Association of early PSMA upregulation with duration of response to enzalutamide with or without [177Lu]Lu-PSMA-617 in poor-risk, metastatic, castration-resistant prostate cancer: Findings from the randomised, phase 2, ENZA-p trial (ANZUP 1901)

Association of early PSMA upregulation with duration of response to enzalutamide with or without [177Lu]Lu-PSMA-617 in poor-risk, metastatic, castration-resistant prostate cancer: Findings from the randomised, phase 2, ENZA-p trial (ANZUP 1901) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Association of early PSMA upregulation with duration of response to enzalutamide with or without [177Lu]Lu-PSMA-617 in poor-risk, metastatic, castration-resistant prostate cancer: Findings from the randomised, phase 2, ENZA-p trial (ANZUP 1901) Louise Emmett, Mina Swiha, Nathan Papa, Shalini Subramaniam, Megan Crumbaker, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6307229/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 15 Apr, 2026 Read the published version in Nature Cancer → Version 1 posted You are reading this latest preprint version Abstract Background Prostate-specific membrane antigen (PSMA) receptor expression alters in response to androgen receptor blockade in metastatic castrate resistant prostate cancer (mCRPC). The ENZA-p trial (ANZUP 1901) demonstrated that the addition of [ 177 Lu]Lu-PSMA-617 to enzalutamide improved overall survival (OS) in mCRPC. In this preplanned imaging substudy, we evaluated the frequency and clinical significance of early changes in PSMA-PET standardised uptake value (SUV) mean with enzalutamide ± [ 177 Lu]Lu-PSMA-617. Materials and Methods Participants in ENZA-p had mCRPC not previously treated with chemotherapy or AR antagonist (abiraterone permitted), [ 68 Ga]Ga-PSMA-avid disease, and at least two risk factors for early progression on enzalutamide alone. Participants were randomised (1:1) to either enzalutamide 160 mg daily or enzalutamide 160 mg daily plus adaptive-dosed [ 177 Lu]Lu-PSMA-617 7.5 GBq (2 or 4 doses). Participants underwent a 68 Ga-PSMA-PET/CT at baseline and day 15 after commencing enzalutamide, with [ 177 Lu]Lu-PSMA-617 administered subsequently in the experimental arm. All 68 Ga-PSMA-PET/CT were analysed with semi-automated software to derive PSMA SUVmean. The study investigated the relationship between early change in SUVmean and the following clinical outcomes: 50% PSA decline (PSA-50), PSA progression-free survival (PSA-PFS), and OS. Results We randomised 162 pts from Aug 2020 to Jul 2022, all of whom underwent baseline imaging. Of the treated participants 96% (154 out of 160) received a PSMA PET/CT at day 15 after commencing enzalutamide. The median age was 71 years (interquartile range, IQR: 65-76), with 53% having received prior docetaxel and 14% prior abiraterone. An increase in SUVmean at day 15, regardless of magnitude was recorded in 105 out of 154 (68%). Among these participants, the median increase in SUVmean was 13% (IQR: 6.0% - 22%). The median PSA-PFS in pts with increasing SUVmean by treatment arm was 5.8 months vs 13.1 months for enzalutamide monotherapy vs enzalutamide plus [ 177 Lu]Lu-PSMA-617 respectively (Log-rank p < 0.001). By contrast, in those with decreasing SUVmean, median PSA-PFS was 12.5 vs 13.3 months for enzalutamide monotherapy vs enzalutamide plus [ 177 Lu]Lu-PSMA-617 (Log-rank p = 0.5). The p-value for an interaction between early increase or decrease in SUVmean and treatment arm for PSA-PFS was p=0.055. Conclusions An early increase in PSMA SUVmean is common with first line enzalutamide in mCRPC, and predictive for shorter PSA-PFS with enzalutamide alone. The addition of [ 177 Lu]Lu-PSMA-617 to enzalutamide mitigated the shorter PSA-PFS in those with early increase in PSMA SUVmean. Biological sciences/Cancer/Cancer imaging Biological sciences/Cancer/Urological cancer/Prostate cancer [177Lu]Lu-PSMA prostate cancer ARPI PSMA upregulation Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction There is a complex intracellular relationship between the androgen receptor and the prostate specific membrane antigen (PSMA) receptors in prostate cancer. In preclinical and PSMA-PET imaging studies, an increase in PSMA expression is seen in response to commencing androgen receptor pathway inhibitors (ARPI), particularly in metastatic castrate resistant prostate cancer (mCRPC)( 1 – 4 ). ENZA-p (ANZUP 1901), a randomised phase II trial in patients with mCRPC and risk factors for early treatment failure on enzalutamide found that the addition of [ 177 Lu]Lu-PSMA-617 to enzalutamide improved both progression-free and overall survival compared to enzalutamide alone( 5 , 6 ). As an integral component of the trial, serial PSMA-PET were undertaken in all patients prior to commencing enzalutamide and at 15 days after commencing enzalutamide prior to [ 177 Lu]Lu-PSMA-617 administration. The pre-determined hypothesis of this ENZA-p sub-study was that PSMA upregulation 15 days after commencing enzalutamide is predictive and prognostic for progression-free and overall survival. Furthermore, it was anticipated this poor prognosis in the subset with PSMA upregulation would be mitigated with the addition of [ 177 Lu]Lu-PSMA-617. Methods ENZA-p (ANZUP 1901; NCT04419402) is a multicentre, open label, randomised, phase 2 trial performed at 15 Australian sites. The trial protocol, primary and key secondary outcomes up to a median follow up of 34 months were previously reported(5-7). ENZA-p enrolled individuals with mCRPC, with progressive disease defined by a rising serum PSA as per Prostate Cancer Working Group 3 (PCWG3) criteria and serum PSA > 5ng/mL. Eligible participants had mCRPC not previously treated with androgen receptor antagonist (prior abiraterone was permitted) and no prior docetaxel for mCRPC. Docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC) was permitted. Eligible participants were those for whom enzalutamide alone was considered the appropriate, next standard treatment, and had two or more risk factors for early progression on enzalutamide alone (8, 9). Treatments: Participants in both the control and experimental groups received enzalutamide 160 mg daily until disease progression or unacceptable toxicity. The experimental group also received two doses of [ 177 Lu]Lu-PSMA-617 2 and 8 weeks after commencing enzalutamide. Those with persistent PSMA-positive disease (above blood-pool) on a centrally reviewed PSMA PET/CT at week 12 were treated with up to a further two doses of [ 177 Lu]Lu-PSMA-617 16 and 24 weeks after commencing enzalutamide. All administered doses of [ 177 Lu]Lu -PSMA-617 were 7.5 GBq. Participants were reviewed every 4 weeks during which they underwent blood tests for haematology, biochemistry, and serum PSA while on study treatment, then every 6 weeks until radiologic progression. CT of the chest, abdomen and pelvis, and 99m Tc-bone scans, were performed every 12 weeks until radiologic progression. PSMA PET: [ 68 Ga]Ga-PSMA-11 was required for PSMA PET/CT imaging at all timepoints. Both the PSMA PET-CT imaging protocol and acquisition procedures were standardised across sites with phantom certification of PET cameras and [ 68 Ga]Ga-PSMA-11 radiopharmacy production through the Australian Radiopharmaceutical Trials Network (ARTnet) (5). All PSMA-PET/CT timepoints were uploaded to a de-identified cloud-based server specific for the ENZA-p trial (WIDEN) and pushed automatically to cloud-based image quantification software (MIM encore) specifically designed for the trial. The semi-quantified workflow utilised a standardised uptake value (SUV) max of 3 and volume of 0.2mL to identify a tumour deposit, with tumour edge defined as 41% maximal voxel intensity. All workflow derived tumour regions were quality assessed by a nuclear medicine investigator. SUVmean was quantitatively derived for each PET imaging timepoint (Figure 1). Screening of potential participants included central review of a [ 68 Ga]Ga-PSMA-11 PET/CT (PSMA PET). Imaging criteria for inclusion were PSMA-positive disease with a maximum standardised uptake value (SUVmax) of 15 or more at a single site of disease, and SUVmax >10 at all sites of measurable disease not affected by partial voluming on PSMA PET. PSMA-PET/CT was also undertaken at day 15 after commencing enzalutamide, day 92 after commencing enzalutamide and at first progression (PSA or radiographic). For this sub-study, only the quantitative analysis of the PSMA PET at screening and day 15 after commencing enzalutamide were evaluated. Statistical analysis: The primary endpoint was 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 from any cause, whichever occurred first. The censoring data for those without the event was 31 July 2024. Secondary endpoints were overall survival, and PSA response rate, specifically achieving a 50% reduction in PSA from baseline (PSA-50). Survival outcomes were analysed by unstratified Cox regression, comparing combination treatment to enzalutamide alone, within early rising SUVmean or early falling SUVmean subgroups. Effect modification between treatment arm and early SUVmean change was examined by entering both variables into a Cox model with an interaction term, the p-value of which is reported. The proportional hazards assumption was tested by inspection of Schoenfeld residuals and in no case was this violated. Survival curves and median survival time were estimated with the Kaplan-Meier method and compared using unstratified log-rank tests. For this sub-study, reported p-values are nominal and inferences should be made in this context. Analysis was performed with Stata v17.0SE (College Station, TX, USA). Results Patient characteristics: We randomised 162 participants, 79 assigned enzalutamide-alone and 83 to enzalutamide plus [ 177 Lu]Lu-PSMA-617. This analysis includes the 154 of 162 (95%) participants who had PSMA-PET imaging at baseline and day 15: 75 assigned enzalutamide-alone and 79 assigned enzalutamide plus [ 177 Lu]Lu-PSMA-617. Baseline characteristics are summarised in Table 1. Notably, 54% had M1 disease at initial diagnosis, 53% had prior treatment with docetaxel, and 14% had prior treatment with abiraterone for mHSPC. Table 1.Baseline Characteristics. Characteristic Enzalutamide n = 75 Enzalutamide + [ 177 Lu]Lu-PSMA-617 n = 79 Age (years) 72 (63-76) 71 (66-77) PSA at enrolment (ng/mL) 33 (13-93) 39 (16-75) > 20 PSMA-avid metastases 45 (60%) 48 (61%) Metastatic disease (M1) at initial diagnosis 44 (59%) 39 (49%) Pain requiring opiates > 14 days 11 (15%) 9 (11%) Previous early docetaxel for castration-sensitive disease 41 (55%) 41 (52%) Prior treatment with abiraterone 9 (12%) 12 (15%) Time since diagnosis (years) 2.9 (1.4-6.6) 2.2 (1.2-6.5) Data are median (IQR) or n (%). ¹⁷⁷Lu=lutetium-177. PSA=prostate-specific antigen. PSMA=prostate-specific membrane antigen. Treatment Outcomes: PSA-progression was observed in 129 of the 154 participants, with a median PSA-PFS of 13.3 months with enzalutamide plus [ 177 Lu]Lu-PSMA-617 arm vs 7.8 months in the enzalutamide alone arm (HR 0.48, 95%CI: 0.34-0.68). PSA-50 was observed in 95% vs 69% of those assigned [ 177 Lu]Lu-PSMA-617 plus enzalutamide vs enzalutamide alone. There were 93 deaths recorded; median OS was 33.8 months in those assigned the combination vs 25.8 months among those assigned enzalutamide alone (HR 0.64, 95%CI: 0.42-0.96). PSMA PET Quantitation: Enzalutamide was administered for 15 days in both trial cohorts with a PSMA-PET undertaken prior to commencing [ 177 Lu]Lu-PSMA-617 in the experimental cohort. Quantitative PSMA PET analysis showed increased in SUVmean in 105 of 154 (68%)(Figure 2).In these participants, the median increase was 13% (IQR: 6.0% - 22%). In 21 participants who had prior abiraterone treatment, 14 (67%) had an increase in SUVmean, with the median rise in those participants being 10% (IQR: 4.5% - 20%). No early change in PSMA expression was noted in the non-tumour PSMA expressing sites of parotid and blood pool (Supplementary Table 1). However, an increased SUVmax in the liver was observed with absolute mean change of +0.4 (95%CI: +0.2 to +0.6) Change in PSMA SUVmean and Outcomes In participants with an increase in PSMA-PET SUVmean after 15 days on enzalutamide, median PSA-PFS was 13.1 vs 5.8 months for enzalutamide plus [ 177 Lu]Lu-PSMA-617 vs enzalutamide alone (HR 0.38, 95%CI: 0.25-0.58; Log-rank p<0.001). Conversely, in participants with a reduction in SUVmean in the first 15 days, median PSA-PFS was 13.3 vs 12.5 months for the combination treatment vs enzalutamide alone (HR 0.80, 95%CI: 0.42-1.53; Log-rank p=0.5) (Figure 3). The p-value for an interaction term between increase or decrease in SUVmean and treatment arm was p=0.055 indicating probable effect modification. Similarly, in those participants with increased SUVmean on day 15, the PSA-50 response rate was 98% with enzalutamide plus [ 177 Lu]Lu-PSMA-617 vs 63% with enzalutamide alone. In contrast, those with a reduction in SUVmean on day 15, the proportions achieving PSA-50 were 90% vs 89%, respectively (Figure 4). Participants with an increase in SUVmean on day 15 had a median OS of 33.8 vs 26.0 months for enzalutamide plus [ 177 Lu]Lu-PSMA-617 vs enzalutamide-alone (HR 0.60, 95%CI: 0.36-0.98; Log-rank p=0.038). In participants with a reduction in SUVmean on day 15, median OS was 33.6 vs 25.8 months for the combination vs enzalutamide alone (HR 0.79, 95%CI: 0.37-1.68; Log-rank p=0.5) (Figure 5). The p-value for an interaction term between rise or fall in SUVmean on day 15 and treatment arm for OS was p=0.6. Discussion This sub-study of the ENZAp trial demonstrated that early PSMA upregulation occurred frequently in mCRPC with enzalutamide. Notably,an early increase in PSMA expression was associated with lower PSA response rates and shorter PSA-PFS with enzalutamide monotherapy compared to those with an early decrease in PSMA expression. Additionally, the short PSA-PFS observed in those with an early increase in PSMA SUVmean on enzalutamide was mitigated with the addition of [ 177 Lu]Lu-PSMA-617. The findings suggest that increased PSMA expression on androgen blockade in mCRPC is a poor prognostic sign and those patients may benefit from treatment intensification with [ 177 Lu]Lu-PSMA-617. PSMA is a transmembrane glycoprotein that is involved in cellular proliferation within the PI3K/AKT/MTOR pathway(10). It is more highly expressed in prostate cancers that are metastatic and/or castration-resistant (11, 12). Higher baseline PSMA expression in the primary prostate tumour appears to be prognostic in both high-risk localised disease and metastatic disease (13, 14). In contrast, response to enzalutamide monotherapy in mCRPC has been shown to be higher among those with lower pretreatment PSMA expression(15). Increased PSMA expression has been reported previously in response to commencing an ARPI in mCRPC, but evidence on the frequency and clinical significance is limited(16). Zukotynski et al reported a retrospective study of 16 patients who had PSMA PET performed at baseline and within 2-4 months of starting an ARPI in mCRPC. They found that any increase in PSMA expression on ARPI was associated with shorter time to change in therapy and overall survival(17). This substudy of ENZA-p confirms that early upregulation of PSMA expression is associated with shorter PSA-PFS and limited depth of response on enzalutamide monotherapy but had more modest impact on overall survival. The difference between the studies for prediction of overall survival is likely reflective of the interval between the PSMA-PET scans. In ENZA-p, change in PSMA expression was evaluated 2 weeks after enzalutamide, whereas Zukotynski et al evaluated the change in expression 2-4 months after starting ARPI. It is possible that the longer imaging interval was measuring actual disease progression rather than rapid receptor upregulation in response to androgen blockade, leading to a stronger association with overall survival. Further evaluation is needed to determine if persistence of increased PSMA expression beyond 12 weeks of treatment should be considered a marker of disease progression on PSMA-PET. Early PSMA upregulation did not indicate a poor response to the combination of enzalutamide plus [ 177 Lu]Lu-PSMA-617. In fact, participants with an early increase in PSMA expression had a higher PSA response rate than participants with decreased PSMA expression . This likely reflects increased uptake of [ 177 Lu]Lu-PSMA-617 associated with increased PSMA expression, resulting in increased tumour radiation damage, reflected by improved treatment response to [ 177 Lu]Lu-PSMA-617. We know that higher baseline PSMA expression is associated with a higher PSA-50 response rate after treatment with single-agent [ 177 Lu]Lu-PSMA-617 (18, 19). These data suggest possible treatment synergy between enzalutamide and [ 177 Lu]Lu-PSMA-617, although the predominant efficacy effect may also be simply additive as a result of complementary treatments targeting distinct clonal populations. Tracking early PSMA kinetics with serial PET/CT allows a deeper understanding of the biology behind the longer overall survival with enzalutamide plus [ 177 Lu]Lu-PSMA-617 compared to published [ 177 Lu]Lu-PSMA-617 monotherapy trials(20-22). This study has several limitations. Firstly, the proportion of patients who had early increased PSMA expression after 14 days of enzalutamide was high. ENZA-p enrolled patients who had risk factors for early treatment failure on enzalutamide alone, which may have elevated the proportion of patients with metastatic deposits capable of increasing PSMA expression with androgen blockade. It is possible that in a lower risk early mCRPC population the proportion of patients with increased PSMA expression with enzalutamide may be lower. Secondly, it may be difficult to differentiate PSMA expression upregulation from primary treatment resistance and disease progression. While a few patients in the study who are classified as having PSMA upregulation may be experiencing early true progression, we know that the PSA 50% response rates were high in the trial for both arms. Additionally, participants on the combination arm had excellent treatment responses independent of an early increase or decreasel in PSMA SUVmean. Finally, change in SUVmean was evaluated as a continuous variable with any change in SUVmean considered significant without accounting for reproducibility of SUVmean analysis. That participants outcomes varied significantly with any change in SUVmean highlights the strength of change in SUVmean as a clinical tool. Future research should focus on analysing the reproducibility of measures of change in SUVmean and establishing clinically relevant cut points. In summary, early increase in PSMA expression appears frequent with enzalutamide in mCRPC, and is associated with limited PSA progression-free survival. This may help identify patients at high risk of failure on enzalutamide monotherapy who will benefit from the addition of [ 177 Lu]Lu-PSMA-617. Declarations Contributors LE, NP AJM, MSH,SSa, MRS, IDD were members of the working party contributing to conceptualisation and writing the first version of the analysis plan. LE, SSu, MC, AMJ, AN, AW, S-TL, MS, NA, SP, SSa, MSH, DAP, MRS, and IDD accrued patients and collected data. MS, NA, SP performed imaging analysis. NP,AJM and HT led the statistical analysis and verified underlying data. LE, NP, IDD, MRS, AJM, HT, and SSu have accessed and verified the data. LE was the coordinating principal investigator and wrote the first draft of the manuscript. All authors contributed to the writing and approval of this manuscript. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. 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 (challenge award), Movember, 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. 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. All other authors declare no competing interests. Acknowledgments ENZA-p is an investigator-initiated trial led by the ANZUP Cancer Trials Group in partnership with the Prostate Cancer Research Alliance, a joint initiative between the Australian Federal Government and the Movember Foundation. ENZA-p is a collaboration between ANZUP, the NHMRC Clinical Trials Centre at the University of Sydney and the Australasian Radiopharmaceutical Trials Network with support from AdAcAp (a Novartis company), St Vincent’s Clinic Foundation, GenesisCare, and Roy Morgan Research. Astellas provided drug support for the trial. ANZUP receives infrastructure funding from Cancer Australia. This sub-study was funded through a prostate cancer foundation challenge award. We acknowledge and thank the 162 participants for their participation in the ENZA-p study; and the principal investigators, co-investigators, and study coordinators at the 15 centres across Australia for their dedication and enthusiasm. References Emmett L, Yin C, Crumbaker M, Hruby G, Kneebone A, Epstein R, et al. Rapid Modulation of PSMA Expression by Androgen Deprivation: Serial (68)Ga-PSMA-11 PET in Men with Hormone-Sensitive and Castrate-Resistant Prostate Cancer Commencing Androgen Blockade. J Nucl Med. 2019;60(7):950-4. 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Buteau JP, Martin AJ, Emmett L, Iravani A, Sandhu S, Joshua AM, et al. PSMA and FDG-PET as predictive and prognostic biomarkers in patients given [(177)Lu]Lu-PSMA-617 versus cabazitaxel for metastatic castration-resistant prostate cancer (TheraP): a biomarker analysis from a randomised, open-label, phase 2 trial. Lancet Oncol. 2022;23(11):1389-97. Kuo P, Hesterman J, Rahbar K, Kendi AT, Wei XX, Fang B, et al. [68Ga]Ga-PSMA-11 PET baseline imaging as a prognostic tool for clinical outcomes to [177Lu]Lu-PSMA-617 in patients with mCRPC: A VISION substudy. Journal of Clinical Oncology. 2022;40(16_suppl):5002-. Hofman MS, Emmett L, Sandhu S, Iravani A, Buteau JP, Joshua AM, et al. Overall survival with [(177)Lu]Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer (TheraP): secondary outcomes of a randomised, open-label, phase 2 trial. Lancet Oncol. 2024;25(1):99-107. Morris MJ, Castellano D, Herrmann K, de Bono JS, Shore ND, Chi KN, et al. (177)Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial. Lancet. 2024;404(10459):1227-39. Sartor O, de Bono J, Chi KN, Fizazi K, Herrmann K, Rahbar K, et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021;385(12):1091-103. Additional Declarations Yes there is potential Competing Interest. These are listed for all authors in a paragraph at the end of the manuscript. For the principal investigator, Prof Emmett has received research grants from Movember, PCF challenge award, St Vincents Curran Foundation and St Vincent's clinic foundation. Trial support from Novartis, Clarity and Astellas. Speakers bureau for Novartis, Janssen, GE healthcare. Scientific advisory board for Clarity pharma and Advancell. Supplementary Files ConsortDiagram.pdf ENZA-p Consort Diagram ENZApLancetOnc.pdf ENZA-p Lancet Oncology ENZAPtrialinfographicv7.pdf ENZA-p Infographic ENZApProtocolv2.12020.06.22clean.pdf ENZA-p Protocol SupplementaryTable1.docx Cite Share Download PDF Status: Published Journal Publication published 15 Apr, 2026 Read the published version in Nature Cancer → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6307229","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":440183528,"identity":"66b25c48-35e2-432d-a3df-f2e72edbedda","order_by":0,"name":"Louise 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Sandhu","email":"","orcid":"","institution":"Peter MacCallum Cancer Centre","correspondingAuthor":false,"prefix":"","firstName":"Shahneen","middleName":"","lastName":"Sandhu","suffix":""},{"id":440183545,"identity":"0ef96e90-bbb4-46a7-a707-70bb2be222a6","order_by":17,"name":"Andrew Martin","email":"","orcid":"","institution":"Centre for Clinical Research, University of Queensland","correspondingAuthor":false,"prefix":"","firstName":"Andrew","middleName":"","lastName":"Martin","suffix":""},{"id":440183546,"identity":"ed0b9010-217e-4a3e-af2b-cc4eacc498cf","order_by":18,"name":"Hayley Thomas","email":"","orcid":"","institution":"NHMRC Clinical Trials Centre, University of Sydney","correspondingAuthor":false,"prefix":"","firstName":"Hayley","middleName":"","lastName":"Thomas","suffix":""},{"id":440183547,"identity":"8b5230bf-7a7c-42c7-a5e8-c781de428338","order_by":19,"name":"Martin Stockler","email":"","orcid":"https://orcid.org/0000-0003-3793-8724","institution":"The University of Sydney","correspondingAuthor":false,"prefix":"","firstName":"Martin","middleName":"","lastName":"Stockler","suffix":""},{"id":440183548,"identity":"78f55d2e-d025-4137-9b6e-70e0dbc9cbf2","order_by":20,"name":"Ian Davis","email":"","orcid":"https://orcid.org/0000-0002-9066-8244","institution":"Monash University and Eastern Health","correspondingAuthor":false,"prefix":"","firstName":"Ian","middleName":"","lastName":"Davis","suffix":""}],"badges":[],"createdAt":"2025-03-26 00:10:25","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6307229/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6307229/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s43018-026-01140-3","type":"published","date":"2026-04-15T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":80211225,"identity":"c7fe68f1-1083-428f-841e-0c16831c3f62","added_by":"auto","created_at":"2025-04-09 08:49:46","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1272802,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTotal body quantitation on PSMA-PET undertaken at baseline and day 15 after commencing enzalutamide in A: A participant with a documented increase in SUVmean, and B: A participant documented as having a decrease in SUVmean.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSUV=standardised uptake value (SUVmean is the mean SUV of all voxels within the sum total body tumour region)\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6307229/v1/3026af931a4aaa41e59eb1f6.png"},{"id":80211228,"identity":"d399809a-fb16-4eb4-ad09-4f7fdad721fe","added_by":"auto","created_at":"2025-04-09 08:49:46","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":152899,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFrequency and magnitude of change in SUVmean with 15 days of enzalutamide\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSUV=standardised uptake value\u003c/p\u003e","description":"","filename":"d15fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-6307229/v1/ba27dd34d0270aa301a983ce.png"},{"id":80212410,"identity":"88f7529e-2c7f-4b17-8aea-0b294bd33de2","added_by":"auto","created_at":"2025-04-09 08:57:46","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":282843,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan Meier plot for PSA-PFS by treatment arm and early rising or falling SUVmean.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e¹⁷⁷Lu=lutetium-177. PSA-PFS = prostate specific antigen – progression free survival, PSMA=prostate-specific membrane antigen. SUV=standardised uptake value.\u003c/p\u003e","description":"","filename":"d15fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-6307229/v1/716463d63178530aab295a92.png"},{"id":80212413,"identity":"3d136632-f5ce-4310-8fa5-424638920d3f","added_by":"auto","created_at":"2025-04-09 08:57:46","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":174198,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eWaterfall plots of best PSA response by early rising or falling SUVmean.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e¹⁷⁷Lu=lutetium-177. PSA=prostate-specific antigen. PSMA=prostate-specific membrane antigen. SUV=standardised uptake value.\u003c/p\u003e","description":"","filename":"d15fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-6307229/v1/fbc575e5bb1fb4ddbb76b988.png"},{"id":80214025,"identity":"bad69c03-8f01-43c4-a7df-25309cb3295a","added_by":"auto","created_at":"2025-04-09 09:13:46","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":296281,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan Meier plot for OS by treatment arm and early rising or falling SUVmean.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e¹⁷⁷Lu=lutetium-177. OS=overall survival. PSMA=prostate-specific membrane antigen. SUV=standardised uptake value\u003c/p\u003e","description":"","filename":"d15fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-6307229/v1/023e3a97869a34ce24d98898.png"},{"id":107045276,"identity":"0b156b43-06df-4516-b21f-074122e5d2ac","added_by":"auto","created_at":"2026-04-16 07:16:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2597826,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6307229/v1/c7111700-559c-4d82-9902-7ba48b5bcd1a.pdf"},{"id":80211223,"identity":"1cf512fb-c985-499a-a74d-03c9f0cb410a","added_by":"auto","created_at":"2025-04-09 08:49:46","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":60938,"visible":true,"origin":"","legend":"ENZA-p Consort Diagram","description":"","filename":"ConsortDiagram.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6307229/v1/9a3305135fa12e5eb430ef8a.pdf"},{"id":80211229,"identity":"e2f48330-e4fe-47f8-9288-a7069f0bbf3c","added_by":"auto","created_at":"2025-04-09 08:49:46","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":608780,"visible":true,"origin":"","legend":"ENZA-p Lancet Oncology","description":"","filename":"ENZApLancetOnc.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6307229/v1/abeeed71378627bf9f58b5c2.pdf"},{"id":80211237,"identity":"640c1b43-f917-4785-a3af-23feed342697","added_by":"auto","created_at":"2025-04-09 08:49:46","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":2433584,"visible":true,"origin":"","legend":"ENZA-p Infographic","description":"","filename":"ENZAPtrialinfographicv7.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6307229/v1/6a91cfe0f27c05591147dc61.pdf"},{"id":80211238,"identity":"3cbc65a9-82bd-4476-af3f-3c35c7192d81","added_by":"auto","created_at":"2025-04-09 08:49:46","extension":"pdf","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":1413410,"visible":true,"origin":"","legend":"ENZA-p Protocol","description":"","filename":"ENZApProtocolv2.12020.06.22clean.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6307229/v1/78909615ef0f1553f7ba665c.pdf"},{"id":80212406,"identity":"ff262a61-7ca6-4e66-8e30-630ad2ec7e0e","added_by":"auto","created_at":"2025-04-09 08:57:46","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":15041,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-6307229/v1/c89712db904ec675c8beed2e.docx"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nThese are listed for all authors in a paragraph at the end of the manuscript. For the principal investigator, Prof Emmett has received research grants from Movember, PCF challenge award, St Vincents Curran Foundation and St Vincent's clinic foundation. Trial support from Novartis, Clarity and Astellas. Speakers bureau for Novartis, Janssen, GE healthcare. Scientific advisory board for Clarity pharma and Advancell.","formattedTitle":"Association of early PSMA upregulation with duration of response to enzalutamide with or without [177Lu]Lu-PSMA-617 in poor-risk, metastatic, castration-resistant prostate cancer: Findings from the randomised, phase 2, ENZA-p trial (ANZUP 1901)","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThere is a complex intracellular relationship between the androgen receptor and the prostate specific membrane antigen (PSMA) receptors in prostate cancer. In preclinical and PSMA-PET imaging studies, an increase in PSMA expression is seen in response to commencing androgen receptor pathway inhibitors (ARPI), particularly in metastatic castrate resistant prostate cancer (mCRPC)(\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). ENZA-p (ANZUP 1901), a randomised phase II trial in patients with mCRPC and risk factors for early treatment failure on enzalutamide found that the addition of [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 to enzalutamide improved both progression-free and overall survival compared to enzalutamide alone(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). As an integral component of the trial, serial PSMA-PET were undertaken in all patients prior to commencing enzalutamide and at 15 days after commencing enzalutamide prior to [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 administration. The pre-determined hypothesis of this ENZA-p sub-study was that PSMA upregulation 15 days after commencing enzalutamide is predictive and prognostic for progression-free and overall survival. Furthermore, it was anticipated this poor prognosis in the subset with PSMA upregulation would be mitigated with the addition of [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eENZA-p (ANZUP 1901; NCT04419402) is a multicentre, open label, randomised, phase 2 trial performed at 15 Australian sites. The trial protocol, primary and key secondary outcomes up to a median follow up of 34 months were previously reported(5-7). ENZA-p enrolled individuals with mCRPC, with progressive disease defined by a rising serum PSA as per Prostate Cancer Working Group 3 (PCWG3) criteria and serum PSA \u0026gt; 5ng/mL. Eligible participants had mCRPC not previously treated with androgen receptor antagonist (prior abiraterone was permitted) and no prior docetaxel for mCRPC. Docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC) was permitted. Eligible participants were those for whom enzalutamide alone was considered the appropriate, next standard treatment, and had two or more risk factors for early progression on enzalutamide alone (8, 9). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatments:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants in both the control and experimental groups received enzalutamide 160 mg daily until disease progression or unacceptable toxicity. The experimental group also received two doses of [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 2 and 8 weeks after commencing enzalutamide. Those with persistent PSMA-positive disease (above blood-pool) on a centrally reviewed PSMA PET/CT at week 12 were treated with up to a further two doses of [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 16 and 24 weeks after commencing enzalutamide. All administered doses of [\u003csup\u003e177\u003c/sup\u003eLu]Lu -PSMA-617 were 7.5 GBq. Participants were reviewed every 4 weeks during which they underwent blood tests for haematology, biochemistry, and serum PSA while on study treatment, then every 6 weeks until radiologic progression. CT of the chest, abdomen and pelvis, and \u003csup\u003e99m\u003c/sup\u003eTc-bone scans, were performed every 12 weeks until radiologic progression. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePSMA PET:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e[\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 was required for PSMA PET/CT imaging at all timepoints. Both the PSMA PET-CT imaging protocol and acquisition procedures were standardised across sites with phantom certification of PET cameras and [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 radiopharmacy production through the Australian Radiopharmaceutical Trials Network (ARTnet) (5). All PSMA-PET/CT timepoints were uploaded to a de-identified cloud-based server specific for the ENZA-p trial (WIDEN) and pushed automatically to cloud-based image quantification software (MIM encore) specifically designed for the trial. The semi-quantified workflow utilised a standardised uptake value (SUV) max of 3 and volume of 0.2mL to identify a tumour deposit, with tumour edge defined as 41% maximal voxel intensity. All workflow derived tumour regions were quality assessed by a nuclear medicine investigator. SUVmean was quantitatively derived for each PET imaging timepoint (Figure 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eScreening of potential participants included central review of a [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 PET/CT (PSMA PET). Imaging criteria for inclusion were PSMA-positive disease with a maximum standardised uptake value (SUVmax) of 15 or more at a single site of disease, and SUVmax \u0026gt;10 at all sites of measurable disease not affected by partial voluming on PSMA PET. PSMA-PET/CT was also undertaken at day 15 after commencing enzalutamide, day 92 after commencing enzalutamide and at first progression (PSA or radiographic). For this sub-study, only the quantitative analysis of the PSMA PET at screening and day 15 after commencing enzalutamide were evaluated.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoint was 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 from any cause, whichever occurred first. The censoring data for those without the event was 31 July 2024. Secondary endpoints were overall survival, and PSA response rate, specifically achieving a 50% reduction in PSA from baseline (PSA-50). Survival outcomes were analysed by unstratified Cox regression, comparing combination treatment to enzalutamide alone, within early rising SUVmean or early falling SUVmean subgroups. Effect modification between treatment arm and early SUVmean change was examined by entering both variables into a Cox model with an interaction term, the p-value of which is reported. The proportional hazards assumption was tested by inspection of Schoenfeld residuals and in no case was this violated. Survival curves and median survival time were estimated with the Kaplan-Meier method and compared using unstratified log-rank tests. For this sub-study, reported p-values are nominal and inferences should be made in this context. Analysis was performed with Stata v17.0SE (College Station, TX, USA).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient characteristics:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe randomised 162 participants, 79 assigned enzalutamide-alone and 83 to enzalutamide plus [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617. This analysis includes the 154 of 162 (95%) participants who had PSMA-PET imaging at baseline and day 15: 75 assigned enzalutamide-alone and 79 assigned enzalutamide plus [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617. Baseline characteristics are summarised in Table 1. Notably, 54% had M1 disease at initial diagnosis, 53% had prior treatment with docetaxel, and 14% had prior treatment with abiraterone for mHSPC. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.Baseline Characteristics.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"590\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.6102%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.7797%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEnzalutamide\u0026nbsp;\u003cbr\u003e\u0026nbsp;n = 75\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.6102%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEnzalutamide + [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617\u003cbr\u003e\u0026nbsp;n = 79\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.6102%;\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.7797%;\"\u003e\n \u003cp\u003e72 (63-76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.6102%;\"\u003e\n \u003cp\u003e71 (66-77)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.6102%;\"\u003e\n \u003cp\u003ePSA at enrolment (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.7797%;\"\u003e\n \u003cp\u003e33 (13-93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.6102%;\"\u003e\n \u003cp\u003e39 (16-75)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.6102%;\"\u003e\n \u003cp\u003e\u0026gt; 20 PSMA-avid metastases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.7797%;\"\u003e\n \u003cp\u003e45 (60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.6102%;\"\u003e\n \u003cp\u003e48 (61%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.6102%;\"\u003e\n \u003cp\u003eMetastatic disease (M1) at initial diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.7797%;\"\u003e\n \u003cp\u003e44 (59%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.6102%;\"\u003e\n \u003cp\u003e39 (49%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.6102%;\"\u003e\n \u003cp\u003ePain requiring opiates \u0026gt; 14 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.7797%;\"\u003e\n \u003cp\u003e11 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.6102%;\"\u003e\n \u003cp\u003e9 (11%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.6102%;\"\u003e\n \u003cp\u003ePrevious early docetaxel for castration-sensitive disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.7797%;\"\u003e\n \u003cp\u003e41 (55%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.6102%;\"\u003e\n \u003cp\u003e41 (52%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.6102%;\"\u003e\n \u003cp\u003ePrior treatment with abiraterone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.7797%;\"\u003e\n \u003cp\u003e9 (12%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.6102%;\"\u003e\n \u003cp\u003e12 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.6102%;\"\u003e\n \u003cp\u003eTime since diagnosis (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.7797%;\"\u003e\n \u003cp\u003e2.9 (1.4-6.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.6102%;\"\u003e\n \u003cp\u003e2.2 (1.2-6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eData are median (IQR) or n (%). \u0026sup1;⁷⁷Lu=lutetium-177. PSA=prostate-specific antigen. PSMA=prostate-specific membrane antigen.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment Outcomes:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePSA-progression was observed in 129 of the 154 participants, with a median PSA-PFS of 13.3 months with enzalutamide plus [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 arm vs 7.8 months in the enzalutamide alone arm (HR 0.48, 95%CI: 0.34-0.68). PSA-50 was observed in 95% vs 69% of those assigned [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 plus enzalutamide vs enzalutamide alone. There were 93 deaths recorded; median OS was 33.8 months in those assigned the combination vs 25.8 months among those assigned enzalutamide alone (HR 0.64, 95%CI: 0.42-0.96).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePSMA PET Quantitation:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEnzalutamide was administered for 15 days in both trial cohorts with a PSMA-PET undertaken prior to commencing [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 in the experimental cohort. Quantitative PSMA PET analysis showed increased in SUVmean in 105 of 154 (68%)(Figure 2).In these participants, the median increase was 13% (IQR: 6.0% - 22%). In 21 participants who had prior abiraterone treatment, 14 (67%) had an increase in SUVmean, with the median rise in those participants being 10% (IQR: 4.5% - 20%).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNo early change in PSMA expression was noted in the non-tumour PSMA expressing sites of parotid and blood pool (Supplementary Table 1). However, an increased SUVmax in the liver was observed with absolute mean change of +0.4 (95%CI: +0.2 to +0.6)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eChange in PSMA SUVmean and Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn participants with an increase in PSMA-PET SUVmean after 15 days on enzalutamide, median PSA-PFS was 13.1 vs 5.8 months for enzalutamide plus [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 vs enzalutamide alone (HR 0.38, 95%CI: 0.25-0.58; Log-rank p\u0026lt;0.001). Conversely, in participants with a reduction in SUVmean in the first 15 days, median PSA-PFS was 13.3 vs 12.5 months for the combination treatment vs enzalutamide alone (HR 0.80, 95%CI: 0.42-1.53; Log-rank p=0.5) (Figure 3). The p-value for an interaction term between increase or decrease in SUVmean and treatment arm was p=0.055 indicating probable effect modification.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSimilarly, in those participants with increased SUVmean on day 15, the PSA-50 response rate was 98% with enzalutamide plus [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 vs 63% with enzalutamide alone. In contrast, those with a reduction in SUVmean on day 15, the proportions achieving PSA-50 were 90% vs 89%, respectively (Figure 4). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eParticipants with an increase in SUVmean on day 15 had a median OS of 33.8 vs 26.0 months for enzalutamide plus [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 vs enzalutamide-alone (HR 0.60, 95%CI: 0.36-0.98; Log-rank p=0.038). In participants with a reduction in SUVmean on day 15, median OS was 33.6 vs 25.8 months for the combination vs enzalutamide alone (HR 0.79, 95%CI: 0.37-1.68; Log-rank p=0.5) (Figure 5). The p-value for an interaction term between rise or fall in SUVmean on day 15 and treatment arm for OS was p=0.6.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis sub-study of the ENZAp trial demonstrated that early PSMA upregulation occurred frequently in mCRPC with enzalutamide. Notably,an early increase in PSMA expression was associated with lower PSA response rates and shorter PSA-PFS with enzalutamide monotherapy compared to those with an early decrease in PSMA expression. Additionally, the short PSA-PFS observed in those with an early increase in PSMA SUVmean on enzalutamide was mitigated with the addition of\u0026nbsp;[\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617. The findings suggest that increased PSMA expression on androgen blockade in mCRPC is a poor prognostic sign and those patients may benefit from treatment intensification with [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617.\u003c/p\u003e\n\u003cp\u003ePSMA is a transmembrane glycoprotein that is involved in cellular proliferation within the PI3K/AKT/MTOR pathway(10). It is more highly expressed in prostate cancers that are metastatic and/or castration-resistant (11, 12). Higher baseline PSMA expression in the primary prostate tumour appears to be prognostic in both high-risk localised disease and metastatic disease (13, 14). In contrast, response to enzalutamide monotherapy in mCRPC has been shown to be higher among those with lower pretreatment PSMA expression(15). Increased PSMA expression has been reported previously in response to commencing an ARPI in mCRPC, but \u0026nbsp;evidence on the frequency and clinical significance is limited(16). Zukotynski et al reported a retrospective study of 16 patients who had PSMA PET performed at baseline and within 2-4 months of starting an ARPI in mCRPC. They found that any increase in PSMA expression on ARPI was associated with shorter time to change in therapy and overall survival(17). This substudy of ENZA-p confirms that early upregulation of PSMA expression is associated with shorter PSA-PFS and limited depth of response on enzalutamide monotherapy but had more modest impact on overall survival. The difference between the studies for prediction of overall survival is likely reflective of the interval between the PSMA-PET scans. In ENZA-p, change in PSMA expression was evaluated 2 weeks after enzalutamide, whereas Zukotynski et al evaluated the change in expression \u0026nbsp;2-4 months after starting ARPI. It is possible that the longer imaging interval was measuring actual disease progression rather than rapid receptor upregulation in response to androgen blockade, leading to a stronger association with overall survival. Further evaluation is needed to determine if persistence of increased PSMA expression beyond 12 weeks of treatment should be considered a marker of disease progression on PSMA-PET.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEarly PSMA upregulation did not indicate a poor response to the combination of enzalutamide plus [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617. In fact, participants with an early increase in PSMA expression had a higher PSA response rate than participants with decreased PSMA expression . This likely reflects increased uptake of \u0026nbsp;[\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 associated with increased PSMA expression, resulting in increased tumour radiation damage, reflected by improved treatment response to [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617. We know that higher baseline PSMA expression is associated with a higher PSA-50 response rate after treatment with single-agent [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 (18, 19). These data suggest possible treatment synergy between enzalutamide and [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617, although the predominant efficacy effect may also be simply additive as a result of complementary treatments targeting distinct clonal populations. Tracking early PSMA kinetics with serial PET/CT allows a deeper understanding of the biology behind the longer overall survival with enzalutamide plus [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 compared to published [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 monotherapy trials(20-22).\u003c/p\u003e\n\u003cp\u003eThis study has several limitations. Firstly, the proportion of patients who had early increased PSMA expression after 14 days of enzalutamide was high. ENZA-p enrolled patients who had risk factors for early treatment failure on enzalutamide alone, which may have elevated the proportion of patients with metastatic deposits capable of increasing PSMA expression with androgen blockade. It is possible that in a lower risk early mCRPC population the proportion of patients with increased PSMA expression with enzalutamide may be lower. Secondly, it may be difficult to differentiate PSMA expression upregulation from primary treatment resistance and disease progression. While a few patients in the study who are classified as having PSMA upregulation may be experiencing early true progression, we know that the PSA 50% response rates were high in the trial for both arms. \u0026nbsp;Additionally, participants on the combination arm had excellent treatment responses independent of an early increase or decreasel in PSMA SUVmean. Finally, change in SUVmean was evaluated as a continuous variable with any change in SUVmean considered significant without accounting for reproducibility of SUVmean analysis. \u0026nbsp; That participants outcomes varied significantly with any change in SUVmean highlights the strength of change in SUVmean as a clinical tool. Future research should \u0026nbsp;focus on analysing the reproducibility of measures of change in SUVmean and establishing clinically relevant cut points.\u003c/p\u003e\n\u003cp\u003eIn summary, early increase in PSMA expression appears frequent with enzalutamide in mCRPC, and is associated with limited PSA progression-free survival. This may help identify patients at high risk of failure on enzalutamide monotherapy who will benefit from the addition of [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eContributors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLE, NP AJM, MSH,SSa, MRS, IDD were members of the working party contributing to conceptualisation and writing the first version of the analysis plan. LE, SSu, MC, AMJ, AN, AW, S-TL, MS, NA, SP, SSa, MSH, DAP, MRS, and IDD accrued patients and collected data. MS, NA, SP performed imaging analysis. NP,AJM and HT led the statistical analysis and verified underlying data. LE, NP, IDD, MRS, AJM, HT, and SSu have accessed and verified the data. LE was the coordinating principal investigator and wrote the first draft of the manuscript. All authors contributed to the writing and approval of this manuscript. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLE 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 (challenge award), Movember, St Vincent\u0026rsquo;s Clinic Research Foundation, and Curran Foundation. SSa reports grants from Novartis/AAA, AstraZeneca, Merck Sharp \u0026amp; Dohme, Genentech, Pfizer, Amgen, and Senhwa to their institution; and personal fees from AstraZeneca, Merck Sharp \u0026amp; Dohme, Bristol Myers Squibb, and AstraZeneca to their institution, outside the submitted work. 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 \u0026amp; Dohme and Novartis; honoraria from Janssen, Novartis, AstraZeneca, and Astellas; support for meetings from Merck Sharp \u0026amp; 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 \u0026amp; 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 \u0026amp; 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 \u0026amp; 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. All other authors declare no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eENZA-p is an investigator-initiated trial led by the ANZUP Cancer Trials Group in partnership with the Prostate Cancer Research Alliance, a joint initiative between the Australian Federal Government and the Movember Foundation. ENZA-p is a collaboration between ANZUP, the NHMRC Clinical Trials Centre at the University of Sydney and the Australasian Radiopharmaceutical Trials Network with support from AdAcAp (a Novartis company), St Vincent\u0026rsquo;s Clinic Foundation, GenesisCare, and Roy Morgan Research. Astellas provided drug support for the trial. ANZUP receives infrastructure funding from Cancer Australia. This sub-study was funded through a prostate cancer foundation challenge award. We acknowledge and thank the 162 participants for their participation in the ENZA-p study; and the principal investigators, co-investigators, and study coordinators at the 15 centres across Australia for their dedication and enthusiasm.\u003cbr\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eEmmett L, Yin C, Crumbaker M, Hruby G, Kneebone A, Epstein R, et al. Rapid Modulation of PSMA Expression by Androgen Deprivation: Serial (68)Ga-PSMA-11 PET in Men with Hormone-Sensitive and Castrate-Resistant Prostate Cancer Commencing Androgen Blockade. J Nucl Med. 2019;60(7):950-4.\u003c/li\u003e\n\u003cli\u003eEvans MJ, Smith-Jones PM, Wongvipat J, Navarro V, Kim S, Bander NH, et al. Noninvasive measurement of androgen receptor signaling with a positron-emitting radiopharmaceutical that targets prostate-specific membrane antigen. Proc Natl Acad Sci U S A. 2011;108(23):9578-82.\u003c/li\u003e\n\u003cli\u003eMeller B, Bremmer F, Sahlmann CO, Hijazi S, Bouter C, Trojan L, et al. Alterations in androgen deprivation enhanced prostate-specific membrane antigen (PSMA) expression in prostate cancer cells as a target for diagnostics and therapy. EJNMMI Res. 2015;5(1):66.\u003c/li\u003e\n\u003cli\u003eMurga JD, Moorji SM, Han AQ, Magargal WW, DiPippo VA, Olson WC. Synergistic co-targeting of prostate-specific membrane antigen and androgen receptor in prostate cancer. Prostate. 2015;75(3):242-54.\u003c/li\u003e\n\u003cli\u003eEmmett L, Subramaniam S, Joshua AM, Crumbaker M, Martin A, Zhang AY, et al. ENZA-p trial protocol: a randomized phase II trial using prostate-specific membrane antigen as a therapeutic target and prognostic indicator in men with metastatic castration-resistant prostate cancer treated with enzalutamide (ANZUP 1901). BJU Int. 2021.\u003c/li\u003e\n\u003cli\u003eEmmett L, Subramaniam S, Crumbaker M, Nguyen A, Joshua AM, Weickhardt A, et al. [(177)Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 2024;25(5):563-71.\u003c/li\u003e\n\u003cli\u003eEmmett L, Subramaniam S, Crumbaker M, Joshua AM, Sandhu S, Nguyen A, et al. Overall survival and quality of life with [(177)Lu]Lu-PSMA-617 plus enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer (ENZA-p): secondary outcomes from a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2025.\u003c/li\u003e\n\u003cli\u003eArmstrong AJ, Lin P, Tombal B, Saad F, Higano CS, Joshua AM, et al. Five-year Survival Prediction and Safety Outcomes with Enzalutamide in Men with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer from the PREVAIL Trial. Eur Urol. 2020;78(3):347-57.\u003c/li\u003e\n\u003cli\u003eArmstrong AJ, Halabi S, Luo J, Nanus DM, Giannakakou P, Szmulewitz RZ, et al. Prospective Multicenter Validation of Androgen Receptor Splice Variant 7 and Hormone Therapy Resistance in High-Risk Castration-Resistant Prostate Cancer: The PROPHECY Study. J Clin Oncol. 2019;37(13):1120-9.\u003c/li\u003e\n\u003cli\u003eCaromile LA, Shapiro LH. PSMA redirects MAPK to PI3K-AKT signaling to promote prostate cancer progression. Mol Cell Oncol. 2017;4(4):e1321168.\u003c/li\u003e\n\u003cli\u003eKaittanis C, Andreou C, Hieronymus H, Mao N, Foss CA, Eiber M, et al. Prostate-specific membrane antigen cleavage of vitamin B9 stimulates oncogenic signaling through metabotropic glutamate receptors. J Exp Med. 2018;215(1):159-75.\u003c/li\u003e\n\u003cli\u003eBakht MK, Oh SW, Youn H, Cheon GJ, Kwak C, Kang KW. Influence of Androgen Deprivation Therapy on the Uptake of PSMA-Targeted Agents: Emerging Opportunities and Challenges. Nucl Med Mol Imaging. 2017;51(3):202-11.\u003c/li\u003e\n\u003cli\u003eRoberts MJ, Morton A, Donato P, Kyle S, Pattison DA, Thomas P, et al. (68)Ga-PSMA PET/CT tumour intensity pre-operatively predicts adverse pathological outcomes and progression-free survival in localised prostate cancer. Eur J Nucl Med Mol Imaging. 2021;48(2):477-82.\u003c/li\u003e\n\u003cli\u003eHadaschik BA, Eiber M, Weber M, Ravi Kumar A, Calais J, Czernin J, et al. Prostate-specific membrane antigen ligand positron emission tomography (PSMA-PET) disease extent and overall survival (OS) in patients (pts) with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC): An international multicenter retrospective study. Journal of Clinical Oncology. 2023;41(16_suppl):5010-.\u003c/li\u003e\n\u003cli\u003ede Kouchkovsky I, Moradpour M, Zhang L, Moradi Tuchayi A, Zhu X, Juarez R, et al. Impact of baseline PSMA PET in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) starting first-line (1L) androgen receptor signaling inhibitor (ARSI) therapy. Journal of Clinical Oncology. 2025;43(5_suppl):46-.\u003c/li\u003e\n\u003cli\u003eEmmett L, Anthony Joshua, Richard Epstein, Venu Chalasani, Andrew Kneebone, George Hruby, Gordon O\u0026apos;Neill, Phillip Stricker, Phillip Stricker, Quoc Nguyen, and Bao Ho. Modulation of PSMA expression by Androgen deprivation therapy (ADT): Serial PSMA PET in men with hormone sensitive, and castrate resistant prostate cancer commencing androgen blockade. J Nucl Med 2018 59:92. 2018.\u003c/li\u003e\n\u003cli\u003eZukotynski KA, Emmenegger U, Hotte S, Kapoor A, Fu W, Blackford AL, et al. Prospective, Single-Arm Trial Evaluating Changes in Uptake Patterns on Prostate-Specific Membrane Antigen-Targeted (18)F-DCFPyL PET/CT in Patients with Castration-Resistant Prostate Cancer Starting Abiraterone or Enzalutamide. J Nucl Med. 2021;62(10):1430-7.\u003c/li\u003e\n\u003cli\u003eButeau JP, Martin AJ, Emmett L, Iravani A, Sandhu S, Joshua AM, et al. PSMA and FDG-PET as predictive and prognostic biomarkers in patients given [(177)Lu]Lu-PSMA-617 versus cabazitaxel for metastatic castration-resistant prostate cancer (TheraP): a biomarker analysis from a randomised, open-label, phase 2 trial. Lancet Oncol. 2022;23(11):1389-97.\u003c/li\u003e\n\u003cli\u003eKuo P, Hesterman J, Rahbar K, Kendi AT, Wei XX, Fang B, et al. [68Ga]Ga-PSMA-11 PET baseline imaging as a prognostic tool for clinical outcomes to [177Lu]Lu-PSMA-617 in patients with mCRPC: A VISION substudy. Journal of Clinical Oncology. 2022;40(16_suppl):5002-.\u003c/li\u003e\n\u003cli\u003eHofman MS, Emmett L, Sandhu S, Iravani A, Buteau JP, Joshua AM, et al. Overall survival with [(177)Lu]Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer (TheraP): secondary outcomes of a randomised, open-label, phase 2 trial. Lancet Oncol. 2024;25(1):99-107.\u003c/li\u003e\n\u003cli\u003eMorris MJ, Castellano D, Herrmann K, de Bono JS, Shore ND, Chi KN, et al. (177)Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial. Lancet. 2024;404(10459):1227-39.\u003c/li\u003e\n\u003cli\u003eSartor O, de Bono J, Chi KN, Fizazi K, Herrmann K, Rahbar K, et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021;385(12):1091-103.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"[177Lu]Lu-PSMA, prostate cancer, ARPI, PSMA upregulation","lastPublishedDoi":"10.21203/rs.3.rs-6307229/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6307229/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003cbr\u003e\n\u003c/strong\u003eProstate-specific membrane antigen (PSMA) receptor expression alters in response to androgen receptor blockade in metastatic castrate resistant prostate cancer (mCRPC). The ENZA-p trial (ANZUP 1901) demonstrated that the addition of\u0026nbsp; [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 to enzalutamide improved overall survival (OS) in mCRPC. In this preplanned imaging substudy, we evaluated the frequency and clinical significance of early changes in PSMA-PET standardised uptake value (SUV) mean with enzalutamide ± [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterials and Methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants in ENZA-p had mCRPC not previously treated with chemotherapy or AR antagonist (abiraterone permitted), [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-avid disease, and at least two risk factors for early progression on enzalutamide alone. Participants were randomised (1:1) to either enzalutamide 160 mg daily or enzalutamide 160 mg daily plus adaptive-dosed [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 7.5 GBq (2 or 4 doses). Participants underwent a \u003csup\u003e68\u003c/sup\u003eGa-PSMA-PET/CT at baseline and day 15 after commencing enzalutamide, with [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 administered subsequently in the experimental arm. All \u003csup\u003e68\u003c/sup\u003eGa-PSMA-PET/CT were analysed with semi-automated software to derive PSMA SUVmean. The study investigated the relationship between \u0026nbsp;early change in SUVmean and the following clinical outcomes: 50% PSA decline (PSA-50), PSA progression-free survival (PSA-PFS), and OS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe randomised 162 pts from Aug 2020 to Jul 2022, all of whom underwent baseline imaging. Of the treated participants 96% (154 out of 160) received a PSMA PET/CT at day 15 after commencing enzalutamide. The median age was 71 years (interquartile range, IQR: 65-76), with 53% having received prior docetaxel and 14% prior abiraterone. An increase in SUVmean at day 15, regardless of magnitude was recorded in 105 out of 154 (68%). Among these participants, the median increase in SUVmean was 13% (IQR: 6.0% - 22%).\u003c/p\u003e\n\u003cp\u003eThe median PSA-PFS in pts with increasing SUVmean by treatment arm was 5.8 months vs 13.1 months for enzalutamide monotherapy vs enzalutamide plus [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 respectively (Log-rank p \u0026lt; 0.001). By contrast, in those with decreasing SUVmean, median PSA-PFS was 12.5 vs 13.3 months for enzalutamide monotherapy vs enzalutamide plus [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 (Log-rank p = 0.5). The p-value for an interaction between early increase or decrease in SUVmean and treatment arm for PSA-PFS was p=0.055.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn early increase in PSMA SUVmean is common with first line enzalutamide in mCRPC, and predictive for shorter PSA-PFS with enzalutamide alone. The addition of [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 to enzalutamide mitigated the shorter PSA-PFS in those with \u0026nbsp;early increase in PSMA SUVmean.\u003c/p\u003e","manuscriptTitle":"Association of early PSMA upregulation with duration of response to enzalutamide with or without [177Lu]Lu-PSMA-617 in poor-risk, metastatic, castration-resistant prostate cancer: Findings from the randomised, phase 2, ENZA-p trial (ANZUP 1901)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-09 08:49:41","doi":"10.21203/rs.3.rs-6307229/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-cancer","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"natcancer","sideBox":"Learn more about [Nature Cancer](http://www.nature.com/natcancer/)","snPcode":"","submissionUrl":"","title":"Nature Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"0753cea1-8d5a-46cc-a80b-0c8161fe6c57","owner":[],"postedDate":"April 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":46887156,"name":"Biological sciences/Cancer/Cancer imaging"},{"id":46887157,"name":"Biological sciences/Cancer/Urological cancer/Prostate cancer"}],"tags":[],"updatedAt":"2026-04-16T07:15:51+00:00","versionOfRecord":{"articleIdentity":"rs-6307229","link":"https://doi.org/10.1038/s43018-026-01140-3","journal":{"identity":"nature-cancer","isVorOnly":false,"title":"Nature Cancer"},"publishedOn":"2026-04-15 04:00:00","publishedOnDateReadable":"April 15th, 2026"},"versionCreatedAt":"2025-04-09 08:49:41","video":"","vorDoi":"10.1038/s43018-026-01140-3","vorDoiUrl":"https://doi.org/10.1038/s43018-026-01140-3","workflowStages":[]},"version":"v1","identity":"rs-6307229","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6307229","identity":"rs-6307229","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}