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Background: Interim analysis of the ENZA-p trial showed improved prostate-specific antigen (PSA) progression-free survival with the addition of lutetium-177 [ 177 Lu]Lu-prostate-specific membrane antigen (PSMA)-617 to enzalutamide as first-line treatment of metastatic castration-resistant prostate cancer. Here, we report the secondary endpoints of overall survival and health-related quality of life (HRQOL) with longer follow-up., Methods: ENZA-p was a multicentre, open-label, randomised, phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older who had not previously been treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [ 68 Ga]Ga PSMA-PET-CT-positive disease, an 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, early docetaxel, and previous treatment with abiraterone. Treatment was 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. The primary endpoint was prostate-specific antigen (PSA) progression-free survival, which has been previously reported. Overall survival, defined as the interval from the date of randomisation to date of death from any cause, or the date last known alive, and HRQOL were key secondary endpoints. HRQOL was assessed with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and the Patient Disease and Treatment Assessment Form. For HRQOL analyses, deterioration-free survival was measured from randomisation until the earliest occurrence of death, clinical progression, discontinuation of study treatment; or a worsening of 10 points or more from baseline in physical function, or in overall health and QOL. Analyses of these secondary endpoints were prespecified and are by intention to treat. The trial is registered with ClinicalTrials.gov, NCT04419402, and follow-up is complete., Findings: Between Aug 17, 2020, and July 26, 2022, 79 patients were randomly assigned to enzalutamide and 83 to enzalutamide plus [ 177 Lu]Lu-PSMA-617. 96 deaths was reported after a median follow-up of 34 months (IQR 29-39): 53 (67%) in the enzalutamide group and 43 (52%) in the enzalutamide plus [ 177 Lu]Lu-PSMA-617 group. Overall survival was longer in the enzalutamide plus [ 177 Lu]Lu-PSMA-617 group than the enzalutamide group (median 34 months [95% CI 30-37] vs 26 months [23-31]; HR 0·55 [95% CI 0·36-0·84], log-rank p=0·0053). HRQOL was rated by 154 (95%) of 162 participants. Deterioration-free survival at 12 months and stratified log-rank p values favoured enzalutamide plus [ 177 Lu]Lu-PSMA-617 for both physical function (median 10·64 months [95% CI 7·66-12·42] vs 3·42 months [3·19-7·89]; HR 0·51 [95% CI 0·36-0·72], log-rank p<0·0001) and overall health and QOL (8·71 months [6·41-11·56] vs 3·32 months [3·09-5·26]; HR 0·47 [95% CI 0·33-0·67], log-rank p=0·0001). Mean scores for pain until progression favoured enzalutamide plus [ 177 Lu]Lu-PSMA-617 over enzalutamide (difference 7·3 [95% CI 1·6-12·9]; p=0·012). Mean scores for fatigue until progression favoured enzalutamide plus [ 177 Lu]Lu-PSMA-617 over enzalutamide (difference 5·9 [95% CI 1·1-10·7]; p=0·016). The frequency of self-rated xerostomia was lower in the enzalutamide group than in the enzalutamide plus [ 177 Lu]Lu-PSMA-617 group (43 [57%] of 75 vs 58 [74%] of 78; p=0·039), and scores were not significantly different between groups for all other domains. Grade 3-5 adverse events occurred in 35 (44%) of 79 patients in the enzalutamide group and 37 (46%) of 81 patients in the enzalutamide plus [ 177 Lu]Lu-PSMA-617 group. No deaths were attributed to study treatment in either group., Interpretation: The addition of [ 177 Lu] Lu-PSMA-617 to enzalutamide was associated with improved survival and some aspects of HRQOL in patients with high-risk metastatic castration-resistant prostate cancer. Our findings warrant phase 3 evaluation of adaptive-dosed [ 177 Lu] Lu-PSMA-617 in combination with androgen receptor pathway inhibitors in people with metastatic prostate cancer., Funding: The Prostate Cancer Research Alliance initiative (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, RoyMorgan, AdAcAp (a Novartis company), and Astellas., 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, Advancell, 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. 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; 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, Australian 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 the Peter MacCallum Cancer Centre and the University of Melbourne (Melbourne, VIC, Australia). 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 Australian 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. AR reports honoraria and speakers fees from AstraZeneca, Daiichi Sankyo, Roche, Novartis, and Pfizer. 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. LK reports advisory board fees from MSD, Bayer, Bristol Myers Squibb, Merk, Ipsen, Janssen-Cilag, Telix, Roche, AstraZeneca, and Astellas and speakers bureau fees from Ipsen, Janssen-Cilag, MSD, Bayer, Merk, Bristol Myers Squibb, and Astellas. 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. All other authors declare no competing interests., (Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

[ 177 Lu]Lu-prostate-specific membrane antigen (PSMA)-617 is a standard treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel and an androgen receptor pathway inhibitor. However, for many, responses are short and progression is inevitable. Contributing factors to treatment resistance include molecular heterogeneity with variable PSMA expression, micrometastases that may not absorb sufficient radiation from 177 Lu to result in cell death, and inherent or acquired radioresistance because of genomic alterations or the tumor microenvironment. Cabazitaxel is a radiosensitizer and may treat PSMA-negative disease that would otherwise evade targeting by [ 177 Lu]Lu-PSMA-617. We hypothesize that the combination of [ 177 Lu]Lu-PSMA-617 and cabazitaxel will be synergistic with an acceptable safety profile. Methods: This investigator-initiated phase I-II trial aims to evaluate the safety, tolerability, and preliminary efficacy of cabazitaxel and [ 177 Lu]Lu-PSMA-617 in combination. Up to 38 patients with mCRPC will receive up to 6 doses of [ 177 Lu]Lu-PSMA-617 administered intravenously every 6 wk at a fixed dose of 7.4 GBq. Cabazitaxel will be administered concurrently (dose range, 12.5-20 mg/m 2 ) on day 2 and day 23 of each 6-wk cycle, with dose escalation determined using a traditional 3 + 3 design to establish the maximum tolerated or administered dose. Key eligibility criteria include a diagnosis of progressive mCRPC with PSMA-positive disease on PSMA PET/CT (SUV max ≥ 15) and no sites of discordance on [ 18 F]F-FDG PET/CT. Patients must have received prior docetaxel and an androgen receptor pathway inhibitor, have adequate bone marrow and organ function, and have an Eastern Cooperative Oncology Group performance status of 0 or 1. The primary objective is to assess for dose-limiting toxicities and determine the recommended phase II dose of cabazitaxel and [ 177 Lu]Lu-PSMA-617 in combination. Secondary objectives include further safety evaluation through the measurement of the frequency and severity of adverse events, assessment of efficacy, and evaluation of changes in pain and health-related quality of life over the first 12 mo from treatment commencement. Plasma will be collected at baseline, during treatment, and at disease progression for circulating tumor DNA analysis, which will be correlated with clinical outcomes to identify potential biomarkers of treatment response or resistance. Conclusion: Enrollment commenced in August 2022, with anticipated completion in 2025., (© 2025 by the Society of Nuclear Medicine and Molecular Imaging.)

Background and Objective: Patients receiving immune checkpoint blockade (ICB) therapy may experience periods of prolonged disease control without a need for systemic therapy. Treatment-free survival (TFS) is an important measure for this period, but no data are available for patients with metastatic renal cell carcinoma (mRCC) starting first-line agents. Our aim was to analyze TFS outcomes for patients with mRCC starting first-line therapy., Methods: We analyzed data for patients with mRCC starting first-line systemic therapy with VEGFR-targeted monotherapy, an ICB + VEGFR combination, or an ICB doublet from February 1, 2014 to February 1, 2023 from the multicenter International Metastatic RCC Database Consortium (IMDC) database. We estimated 36-mo TFS as the difference in restricted mean survival time between (1) the time to first-line therapy discontinuation and (2) the time to subsequent systemic therapy initiation., Key Findings and Limitations: The study population included 3758 patients receiving either first-line VEGFR monotherapy (n = 2635), an ICB + VEGFR combination (n = 354), or doublet ICB (n = 769) were included. For the IMDC favorable-risk cohort, the 36-mo TFS estimate was 3.1 mo (95% confidence interval [CI] 1.5-4.6) for the VEGFR monotherapy group and 3.7 mo (95% CI 0.2-7.2) for the ICB + VEGFR group. For the IMDC intermediate-/poor-risk cohort, TFS was 2.1 mo (95% CI 1.4-2.8) for the VEGFR monotherapy group, 3.7 mo (95% CI 1.0-6.4) for the ICB + VEGFR group, and 5.3 mo (95% CI 3.8-6.8) for ICB doublet group. Limitations include the retrospective design and an inability to quantify time spent with adverse events., Conclusions and Clinical Implications: Our study demonstrates that patients with IMDC intermediate or poor risk treated with ICB doublet therapy experienced longer TFS than those treated with VEGFR monotherapy in the first-line setting. These results emphasize the utility of TFS as an informative endpoint and provide survival estimates to inform decision-making in mRCC., Patient Summary: For patients with metastatic kidney cancer, we compared the survival time free from a second treatment line for different first-line treatment options. The results show that the time free from second-line treatment was longer when first-line treatment was with a combination of two immunotherapy drugs (ipilimumab and nivolumab) in comparison to other treatment options., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

[ 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.)

Despite a high detection rate of 68 Ga-prostate-specific membrane antigen (PSMA) PET/CT in biochemical recurrence (BCR) of prostate cancer, a significant proportion of men have negative 68 Ga-PSMA-11 PET/CT results. Gastrin-releasing peptide receptor, targeted by the copper-chelated bombesin analog 64 Cu-sarcophagine-bombesin (SAR-BBN) PET/CT, is also overexpressed in prostate cancer. In this prospective imaging study, we investigate the detection rate of 64 Cu-SAR-BBN PET/CT in patients with BCR and negative or equivocal 68 Ga-PSMA-11 PET/CT results. Methods: Men with confirmed adenocarcinoma of the prostate, prior definitive therapy, and BCR (defined as a prostate-specific antigen [PSA] level > 0.2 ng/mL) with negative or equivocal 68 Ga-PSMA-11 PET/CT results within 3 mo were eligible for enrollment. 64 Cu-SAR-BBN PET/CT scans were acquired at 1 and 3 h after administration of 200 MBq of 64 Cu-SAR-BBN, with further delayed imaging undertaken optionally at 24 h. PSA (ng/mL) was determined at baseline. All PET (PSMA and bombesin) scans were assessed visually. Images were read with masking of the clinical results by 2 experienced nuclear medicine specialists, with a third reader in cases of discordance. Accuracy was defined using a standard of truth that included biopsy confirmation, confirmatory imaging, or response to targeted treatment. Results: Twenty-five patients were enrolled. Prior definitive therapy was radical prostatectomy ( n = 24, 96%) or radiotherapy ( n = 1, 4%). The median time since definitive therapy was 7 y (interquartile range [IQR], 4-11 y), and the Gleason score was 7 or less ( n = 15, 60%), 8 ( n = 3, 12%), or 9 ( n = 7, 28%). The median PSA was 0.69 ng/mL (IQR, 0.28-2.45 ng/mL). Baseline PSMA PET scans were negative in 19 patients (76%) and equivocal in 6 (24%). 64 Cu-SAR-BBN PET-avid disease was identified in 44% (11/25): 12% (3/25) with local recurrence, 20% (5/25) with pelvic node metastases, and 12% (3/25) with distant metastases. The κ-score between readers was 0.49 (95% CI, 0.16-0.82). Patients were followed up for a median of 10 mo (IQR, 9-12 mo). Bombesin PET/CT results were true-positive in 5 of 25 patients (20%), false-positive in 2 of 25 (8%), false-negative in 7 of 25 (28%), and unverified in 11 of 25 (44%). Conclusion: 64 Cu-SAR-BBN PET/CT demonstrated sites of disease recurrence in 44% of BCR cases with negative or equivocal 68 Ga-PSMA-11 PET/CT results. Further evaluation to confirm diagnostic benefit is warranted., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

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: 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: 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.)

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.)

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-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.)

Metastatic prostate cancer remains a major clinical challenge and metastatic lesions are highly heterogeneous and difficult to biopsy. Liquid biopsy provides opportunities to gain insights into the underlying biology. Here, using the highly sensitive enrichment-based sequencing technology, we provide analysis of 60 and 175 plasma DNA methylomes from patients with localized and metastatic prostate cancer, respectively. We show that the cell-free DNA methylome can capture variations beyond the tumor. A global hypermethylation in metastatic samples is observed, coupled with hypomethylation in the pericentromeric regions. Hypermethylation at the promoter of a glucocorticoid receptor gene NR3C1 is associated with a decreased immune signature. The cell-free DNA methylome is reflective of clinical outcomes and can distinguish different disease types with 0.989 prediction accuracy. Finally, we show the ability of predicting copy number alterations from the data, providing opportunities for joint genetic and epigenetic analysis on limited biological samples., (© 2022. The Author(s).)

Background: Statins and metformin are commonly prescribed for patients, including those with prostate cancer. Preclinical and epidemiologic studies of each agent have suggested anti-cancer properties., Methods: Patient data from three randomised, double-blind, placebo-controlled, phase III studies evaluating enzalutamide (AFFIRM, PREVAIL and PROSPER) in patients with castration-resistant prostate cancer were included in this analysis. This post hoc, retrospective study examined the association of statin and metformin on radiographic progression-free survival (rPFS), metastasis-free survival (MFS), toxicity and overall survival (OS). After adjusting for available clinical prognostic variables, multivariate analyses were performed on pooled data from AFFIRM and PREVAIL, all three trials pooled, and each trial individually, to assess differential efficacy in these end-points associated with the baseline use of these medications., Results: In the multivariate analysis of the individual trials, OS and rPFS/MFS were not significantly influenced by statin or metformin use in AFFIRM or PROSPER. However, in PREVAIL, OS was significantly influenced by statin (hazard ratio [HR] 0.72; 95% confidence interval [CI] 0.59-0.89) and rPFS was significantly influenced by metformin (HR, 0.48; 95% CI 0.34-0.70). In pooled analyses, improved OS was significantly associated with statin use but not metformin use for AFFIRM+PREVAIL trials (HR 0.83; 95% CI 0.72-0.96) and AFFIRM+PREVAIL+PROSPER (HR 0.75; 95% CI 0.66-0.85)., Conclusions: The association between statin or metformin use and rPFS, MFS and OS was inconsistent across three trials. Analyses of all three trials pooled and AFFIRM+PREVAIL pooled revealed that statin but not metformin use was significantly associated with a reduced risk of death in enzalutamide-treated patients. Additional prospective, controlled studies are warranted., Clinical Trial Registration: AFFIRM (NCT00974311), PREVAIL (NCT01212991) and PROSPER (NCT02003924)., Competing Interests: Conflict of interest statement AMJ declares consultant/advisory board member for Neokulin, Janssen Oncology, Ipsen, AstraZeneca, Sanfoi, Noxopharm, IQvia, Pfizer, Novartis, Bristol Myers Squibb, Merck Serono, Eisai. AMJ has received research funding from: Bristol Myers Squibb, Janssen Oncology, Merck Sharp & Dohme, Mayne Pharma, Roche/Genetech, Bayer, Macrogenics, Lilly, Pfizer, AstraZeneca, and Corvus Pharmaceuticals. AA is a paid consultant for and/or receives institutional funding from Astellas, Pfizer, Janssen, Bayer, Dendreon, Genentech/Roche, Bristol Myers Squibb, Merck, and AstraZeneca. AA provides research support to Duke University from Constellation, Beigene, Amgen, Celgene, and Forma. MC has received honoraria from Pfizer and Merck Healthcare. HIS declares consultant/advisory board member for Ambry Genetics Corporation, Amgen, Bayer, ESSA Pharma, Janssen Biotech, Janssen Research & Development, OncLive Insights, Menarini Silicon Biosystems, Physicians Education Resource, Pfizer, Sanofi Aventis, Sun Pharmaceuticals Industries, Inc. and WCG Oncology; Board of Directors’ Member of Asterias Biotherapeutics; Intellectual Property Rights BioNTech, Elucida Oncology, MaBVAX, Y-mAbs Therapeutics, Inc and institutional research funding from Epic Sciences, Illumina, Janssen Diagnostics, Menarini Silicon Biosystems, and ThermoFisher. JDB has served on advisory boards and received fees from Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals. He is an employee of the ICR, which has received funding or other support for his research work from Astellas, AstraZeneca, Bayer, Cellcentric, Daiichi, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals, and which has a commercial interest in abiraterone, PARP inhibition in DNA repair defective cancers and PI3K/AKT pathway inhibitors (no personal income). He was named as an inventor, with no financial interest, for patent 8,822,438. BT has financial or personal interests with AAA International, Astellas, Bayer, Ferring, Janssen, Myovant and Sanofi. MH over the last three years reports receiving lecture fees and travel support from Astellas Pharma, grant support, paid to Northwestern University, from AstraZeneca, grant support, paid to Northwestern University, and advisory board fees from Bayer, advisory board fees from Daiichi Sankyo, Bristol Myers Squibb, grant support, paid to Northwestern University, and advisory board fees from Genentech, grant support, paid to the University of Michigan, from Pfizer, and lecture fees from Sanofi and Genzyme. CNS is a consultant for Pfizer, Merck Sharp & Dohme, Merck, AstraZeneca, Astellas, Sanofi-Genzyme Roche-Genentech, Incyte, Clovis Oncology, Inc, Medscape, UroToday, Janssen Oncology, Foundation Medicine, Bristol Meyers Squibb, Immunomedics (now Gilead). SG in the last three years has received honoraria compensation from Janssen Cilag; served in a consulting or advisory role (including IDMC) to Astellas Pharma, Amgen, Roche, Pfizer, AAA International, Janssen, Innocrin Pharma Inst, Sanofi, Bayer, Orion Pharma GmbH, Clovis Oncology, Menarini Silicon Biosystems, Tolero Pharmaceuticals and Merck Sharp & Dohme; Patents, royalties, other intellectual property include Method for biomarker WO2009138392; Travel grant from ProteoMediX; Other relationships include Aranda. JC is a paid consultant with Amgen, Astellas, Bayer, Bristol Myers Squibb, Merck Sharp & Dohme, Johnson & Johnson, Sanofi, Pfizer; is a member of the Speakers Bureau for Astellas, Bayer, Johnson & Johnson; has engaged in institutional study collaboration with AB Science, Aragon Pharmaceuticals, Arog Pharmaceuticals, Inc, Astellas Pharma., AstraZeneca AB, Aveo Pharmaceuticals Inc, Bayer AG, Blueprint Medicines Corporation, BN Immunotherapeutics Inc, Boehringer Ingelheim España, S.A., Bristol Myers Squibb International Corporation, Clovis Oncology, Inc, Cougar Biotechnology Inc, Deciphera Pharmaceuticals LLC, Exelixis Inc, F. Hoffmann-La Roche LTD, Genentech Inc, Glaxosmithkline, SA, Incyte Corporation, Janssen-Cilag International NV, Karyopharm Therapeutics Inc, Laboratoires Leurquin Mediolanum SAS, Lilly, S.A., Medimmune, Millennium Pharmaceuticals, Inc, Nanobiotix SA, Novartis Farmacéutica, S.A., Pfizer, S.L.U, Puma Biotechnology, Inc, Sanofi-Aventis, S.A., SFJ Pharma LTD. II, Teva Pharma S.L.U. KF has participated on advisory boards and symposia for: Astellas, Bayer, Clovis, Curevac, Janssen, Merck Sharp & Dohme, Orion, Sanofi. PL declares no conflict of interest. WD is an employee of Pfizer and owns stock in the company. JS is an employee of Astellas. DR is an employee of Pfizer. TMB in the past year reports: institutional research funding from Alliance Foundation Trials, Astellas Pharma, Bayer, Boehringer Ingelheim, Corcept Therapeutics, Endocyte Inc., Freenome, Grail Inc, Harpoon Therapeutics, Janssen Research & Development, Medivation, Inc., Sotio, Theraclone Sciences/OncoResponse, and Zenith Epigenetics; has consulted for: Arvinas, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Constellation, Grail Inc, Janssen, Myovant Sciences, Pfizer, and Sanofi, and holds stock in Arvinas Inc, and Salarius Pharmaceuticals., (Copyright © 2022 The Pfizer, The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The evaluation of tumour-infiltrating lymphocytes (TILs) in solid malignancies has yielded insights into immune regulation within the tumour microenvironment and has also led to the development and optimisation of adoptive T cell therapies., Objectives: This study examined the in vitro expansion of TILs from prostate adenocarcinoma, as a preliminary step to evaluate the potential of TILs for adoptive T cell therapy. Design, Setting, and Participants . Malignant and adjacent nonmalignant tissues were obtained from fifteen men undergoing radical prostatectomy. Interventions . There were no study interventions. Outcome Measurements and Statistical Analysis . Expanded cells were analysed by flow cytometry, and the data was assessed for associations between cell subpopulations and expansion rate., Results: Tumour-infiltrating lymphocytes could be expanded to numbers that would be needed to generate a therapeutic infusion product from nine of 15 malignant specimens (60%). The CD4 + T cells predominated over CD8 + T cells (median 56.8% CD4 + , 30.0% CD8 + ), and furthermore, faster TIL expansion was associated with a higher proportion of CD4 + T cells (median 69.8% in faster-growing cultures; 36.8% in slower-growing cultures). A higher proportion of CD3 - CD56 + cells versus CD3 + cells was associated with slower TIL expansion in cultures from malignant specimens (median 13.3% in slower-growing cultures versus 2.05% in faster-growing cultures), but not from nonmalignant specimens., Conclusions: The expansion of TILs for potential therapeutic use is feasible. Our findings also indicate that further examination of TILs from prostate adenocarcinomas may yield insights into mechanisms of regulation of T cells within the tumour microenvironment. Further research is required to evaluate their therapeutic potential., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Linh T. Nguyen et al.)

Aim: Carcinoid heart disease (CHD) is a well-documented complication of neuroendocrine tumors (NETs) due to secreted hormones causing fibrosis. Somatostatin analogues (SSAs) can decrease hormonal secretion and inhibit tumor growth. The reported incidence of CHD has decreased as SSA use has increased. We describe a series of patients who have developed CHD even though they were treated with SSA therapy., Methods: Nine patients were seen in four centers in Australia and New Zealand. The average duration of follow-up from diagnosis was 39 months., Results: Three patients had Grade 1 and six Grade 2 disease by World Health Organization 2010 criteria. All patients had no CHD symptoms at baseline and started SSA therapy soon after diagnosis, yet developed significant, symptomatic cardiac dysfunction in their disease course. The median time from NET diagnosis to SSA initiation was 1 month, and median time from NET diagnosis to CHD diagnosis was 23 months (range 4-52). All patients who were tested had persistently increased hormonal levels (chromogranin A, urinary 5-hydroxyindolacetic acid)., Conclusions: The good symptomatic control afforded by SSAs should not lead to reduced vigilance in screening for CHD, especially in patients with persistently elevated hormonal assays. Clinicians should consider regular echocardiographic screening in patients with a secretory syndrome., (© 2021 John Wiley & Sons Australia, Ltd.)

Objective: To determine the efficacy and safety of intermittent docetaxel chemotherapy guided by circulating methylated glutathione S-transferase Pi-1 ( mGSTP1 ) in men with metastatic castration-resistant prostate cancer (CRPC)., Patients and Methods: GUIDE (NCT04918810) is a randomised, two-arm, non-comparative phase-2 trial recruiting 120 patients at six Australian centres. Patients with Prostate Cancer Working Group-3 defined metastatic CRPC who are commencing docetaxel 75 mg/m 2 q3w will be pre-screened for detectable mGSTP1 at baseline ± following two cycles of treatment. Those with detectable plasma mGSTP1 at baseline that becomes undetectable after two cycles of chemotherapy will be eligible for GUIDE. Prior to Cycle 4 of docetaxel, these patients are randomised 2:1 to one of two treatment arms: Arm A (cease docetaxel and reinstitute if mGSTP1 becomes detectable) or Arm B (continue docetaxel 75 mg/m 2 q3w in accordance with clinician's usual practice). The primary endpoint is radiographic progression-free survival. Secondary endpoints include time on treatment holidays, safety, patient-reported outcomes, overall survival, health resource use, and cost associated with treatment. Enrolment commenced November 2021., Results and Conclusion: The results of this trial will generate data on the clinical utility of mGSTP1 as a novel biomarker to guide treatment de-escalation in metastatic CRPC., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

177 Lu-PSMA-617 is an effective therapy for metastatic castration-resistant prostate cancer (mCRPC). However, treatment resistance occurs frequently, and combination therapies may improve outcomes. We report the final safety and efficacy results of a phase I/II study combining 177 Lu-PSMA-617 with idronoxil (NOX66), a radiosensitizer, and examine potential clinical, blood-based, and imaging biomarkers. Methods: Fifty-six men with progressive mCRPC previously treated with taxane chemotherapy and novel androgen signaling inhibitor (ASI) were enrolled. Patients received up to 6 doses of 177 Lu-PSMA-617 (7.5 GBq) on day 1 in combination with a NOX66 suppository on days 1-10 of each 6-wk cycle. Cohort 1 ( n  = 8) received 400 mg of NOX66, cohort 2 ( n  = 24) received 800 mg, and cohort 3 ( n  = 24) received 1,200 mg. 68 Ga-PSMA and 18 F-FDG PET/CT were performed at study entry, and semiquantitative imaging analysis was undertaken. Blood samples were collected for analysis of blood-based biomarkers, including androgen receptor splice variant 7 expression. The primary outcomes were safety and tolerability; secondary outcomes included efficacy, pain scores, and xerostomia. Regression analyses were performed to explore the prognostic value of baseline clinical, blood-based, and imaging parameters. Results: Fifty-six of the 100 men screened were enrolled (56%), with a screening failure rate of 26% (26/100) for PET imaging criteria. All men had received prior treatment with ASI and docetaxel, and 95% (53/56) had received cabazitaxel. Ninety-six percent (54/56) of patients received at least 2 cycles of combination NOX66 and 177 Lu-PSMA-617, and 46% (26/56) completed 6 cycles. Common adverse events were anemia, fatigue, and xerostomia. Anal irritation attributable to NOX66 occurred in 38%. Forty-eight of 56 had a reduction in prostate-specific antigen (PSA) level (86%; 95% CI, 74%-94%); 34 of 56 (61%; 95% CI, 47%-74%) had a PSA reduction of at least 50%. Median PSA progression-free survival was 7.5 mo (95% CI, 5.9-9 mo), and median overall survival was 19.7 mo (95% CI, 9.5-30 mo). A higher PSMA SUV mean correlated with treatment response, whereas a higher PSMA tumor volume and prior treatment with ASI for less than 12 mo were associated with worse overall survival. Conclusion: NOX66 with 177 Lu-PSMA-617 is a safe and feasible strategy in men being treated with third-line therapy and beyond for mCRPC. PSMA SUV mean , PSMA-avid tumor volume, and duration of treatment with ASI were independently associated with outcome., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Aim: To evaluate disease presentation, treatment practices, and outcomes of patients with germ cell tumor (GCT) treated in a high-volume cancer center in Australia., Methods: This is a retrospective analysis of 609 patients diagnosed with GCT in the Sydney West Cancer Network between 1990 and 2013. Cause and date of death, and second malignancy information was sourced from The Centre for Health Record Linkage., Results: The median age was 33 years (range, 14-85). Primary site was testis in 590 (96.9%), mediastinum in nine (1.5%), and retroperitoneum in nine (1.5%). History of undescended testis was present in 48 (7.9%). Pure seminoma was seen in 334 (54.8%), with 274 (82.0%) being stage I. There was a decline in use of adjuvant radiotherapy from 83% in 1990-1997 to 29% in 2006-2013. Nonseminoma GCT (NSGCT) was diagnosed in 275 (45.2%), with 162 (58.9%) being stage 1. Active surveillance has increased as the initial treatment, from 58% between 1990 and 1997 to 89% between 2006 and 2013. Metastatic disease at presentation was seen in 162 (26.6%): 55 (34.0%) seminoma and 107 (66.0%) NSGCT. With median of 15-year follow-up, 18 (3.0%) have died from GCT and 70 (11.5%) from all causes. Ten-year overall survival was 93% and GCT-specific survival was 97%. Forty patients developed a secondary malignancy, with 38 receiving chemotherapy, radiotherapy, or both., Conclusions: This large Australian series illustrates a changing pattern of care and outcomes and compares them favorably with other series. This serves as a basis for future comparison of outcomes for this malignancy., (© 2021 John Wiley & Sons Australia, Ltd.)

Background: Both changes in circulating lipids represented by a validated poor prognostic 3-lipid signature (3LS) and somatic tumour genetic aberrations are individually associated with worse clinical outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). A key question is how the lipid environment and the cancer genome are interrelated in order to exploit this therapeutically. We assessed the association between the poor prognostic 3-lipid signature (3LS), somatic genetic aberrations and clinical outcomes in mCRPC., Methods: We performed plasma lipidomic analysis and cell-free DNA (cfDNA) sequencing on 106 men with mCRPC commencing docetaxel, cabazitaxel, abiraterone or enzalutamide (discovery cohort) and 94 men with mCRPC commencing docetaxel (validation cohort). Differences in lipid levels between men ± somatic genetic aberrations were assessed with t-tests. Associations between the 3LS and genetic aberrations with overall survival (OS) were examined using Kaplan-Meier methods and Cox proportional hazard models., Results: The 3LS was associated with shorter OS in the discovery (hazard ratio [HR] 2.15, 95% confidence interval [CI] 1.4-3.3, p < 0.001) and validation cohorts (HR 2.32, 95% CI 1.59-3.38, p < 0.001). Elevated plasma sphingolipids were associated with AR, TP53, RB1 and PI3K aberrations (p < 0.05). Men with both the 3LS and aberrations in AR, TP53, RB1 or PI3K had shorter OS than men with neither in both cohorts (p ≤ 0.001). The presence of 3LS and/or genetic aberration was independently associated with shorter OS for men with AR, TP53, RB1 and PI3K aberrations (p < 0.02). Furthermore, aggressive-variant prostate cancer (AVPC), defined as 2 or more aberrations in TP53, RB1 and/or PTEN, was associated with elevated sphingolipids. The combination of AVPC and 3LS predicted for a median survival of ~12 months. The relatively small sample size of the cohorts limits clinical applicability and warrants future studies., Conclusions: Elevated circulating sphingolipids were associated with AR, TP53, RB1, PI3K and AVPC aberrations in mCRPC, and the combination of lipid and genetic abnormalities conferred a worse prognosis. These findings suggest that certain genotypes in mCRPC may benefit from metabolic therapies., (© 2022. The Author(s).)

Background: Trials of lutetium prostate specific membrane antigen (PSMA) in men with metastatic castration-resistant prostate cancer (mCRPC) have demonstrated good safety and efficacy, but combination strategies may improve outcomes. Idronoxil is a synthetic flavonoid derivative with radiosensitising properties., Objective: To evaluate the safety and activity of 177 Lu PSMA 617 (LuPSMA-617) in combination with idronoxil suppositories (NOX66) in patients with end-stage mCRPC., Design, Setting, and Participants: Thirty-two men with progressive mCRPC previously treated with taxane-based chemotherapy (91% treated with both docetaxel and cabazitaxel) and abiraterone and/or enzalutamide were enrolled in this phase I dose escalation study with phase II dose expansion., Intervention: Screening with 68 Ga PSMA and 18 F-fludeoxyglucose positron emission tomography (PET)/computed tomography (CT) was performed. Men received up to six cycles of LuPSMA-617 (7.5 GBq) on day 1, with escalating doses of NOX66 on days 1-10 of a 6-wk cycle. Cohort 1 (n = 8) received 400 mg and cohort 2 (n = 24) 800 mg of NOX66., Outcome Measurements and Statistical Analysis: Adverse events (AEs), pain inventory scores, prostate-specific antigen (PSA) response, progression-free survival, and overall survival were evaluated., Results and Limitations: Fifty-six men were screened and 32 (57%) were enrolled with a screen failure rate of 21% for PET imaging criteria. Dosing was as follows: 97% (31/32) received two or more doses and 47% (15/32) completed six doses. Common AEs included xerostomia, fatigue, and anaemia. Anal irritation attributable to NOX66 occurred in 28%. PSA responses were as follows: 91% (29/32) had any PSA response (median -74%; 95% confidence interval [CI] 76-97) and 62.5% (20/32) had a PSA fall of >50% (95% CI 45-77). The median PSA progression-free survival was 6.1 mo (95% CI 2.8-9.2) and median overall survival was 17.1 mo (95% CI 6.5-27.1)., Conclusions: NOX66 with LuPSMA-617 is a safe and feasible therapeutic strategy in men treated with third-line therapy and beyond for mCRPC., Patient Summary: Addition of NOX66 to 177 Lu prostate-specific membrane antigen 617 is safe, and further studies are needed to assess its potential to augment the anticancer effects of LuPSMA-617., (Copyright © 2020 European Association of Urology. All rights reserved.)

Objectives: To determine the activity and safety of lutetium-177 ( 177 Lu)-prostate-specific membrane antigen (PSMA)-617 in men with metastatic castration-resistant prostate cancer (mCRPC) commencing enzalutamide, who are at high risk of early progression, and to identify potential prognostic and predictive biomarkers from imaging, blood and tissue., Participants and Methods: ENZA-p (ANZUP 1901) is an open-label, randomized, two-arm, multicentre, phase 2 trial. Participants are randomly assigned (1:1) to treatment with enzalutamide 160 mg daily alone or enzalutamide plus 177 Lu-PSMA-617 7.5 GBq on Days 15 and 57. Two additional 177 Lu-PSMA-617 doses are allowed, informed by Day-92 Gallium-68 ( 68 Ga)-PSMA positron emission tomography (PET; up to four doses in total). The primary endpoint is prostate-specific antigen (PSA) progression-free survival (PFS). Other major endpoints include radiological PFS, PSA response rate, overall survival, health-related quality of life, adverse events and cost-effectiveness. Key eligibility criteria include: biochemical and/or clinical progression; 68 Ga-PSMA PET-avid disease; no prior androgen signalling inhibitor, excepting abiraterone; no prior chemotherapy for mCRPC; and ≥2 high-risk features for early enzalutamide failure. Assessments are 4 weekly during study treatment, then 6 weekly until radiographic progression. Response Evaluation Criteria in Solid Tumours (RECIST) are used to assess imaging conducted every 12 weeks, 68 Ga-PSMA PET at baseline, Days 15 and 92, and at progression, and 18 F-fluorine deoxyglucose ( 18 F-FDG) PET at baseline and progression. Translational samples include blood (and optional biopsies) at baseline, Day 92, and first progression. Correlative studies include identification of prognostic and predictive biomarkers from 68 Ga-PSMA and 18 F-FDG PET/CT, circulating tumour cells and circulating tumour DNA. The trial will enrol 160 participants, providing 80% power with a two-sided type-1 error rate of 5% to detect a hazard ratio of 0.625 assuming a median PSA-PFS of 5 months with enzalutamide alone., Results and Conclusion: The combination of 177 Lu-PSMA-617 and enzalutamide may be synergistic. ENZA-p will determine the safety and efficacy of the combination in addition to developing predictive and prognostic biomarkers to better guide treatment decisions., (© 2021 The Authors BJU International © 2021 BJU International.)

Background: Intrinsic resistance to androgen receptor signalling inhibitors (ARSI) occurs in 20-30% of men with metastatic castration-resistant prostate cancer (mCRPC). Ceramide metabolism may have a role in ARSI resistance. Our study's aim is to investigate the association of the ceramide-sphingosine-1-phosphate (ceramide-S1P) signalling axis with ARSI resistance in mCRPC., Methods: Lipidomic analysis (∼700 lipids) was performed on plasma collected from 132 men with mCRPC, before commencing enzalutamide or abiraterone. AR gene aberrations in 77 of these men were identified by deep sequencing of circulating tumour DNA. Associations between circulating lipids, radiological progression-free survival (rPFS) and overall survival (OS) were examined by Cox regression. Inhibition of ceramide-S1P signalling with sphingosine kinase (SPHK) inhibitors (PF-543 and ABC294640) on enzalutamide efficacy was investigated with in vitro assays, and transcriptomic and lipidomic analyses of prostate cancer (PC) cell lines (LNCaP, C42B, 22Rv1)., Findings: Men with elevated circulating ceramide levels had shorter rPFS (HR=2·3, 95% CI=1·5-3·6, p = 0·0004) and shorter OS (HR=2·3, 95% CI=1·4-36, p = 0·0005). The combined presence of an AR aberration with elevated ceramide levels conferred a worse prognosis than the presence of only one or none of these characteristics (median rPFS time = 3·9 vs 8·3 vs 17·7 months; median OS time = 8·9 vs 19·8 vs 34·4 months). SPHK inhibitors enhanced enzalutamide efficacy in PC cell lines. Transcriptomic and lipidomic analyses indicated that enzalutamide combined with SPHK inhibition enhanced PC cell death by SREBP-induced lipotoxicity., Interpretation: Ceramide-S1P signalling promotes ARSI resistance, which can be reversed with SPHK inhibitors., Funding: None., Competing Interests: Declaration of Competing Interest E.M.K.: Honoraria – Janssen, Ipsen, Astellas Pharma, Research Review; Consulting or Advisory Role – Astellas Pharma, Janssen, Ipsen; Research Funding – Astellas Pharma, AstraZeneca; Travel & accommodation – Astellas Pharma, Pfizer, Ipsen, Roche.B.T.: Grants and personal fees – Amgen, AstraZeneca, Astellas, BMS, Janssen, Pfizer, MSD, Ipsen, Bayer; Personal fees – IQVIA, Sanofi, Tolmar, Novartis, Roche.A.Z.: Advisory Role – Astellas; Honoraria – Astellas; Grants and personal fees – Astra Zeneca, Pfizer; Personal fees – Merck Sharp & Dome, Bayer, Mundipharma, Janssen.I.D.D.: Institutional funding – Pfizer, ANZUP Cancer Trials Group, Bayer, Astellas, Janssen, Movember Foundation, Merck Sharp & Dome; Unremunerated chair of ANZUP Cancer Trials Group.T.S.: Travel – Astra Zeneca.D.R.S.: Grants – Regeneron, Amgen, Arrowhead, Espirion, Novartis; Personal fees – Amgen, Sanofi.A.A.: Consultant – Astellas, Janssen, Novartis; Speakers Bureau – Astellas, Janssen, Novartis, Amgen, Ipsen, Bristol Myers Squibb; Merck Serono, Bayer; Honoraria – Astellas, Novartis, Sanofi, AstraZeneca, Tolmar, Telix, Merck Serono; Janssen, Bristol Myers Squibb, Ipsen, Bayer, Pfizer, Amgen, Noxopharm, Merck Sharpe Dome; Scientific Advisory Board – Astellas, Novartis, Sanofi, AstraZeneca, Tolmar, Pfizer, Telix, Merck Serono; Janssen, Bristol Myers Squibb, Ipsen, Bayer, Merck Sharpe Dome, Amgen, Noxopharm; Travel & accommodation – Astellas, Merck Serono, Amgen, Novartis, Janssen, Tolmar, Pfizer; Investigator research funding – Astellas, Merck Serono, Astra Zeneca; Institutional research funding – Bristol Myers Squibb, Astra Zeneca, Aptevo Therapeutics, Glaxo Smith Kline, Pfizer, MedImmune, Astellas, SYNthorx, Bionomics, Sanofi Aventis, Novartis, Ipsen.A.M.J.: Insitutional funding – Pfizer, Astellas.L.G.H.: Research funding – Astellas; Travel sponsorship – Janssen, Pfizer; Honoraria – Imagion Biosystems. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)