This study demonstrates that stratifying how men are treated based on the results of the 6-week SPECT scan and PSA response potentially allows a third of men to have break in treatment and that these men have both longer time to disease progression and OS. Men with an increase in tumour volume and increase in PSA early in treatment (6 weeks) had shorter time to disease progression and OS. Men with early biomarker disease progression were offered alternative treatments early in an attempt to allow the opportunity to allow a more effective potential therapy, if one was available. The study is an analysis of a clinical programme, and was not a prospective trial. As such, there are potential biases that could influence results. Hence, while the study is encouraging for the use of early response biomarkers to guide better treatment decisions, this must be validated in a well-designed clinical trial., Competing Interests: LE – Trials support – Novartis, Astellas, grant funding support from St Vincent’s Clinic Foundation. EH – Bayer Prostate Cancer Advisory Board (2022); Merck Urothelial Cancer Advisory Board (2021); Janssen Frailty in Oncology Advisory Board (2021); Ipsen Renal Cancer Advisory Board (2020, 2022) AG – Advisory Boards BMS, Merck, MSD, Regeneron, Sun Pharma; Unrestricted research support from Astra Zeneca and Sun Pharma No other authors have declared any conflicts of interest., (© The Author(s), 2023.)

177 Lu-PSMA is an effective treatment in metastatic castration-resistant prostate cancer (mCRPC). Our ability to assess response rates and adjust treatment may be improved using predictive tools. This study aimed to evaluate change in 177 Lu-PSMA SPECT quantitative parameters to monitor treatment response. Methods: One hundred twenty-seven men with progressive mCRPC previously treated with androgen-signaling inhibition (99%) and chemotherapy (71%) received a median of 3 (interquartile range [IQR], 2-5) 8-GBq (IQR, 8-8.5 GBq) doses of 177 Lu-PSMA-I&T. Imaging included 68 Ga-PSMA-11 PET/CT (SUV max > 15 at a single site and > 10 at all sites > 2 cm), diagnostic CT, and 177 Lu SPECT/CT from vertex to mid thigh (24 h after treatment). 177 Lu SPECT/CT quantitative analysis was undertaken at cycles 1 (baseline) and 2 (week 6) of treatment. Clinical and biochemical results were assessed to evaluate prostate-specific antigen (PSA) progression-free survival (PFS) and overall survival (OS). Results: A PSA reduction of more than 50% was seen in 58% (74/127). The median PSA PFS was 6.1 mo (95% CI, 5.5-6.7), and OS was 16.8 mo (95% CI, 13.5-20.1). At the time of analysis, 41% (52/127) were deceased. At baseline and week 6, 76% (96/127) had analyzable serial 177 Lu SPECT/CT imaging. SPECT total tumor volume (TTV) was reduced between baseline and week 6 in 74% (71/96; median, -193; IQR, -486 to -41). Any increase in SPECT TTV between baseline and week 6 was associated with significantly shorter PSA PFS (hazard ratio, 2.5; 95% CI, 1.5-4.2; P = 0.0008) but not OS. Median PSA PFS in those with an increase in SPECT TTV was 3.7 mo (95% CI, 2.8-6.8), compared with 6.7 mo (95% CI, 5.8-10.6) in those with no increase in SPECT TTV. An increase in SPECT TTV greater than 20% was also associated with PSA PFS (hazard ratio, 1.9; 95% CI, 1.2-3.0; P = 0.008) but less significantly than any change in SPECT TTV. There was a significant difference in PSA PFS between patients with both increased PSA and SPECT TTV and patients with reduced SPECT TTV and PSA (median, 2.8 vs. 9.0 mo; P < 0.0001). Conclusion: Increasing PSMA SPECT TTV on quantitative 177 Lu SPECT/CT predicts short progression-free survival and may play a future role as an imaging response biomarker, identifying when to cease or intensify 177 Lu-PSMA therapy., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

177 Lu-PSMA-617 is an effective and novel treatment in metastatic castration-resistant prostate cancer (mCRPC). Our ability to assess response rates and therefore efficacy may be improved using predictive tools. This study investigated the predictive value of serial 177 Lu-PSMA-617 SPECT/CT ( 177 Lu SPECT) imaging in monitoring treatment response. Methods: Fifty-six men with progressive mCRPC previously treated with chemotherapy and novel androgen signaling inhibitor were enrolled into the LuPIN trial and received up to 6 doses of 177 Lu-PSMA-617 and a radiation sensitizer (3-(4-hydroxyphenyl)-2H-1-benzopyran-7-ol [NOX66]). 68 Ga-PSMA-11 and 18 F-FDG PET/CT were performed at study entry and exit, and 177 Lu SPECT from vertex to mid thighs was performed 24 h after each treatment. SPECT quantitative analysis was undertaken at cycles 1 (baseline) and 3 (week 12) of treatment. Results: Thirty-two of the 56 men had analyzable serial 177 Lu SPECT imaging at both cycle 1 and cycle 3. In this subgroup, median prostate-specific antigen (PSA) progression-free survival (PFS) was 6.3 mo (95% CI, 5-10 mo) and median overall survival was 12.3 mo (95% CI, 12-24 mo). The PSA 50% response rate was 63% (20/32). 177 Lu SPECT total tumor volume (SPECT TTV) was reduced in 68% (22/32; median, -0.20 m 3 [95% CI, -1.4 to -0.001]) and increased in 31% (10/32; median, 0.36 [95% CI, 0.1-1.4]). Any increase in SPECT TTV was associated with shorter PSA PFS (hazard ratio, 4.1 [95% CI, 1.5-11.2]; P = 0.006). An increase of 30% or more in SPECT TTV was also associated with a shorter PSA PFS (hazard ratio, 3.3 [95% CI, 1.3-8.6]; P =0.02). Tumoral SUV max was reduced in 91% (29/32) and SUV mean in 84% (27/32); neither was associated with PSA PFS or overall survival outcomes. PSA progression by week 12 was also associated with a shorter PSA PFS (hazard ratio, 26.5 [95% CI, 5.4-131]). In the patients with SPECT TTV progression at week 12, 50% (5/10) had no concurrent PSA progression (median PSA PFS, 4.5 mo [95% CI, 2.8-5.6 mo]), and 5 of 10 men had both PSA and SPECT TTV progression at week 12 (median PSA PFS, 2.8 mo [95% CI, 1.8-3.7 mo]). Conclusion: Increasing SPECT TTV on quantitative 177 Lu SPECT predicts a short PFS and may play a future role as an imaging response biomarker., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

177 Lu-PSMA-617 therapy has shown high prostate-specific antigen (PSA) response rates in men with metastatic castration-resistant prostate cancer. However, early treatment resistance is common. This LuPIN substudy aimed to determine the prognostic value of posttreatment quantitative PET for PSA progression-free survival (PFS) and overall survival (OS) with 177 Lu-PSMA-617 therapy. Methods: Fifty-six men with progressive metastatic castration-resistant prostate cancer were enrolled in the LuPIN trial and received up to 6 doses of 177 Lu-PSMA-617 and a radiation sensitizer (NOX66). 68 Ga-PSMA-11 and 18 F-FDG PET/CT, diagnostic CT, and bone scanning were performed at study entry and exit. Quantitative analysis tracked change in total tumor volume (TTV) and SUV. Univariable and multivariable analyses were conducted to examine the association of change in TTV (continuous and >30%), SUV max , PSA, and radiographic progression with PSA PFS and OS. Results: All men (37/56) who underwent both screening and posttreatment molecular imaging were analyzed; 70% (26/37) had a PSA response of more than 50%. Median PSA PFS was 8.6 mo, and median OS was 22 mo. Clinical progression had occurred at trial exit in 54% (20/37). In response to treatment, a reduced PSMA SUV max was demonstrated in 95% (35/37) and a reduced PSMA TTV in 68% (25/37). An increase in PSMA TTV by at least 30% was associated with worse OS (median, 10.2 vs. 23.6 mo; P = 0.002). Change in PSMA SUV max was not associated with PSA PFS or OS. 18 F-FDG SUV max was reduced in 51% (18/35) and 18 F-FDG TTV in 67% (22/35). An increased 18 F-FDG SUV max was associated with worse OS (median, 20.7 vs. 25.7 mo; P < 0.01). An 18 F-FDG TTV increase by more than 30% was associated with a short PSA PFS (median, 3.5 vs. 8.6 mo; P < 0.001) but not OS. Both PSA and radiographic progression were associated with shorter OS (median, 14.5 vs. 25.7 mo [ P < 0.001] and 12.2 vs. 23.6 mo [ P = 0.002]). On multivariable analysis, only increased PSMA TTV and PSA progression remained independently prognostic of OS (hazard ratio, 5.1 [95% CI, 1.5-17.1; P = 0.008] and 3.5 [95% CI, 1.1-10.9; P = 0.03], respectively). Conclusion: Change in quantitative PSMA TTV has strong potential as a prognostic biomarker with 177 Lu-PSMA-617 therapy, independent of 18 F-FDG PET parameters, PSA, or radiographic progression. Further research into the value of posttreatment PET as an imaging biomarker is warranted., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Our objective is to describe the distribution of local recurrences after radical prostatectomy (RP) as delineated using 68-Gallium-prostate-specific membrane antigen positron emission tomography/computed tomography ( 68 Ga-PSMA PET/CT) to identify areas where current consensus guideline clinical target volumes (CTVs) are insufficient or excessive and to identify predictors of recurrence location within the fossa., Methods and Materials: Retrospective review of databases from 2 tertiary referral centers was performed to identify patients who underwent 68 Ga-PSMA PET/CT for biochemical recurrence after RP. Those with a component of local recurrence were included for further analysis. The epicenter of each recurrence was defined relative to reference points in 3 axes, categorized into 1 of 7 levels in the superior/inferior axis relative to the vesicourethral anastomosis, and recorded as within or outside the Faculty of Radiation Oncology Genito-urinary Group (FROGG) and Radiation Therapy Oncology Group consensus CTVs. Univariate and multivariate analysis was performed to identify predictors of recurrence location based on clinical and histopathologic variables., Results: One thousand forty-nine 68 Ga-PSMA PET/CT scans were reviewed. One hundred forty sites of local recurrence were identified on 132 scans. Relative to the vesicourethral anastomosis, 13 (9%), 31 (22%), 17 (12%), 24 (17%), 27 (19%), 20 (14%), and 8 (6%) recurrences occurred >5 mm inferior; within 5 mm above or below; and 6 to 15 mm, 16 to 25 mm, 26 to 35 mm, 36 to 45 mm, and >45 mm superiorly, respectively. Thirteen (9%) and 2 (1.4%) recurrences occurred beyond the FROGG and Radiation Therapy Oncology Group consensus CTVs, respectively, with all below the inferior CTV margin., Conclusions: In the largest study to date mapping local recurrences after RP in 3-dimensions, we provide several insights to inform future contouring guidelines; in particular, 9% of recurrences occurred inferior to the FROGG CTV., (Copyright © 2022 Elsevier Inc. All rights reserved.)