Abiraterone acetate versus enzalutamide against chemo-naïve castration resistant prostate cancer with full dose induction

Abiraterone acetate versus enzalutamide against chemo-naïve castration resistant prostate cancer with full dose induction | 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 Research Article Abiraterone acetate versus enzalutamide against chemo-naïve castration resistant prostate cancer with full dose induction Tatsuya Shimomura, Keiichiro Mori, Keiji Yasue, Akihiro Matsukawa, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4235921/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose We recently released the multi-institutional real-world analysis about the difference of survival outcome between abiraterone acetate and enzalutamide against chemo-naïve castration resistant prostate cancer as first line setting. Although reduced dose induction cases were included in that analysis, induction dose reduction might correlate reduced efficacy. In this study, we analyzed full dose induction subgroups from our overall cohort and investigated true difference of efficacy between these agents. Methods A total of 220 chemotherapy-naïve CRPC cases treated with full dose induction of first-line ARSI were analyzed. Outcome measures were PSA response, PSA progression-free survival (PSA-PFS), treatment failure free survival (TFF), cancer specific survival (CSS) and overall survival (OS). Results Abiraterone acetate (A) and enzalutamide (E) were administered to 58 and 162 patients, respectively. The median PSA response rate (− 65.4% [A] and − 81.5% [E], p = 0.0252), PSA decline ≥ 90% (22.4% [A] and 37.0% [E], p = 0.0478), PSA-PFS (median 4 months [A] and 7 months [E], p = 0.00833), TFF (median 6 months [A] and 15 months [E], p < 0.0001), CSS (median 45 months [A] and not reached [E], p < 0.0001) and OS (median 34 months [A] and 80 months [E], p < 0.001) were significantly better in the enzalutamide group. Conclusion This study showed that PSA response, PSA-PFS, TTF, CSS and OS were better with first-line enzalutamide administration. Direct inhibition of androgen receptor signaling by enzalutamide is associated with better clinical outcomes in full dose induction cohort. chemotherapy naïve CRPC ARSI PSA response survival outcome metastatic and non-metastatic CRPC Figures Figure 1 Figure 2 Figure 3 Introduction Prostate cancer is one of the most common cancers worldwide ( 1 , 2 ). Usually, androgen deprivation therapy (ADT) is introduced at the start of treatment against advanced disease. However, cancer cells become resistant to ADT after 1–4 years, resulting in a progressive form of prostate cancer, called castration-resistant prostate cancer (CRPC) ( 3 ). Abiraterone acetate and enzalutamide are categorized as new generation androgen receptor signaling inhibitor (ARSI) although their therapeutic mechanisms are different. ( 4 – 8 ) And both agents were proven the efficacy against metastatic castration resistant prostate carcinoma (CRPC) both chemotherapy naïve and post chemotherapy CRPC by randomized controlled trial ( 7 , 9 – 11 ). After significant survival benefit by introducing ARSI were shown in chemotherapy naïve metastatic CRPC ( 10 , 11 ), these agents are introduced as first line setting against metastatic CRPC. And because that abiraterone acetate and enzalutamide have different hormonal mechanisms against prostate cancer as mentioned above, which agent should be introduced first was one of the most important clinical problems. Therefor we investigated our chemotherapy naive CRPC cohort and we released the multi-institutional real-world analysis about the difference of survival outcome between abiraterone acetate and enzalutamide as first line setting. ( 12 ) We concluded that enzalutamide induction correlated with significant better survival outcome in our multi-institutional retrospective study. In our real world analysis, included the cases with reduced induction dose in both abiraterone acetate and enzalutamide. However, it was reported that reduced induction dose of ARSI correlated with reduced efficacy. ( 13 – 15 ) Therefore we need to compare full dose induction cohort to analyze the true difference of efficacy between abiraterone acetate and enzalutamide. In this study, we analyzed full dose induction subgroups in our overall cohort and investigated difference of efficacy between abiraterone acetate and enzalutamide. Patients and methods A total of 242 chemotherapy-naïve CRPC patients introduced first-line abiraterone or enzalutamide between June 2014 and December 2016 at Jikei University Hospital and its affiliated institutions were included in our previous analysis, with a data cut-off date of November 2021. ( 12 ) And we reanalyzed full dose induction subgroups from overall cohort. Induction dose was 160 mg daily in enzalutamide or 1000 mg daily in abiraterone acetate (plus 10mg/daily of prednisolone). However, dose was reduced or treatment agent was stopped temporarily, according to a patient’s medical condition during clinical course if needed. Abiraterone acetate and enzalutamide are approved against both non-metastatic and metastatic CRPC in this country. Therefore, both non-metastatic and metastatic CRPC cases were included in this study. And all patients with or without subsequent therapy were included in the study. Parameters included in this analysis were initial PSA, Gleason score at diagnosis of prostate cancer, age, Eastern Corporative Oncology Group performance status (PS), PSA at induction of ARSI, white blood cell (WBC) count, hemoglobin (Hb), alkaline phosphate (ALP), lactate dehydrogenase (LDH), C-reactive protein (CRP) (values < 0.04 or < 0.01 mg/dl were defined as 0.04 or 0.01 mg/dl, respectively), metastasis at the time of initiating ARAT, primary ADT duration, time to introduction of ARAT from the diagnosis of CRPC, and sequential treatment after failure of first-line ARAT. The outcome measures were PSA response rate, PSA decline ≥ 90%, PSA progression free survival (PSA-PFS), treatment failure free survival (TFF), cancer specific survival (CSS) and overall survival (OS). PSA failure was defined according to the PCWC2 criteria. TFF was defined as the time to discontinue the agent due to clinical progression, the patient’s medical condition, or the physician’s judgment. TTF was the same as the treatment duration. This study was approved Jikei university Institutional Review Board (34–189). Statistical analysis We performed the Mann–Whitney U test, t-test, or Fischer test to evaluate the differences between the groups. Survival rates were estimated using the Kaplan–Meier method, and survival distributions were compared using the log-rank test. A Cox proportional hazards model was used for univariate and multivariate analyses. Multiple imputation method was used to complete the data. And inverse probability of treatment weighting (IPTW) approach was introduced to balance observable characteristics between the groups. Statistical significance was defined as a threshold p-value of < 0.05. All statistical analyses were performed using R (The R Foundation for Statistical Computing, Vienna, Austria) and EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan ( 16 ). Results PSA response and survival outcome Patient demographics of full dose induction subgroups are summarized in Supplementary Table 1. Abiraterone acetate and enzalutamide was introduced as first-line ARSI for 58 and 162 patients, respectively. The median follow-up duration was 24.0 months (range: 1–85 months). Survival outcome (PSA-PFS, TTF, CSS and OS) stratified by the level of PSA decline are shown in Supplementary Fig. 1(a-d). Levels of PSA decline correlated survival outcome significantly. (Median PSA-PFS : PSA decline < 0%: 1m (95%CI: 0–2), 0–90%: 6m (95%CI: 4–8), ≥ 90%: 11m (95%CI: 8–15), p < 0.0001. Median TFF: PSA decline < 0%: 2m (95%CI: 1–4), 0–50%: 9m (95%CI: 6–11), ≥ 90%: 25m (95%CI: 20–30), p < 0.0001, Median CSS : PSA decline < 0%: 43m (95%CI: 21–51), 0–90%: 68m (95%CI: 48-NR), ≥ 90%: not reached (NR) (95%CI: NR-NR), p < 0.0001. Median OS : PSA decline < 0%: 22m (95%CI: 15–47), 0–50%: 53m (95%CI: 45-NR), ≥ 90%: NR (95%CI: NR-NR), p < 0.0001) PSA response rate (PSA-RR) significantly correlated with PSA-PFS (p < 0.0001), TFF (p < 0.0001), CSS (p < 0.0001) and OS (p < 0.0001). (Fig. 1 (a-d)) A better PSA response correlated with a better survival outcome. Patient demographics of abiraterone acetate versus enzalutamide Patient demographics (abiraterone acetate versus enzalutamide) are shown in Table 1. There was no significant difference in the baseline parameters at the time of diagnosis of prostate cancer and at the time of treatment initiation between the two groups, except for the visceral metastasis rate (19.0% [A] vs. 5.6% [E]; p < 0.05). Regarding sequential treatment, 2nd line treatment induction rate was 82.2% [A] and 74.6% [E] (p = 0.408) after primary ARSI failure. There were no significant differences in induction rate of 2nd line ARAT and docetaxel between the groups. And in terms of other 2nd line life prolonging agent, 2nd line 223 Ra was introduced one case in abiraterone acetate group, and 2nd line 223 Ra, bicalutamide, flutamide, estramustine phosphate and ethinylestradiol were introduced 2, 1, 1, 1 and 1 case in enzalutamide group, respectively. PSA responses of first-line abiraterone acetate versus enzalutamide In terms of PSA response rate, the median PSA responses rates were − 65.4% [A] and − 81.5% [E] (p = 0.0252) (Supplementary Fig. 2a). A waterfall plot of the best PSA response in this cohort is shown in Supplementary Fig. 2b. PSA decline of ≥ 90% were 22.4% [A] and 37.0% [E] (p = 0.0478). PSA responses were not available in 4 cases each, in both groups. Survival outcome We investigated PSA-PFS, TTF, CSS and OS in this study. The Kaplan–Meier curves of PSA-PFS, TTF, CSS and OS with respect to abiraterone acetate versus enzalutamide are shown in Fig. 1 (a-d). The median PSA-PFS (4 months [A] and 7 months [E]; p = 0.00833), median TFF (6 months [A] and 15 months [E]; p < 0.0001), median CSS (45 months [A] and not reached (NR) [E]; p < 0.0001), median OS (34 months [A] and 80 months [E]; p < 0.001) were better in the enzalutamide group. Analyses of survival outcome using IPTW method IPTW method was used to minimize patients’ demographics. After IPTW adjustment, all absolute value of standardized mean difference (SMD) in weighted comparisons were < 0.10 except for LDH (SMD = 0.13(CSS) and − 0.12 (OS)) which indicated that distribution of baseline factors was similar between abiraterone acetate and enzalutamide group. (Supplementary Table. 2a, b) IPTW- adjusted Kaplan-Meier curves show that median CSS and OS was significantly longer in enzalutamide group (41 months and 80 months [E], p < 0.001 (CSS), and 34 months [A] and 80 months [E], p = 0.011 (OS)). (Figure. 2a, b) Univariate and multivariate analyses for OS and CSS Univariate and multivariate analyses for CSS and OS are shown in Table 2(a,b). In univariate analysis for CSS, age, PSA, Hb, ALP, ARSI (p = 0.0461, < 0.0001, 0.017, < 0.001 and < 0.001, respectively) were significant. In the multivariate analysis for CSS, ALP (p < 0.01) and ARSI (enzalutamide vs. abiraterone acetate, p < 0.01) were significant factors. (Table 2a) In univariate analysis for OS, age, PS, metastasis, PSA, Hb, ALP, LDH and ARSI (p = 0.012, 0.0024, 0.023, < 0.001, < 0.0001, 0.0045, < 0.001 and 0.00126, respectively) were significant factors. And in the multivariate analysis for OS, Hb (p < 0.01) and ARSI (enzalutamide vs. abiraterone acetate, p = 0.0155) were significant factors. (Table 2b) 2nd line treatment and survival outcome Correlation between 2nd line treatment and survival outcome were analyzed. In ARSI-ARSI seqent cohort, overall survival was not different between the groups (median OS was 51 months [A] and 59 months [E] (p = 0.33). (Supplementary Fig. 3a) In ARSI-docetaxelcohort, although it did not reach significant difference (p = 0.0541), OS trended better in enzalutamide group (median OS was 27 months [A] and 63 months [E] (p = 0.0541). (Supplementary Fig. 3b) And in the cohort without subsequent therapy after failure of primary ARSI, although it did not reach significant difference (p = 0.0997), OS of enzalutamide group might be better (median OS was 29.5 months [A] and 61 months [E]. (Supplementary Fig. 3c) Survival outcome of nmCRPC and mCRPC OS of nmCRPC and mCRPC are shown in Supplementary Fig. 4 (a, b) Median OS of non-metastatic disease was 68 months (abirtaterone) and 80 months (enzalutamide) (p = 0.0733), median OS of metastatic disease was 28 months (abiraterone) and 59 months (enzalutamide) (p = 0.00577). Subgroup analysis Forrest plot of HR for PSA-PFS, TFF, CSS and OS are shown in Fig. 3 (a-d). HR of each subgroups are shifted to enzalutamide better in all survival outcome. Discussion Some reports showed that induction dose of ARSI correlates oncological outcome. ( 13 – 15 ) Tsuzuki et al. reported that reduced induction dose of enzalutamide correlated lower PSA response significantly. ( 13 ) PSA response was − 87.4% (standard dose) and − 66.3% (reduced dose) (p = 0.02). Median PFS was 12.1 months (standard dose) and 7.2 months (reduced dose) (p = 0.038). Yokomizo et al. reported reduced induction dose of enzalutamide correlated shorter time to PSA progression in nmCRPC cohort. ( 14 ) And Yamada et al. reported dose reduction was significant prognostic factor for progression free survival (PFS) in multivariate analysis. ( 15 ) Median PFS was 12.1 months (standard dose) and 7.2 months (reduced dose) (p = 0.038). Recently we reported the difference of efficacy between ARSI (abiraterone acetate and enzalutamide) against chemo-naïve CRPC in real world setting and concluded that introducing enzalutamide first correlates better survival outcome. ( 17 ) Although induction dose correlates oncological outcome mentioned above, our cohort included both full (standard) dose and reduced dose induction cases. Therefor we reanalyzed full dose induction subgroups from our overall cohort to compare true difference of efficacy of ARSI against chemo-naïve CRPC in this study. We showed the results as below, 1. PSA decline correlated survival outcome (PSA-PFS, TFF, CSS and OS). 2. PSA responses was better in enzalutamide group. 3. Therefore, survival outcome (PSA-PFS, TFF, CSS and OS) was better in enzalutamide group. Advantages of enzalutamide were also proved in multivariate analysis, IPTW method and subgroup analysis in this study. PSA response correlates survival outcome ( 17 – 19 ) and better PSA response in enzalutamide were proved in randomized prospective trial previously. ( 20 ) In terms of comparison of survival outcome between ARSI, although phase 2 randomized prospective ARSI cross over trial showed same OS ( 20 ), some meta-analyses studies and two retrospective large cohort studies showed survival benefit with induction enzalutamide first. ( 21 – 25 ) Although, these results were almost same as our overall cohort ( 12 ), true difference of efficacy was shown in this full dose induction analysis. In this study, we focused the efficacy of ARSI against chemo-naïve CRPC. However, ARSI is introduced upfront setting (against metastatic hormone sensitive prostate cancer: mHSPC) nowadays after survival benefit were proved in randomized controlled trial ( 26 – 30 ). Although the induction timing of ARSI is different between conventional setting and upfront setting, the biological feature of prostate cancer would be same at the failure of first line ARSI. Therefore, our results could be referred when consider using ARSI as upfront setting against mHSPC. Because there is no published prospective trial comparing the survival benefit between ARSI against mHSPC, our results would be informative to select the treatment agent. Biologically, time to CRPC in upfront setting might be same as time to progression after introduction of first ARSI in conventional setting. In our study, enzalutamide induction correlated better PSA-PFS and TFF. Therefore, enzalutamide induction in upfront setting would correlate better survival outcome also. Although we could not mention about apalutamide because it is not approved against mCRPC, anti-androgen agent might have more benefit than androgen synthesis inhibitor against mHSPC. This study has some limitations. They are same as our overall cohort study. ( 12 ) First, this was a retrospective analysis, the follow-up regimen was not standardized, and the cohort size was relatively small. Moreover, the number of cases in the abiraterone acetate and enzalutamide groups were unbalanced. This was because enzalutamide was approved earlier than abiraterone acetate in Japan. Conclusion The results of this study indicate that the PSA response, PSA-PFS, TFF, CSS and OS were better with full dose enzalutamide induction first than full dose abiraterone acetate induction. Direct inhibition of AR signaling by enzalutamide was associated with better PSA decline and longer survival outcome (PSA-PFS, TFF, CSS, and OS). Declarations Author Contribution T.S: data analysis and writing manuscript. K.M, K.Y, A.M, W.F, T.Y, K.H, M.M, Y.K and F.U: data collection. J.M and H.Y: supervision. T.K: edit manuscript and supervision. Data Availability The data of this study are available from the corresponding author upon reasonable request. Ethics Statement: This study received Institutional Review Board approval (Jikei University School of Medicine, Tokyo, IRB No. 34-189). conflict of interest Takahiro Kimura is a paid consultant/advisor of Astellas, Bayer, Janssen, and Sanofi. References Ferlay J, Autier P, Boniol M, et al. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol. 2007;18(3):581–92. Siegel R, DeSantis C, Virgo K, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012;62(4):220–41 Mottet N, Bellmunt J, Bolla M, et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2011;59(4):572–83. Tran C, Ouk S, Clegg NJ, et al. 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Supplementary Files ARSIABIvsENZsupplementaryTableFigureforInternationalUrologyandNephrology.pptx Supplementary figure 1. Survival outcome (PSA-PFS, TTF, CSS and OS) stratified by the level of PSA decline 1a: Kaplan–Meier curves of PSA-PFS stratified by the level of PSA decline 1b: Kaplan–Meier curves of TFF stratified by the level of PSA decline 1c: Kaplan–Meier curves of CSS stratified by the level of PSA decline 1d: Kaplan–Meier curves of OS stratified by the level of PSA decline Supplementary figure 2. PSA response rate (best PSA response) of Abiraterone acetate group and Enzalutamide group 2a: median PSA decline of Abiraterone group and Enzalutamide group 2b: waterfall plot of the best PSA response Supplementary figure 3. 2 nd line treatment and survival outcome 3a. Kaplan–Meier curves of OS in 2 nd line ARAT cohort 3b. Kaplan–Meier curves of OS in 2 nd line ARAT cohort 3c. Kaplan–Meier curves of OS in the cohort without 2 nd line treatment after primary ARAT failure Supplementary figure 4. Kaplan–Meier curve of OS in metastatic and non-metastatic CRPC 4a. Kaplan–Meier curve of OS in non- metastatic CRPC subgroup 4b. Kaplan–Meier curve of OS in metastatic CRPC subgroup ARSIABIvsENZTableforInternationalUrologyandNephrology.pptx Cite Share Download PDF Status: Posted 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. 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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-4235921","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":290863321,"identity":"2a9155d3-e944-4380-92c2-a84192d0d819","order_by":0,"name":"Tatsuya 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Medicine","correspondingAuthor":false,"prefix":"","firstName":"Masaya","middleName":"","lastName":"Murakami","suffix":""},{"id":290863335,"identity":"9ce8ea1d-7749-4fc6-acfc-41502e0faa3d","order_by":8,"name":"Yusuke Koike","email":"","orcid":"","institution":"Jikei University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yusuke","middleName":"","lastName":"Koike","suffix":""},{"id":290863336,"identity":"974622a2-0c59-40df-bf41-d73b38cf0f37","order_by":9,"name":"Fumihiko Urabe","email":"","orcid":"","institution":"Jikei University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Fumihiko","middleName":"","lastName":"Urabe","suffix":""},{"id":290863337,"identity":"8f6ba019-9b8d-4c04-824d-8f3beb16a096","order_by":10,"name":"Jun Miki","email":"","orcid":"","institution":"Jikei University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Miki","suffix":""},{"id":290863338,"identity":"65f2edbf-58c5-4116-bc9c-af455028e313","order_by":11,"name":"Hiroki Yamada","email":"","orcid":"","institution":"Jikei University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hiroki","middleName":"","lastName":"Yamada","suffix":""},{"id":290863339,"identity":"a7608756-e9eb-478b-a8a9-f9a54be3f0de","order_by":12,"name":"Takahiro Kimura","email":"","orcid":"","institution":"Jikei University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Takahiro","middleName":"","lastName":"Kimura","suffix":""}],"badges":[],"createdAt":"2024-04-08 11:14:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4235921/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4235921/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":54931592,"identity":"5db6bba0-220d-41b3-82c2-d6bbb52c03dc","added_by":"auto","created_at":"2024-04-18 18:48:05","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":96602,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival outcome of Abiraterone group and Enzalutamide group\u003c/p\u003e\n\u003cp\u003e1a: Kaplan–Meier curves of PSA-PFS in Abiraterone group and Enzalutamide group\u003c/p\u003e\n\u003cp\u003e1b: Kaplan–Meier curves of TFF in Abiraterone group and Enzalutamide group\u003c/p\u003e\n\u003cp\u003e1c: Kaplan–Meier curves of CSS in Abiraterone group and Enzalutamide group\u003c/p\u003e\n\u003cp\u003e1d: Kaplan–Meier curves of OS in Abiraterone group and Enzalutamide group\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4235921/v1/3b7bae95cb87316b758032b8.png"},{"id":54931597,"identity":"2951b3ff-1548-412e-8f64-1f6cc5d973df","added_by":"auto","created_at":"2024-04-18 18:48:05","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":130246,"visible":true,"origin":"","legend":"\u003cp\u003eIPTW- adjusted Kaplan-Meier curves\u003c/p\u003e\n\u003cp\u003e2a. IPTW- adjusted Kaplan-Meier curves for CSS\u003c/p\u003e\n\u003cp\u003e2b. IPTW- adjusted Kaplan-Meier curves for OS\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4235921/v1/8898d388a3e9fc9ea401220a.png"},{"id":54931596,"identity":"d7e78d61-0607-4de6-ac06-606e82e7b15b","added_by":"auto","created_at":"2024-04-18 18:48:05","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":214990,"visible":true,"origin":"","legend":"\u003cp\u003eForrest plot of subgroup analysis for CSS and OS\u003c/p\u003e\n\u003cp\u003e3a. Forrest plot of subgroup analysis for CSS\u003c/p\u003e\n\u003cp\u003e3b: Forrest plot of subgroup analysis for OS\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4235921/v1/a99a5842813f955fd8480b97.png"},{"id":54932515,"identity":"ccdac96d-dcb0-4869-ade4-cd9d4e656e3d","added_by":"auto","created_at":"2024-04-18 19:04:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":719029,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4235921/v1/d9ea0d63-5028-41e5-b6a2-40c2efc7e3cb.pdf"},{"id":54931593,"identity":"314750f4-767f-4192-8ba8-b7ba80e778bc","added_by":"auto","created_at":"2024-04-18 18:48:05","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":311734,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary figure 1. Survival outcome (PSA-PFS, TTF, CSS and OS) stratified by the level of PSA decline\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; 1a: Kaplan–Meier curves of PSA-PFS stratified by the level of PSA decline\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; 1b: Kaplan–Meier curves of TFF stratified by the level of PSA decline\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; 1c: Kaplan–Meier curves of CSS stratified by the level of PSA decline\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; 1d: Kaplan–Meier curves of OS stratified by the level of PSA decline\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSupplementary figure 2. PSA response rate (best PSA response) of Abiraterone acetate group and Enzalutamide group\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; 2a: median PSA decline of Abiraterone group and Enzalutamide group\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; 2b: waterfall plot of the best PSA response\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSupplementary figure 3. 2\u003csup\u003end\u003c/sup\u003e line treatment and survival outcome\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; 3a. Kaplan–Meier curves of OS in 2\u003csup\u003end\u003c/sup\u003e line ARAT cohort\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp;3b. Kaplan–Meier curves of OS in 2\u003csup\u003end\u003c/sup\u003e line ARAT cohort\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp;3c. Kaplan–Meier curves of OS in the cohort without 2\u003csup\u003end\u003c/sup\u003e line treatment after primary ARAT failure\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSupplementary figure 4. Kaplan–Meier curve of OS in metastatic and non-metastatic CRPC\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; 4a. Kaplan–Meier curve of OS in non- metastatic CRPC subgroup\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; 4b. Kaplan–Meier curve of OS in metastatic CRPC subgroup\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"ARSIABIvsENZsupplementaryTableFigureforInternationalUrologyandNephrology.pptx","url":"https://assets-eu.researchsquare.com/files/rs-4235921/v1/26578ade56d2cfad23aac32b.pptx"},{"id":54931594,"identity":"75aeb412-80b8-4b7d-b694-8ed74150c797","added_by":"auto","created_at":"2024-04-18 18:48:05","extension":"pptx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":56672,"visible":true,"origin":"","legend":"","description":"","filename":"ARSIABIvsENZTableforInternationalUrologyandNephrology.pptx","url":"https://assets-eu.researchsquare.com/files/rs-4235921/v1/8039b657c5ec4a4dccb3df8d.pptx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Abiraterone acetate versus enzalutamide against chemo-naïve castration resistant prostate cancer with full dose induction","fulltext":[{"header":"Introduction","content":"\u003cp\u003eProstate cancer is one of the most common cancers worldwide (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Usually, androgen deprivation therapy (ADT) is introduced at the start of treatment against advanced disease. However, cancer cells become resistant to ADT after 1–4 years, resulting in a progressive form of prostate cancer, called castration-resistant prostate cancer (CRPC) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAbiraterone acetate and enzalutamide are categorized as new generation androgen receptor signaling inhibitor (ARSI) although their therapeutic mechanisms are different. (\u003cspan additionalcitationids=\"CR5 CR6 CR7\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e–\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) And both agents were proven the efficacy against metastatic castration resistant prostate carcinoma (CRPC) both chemotherapy naïve and post chemotherapy CRPC by randomized controlled trial (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e–\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). After significant survival benefit by introducing ARSI were shown in chemotherapy naïve metastatic CRPC (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e), these agents are introduced as first line setting against metastatic CRPC. And because that abiraterone acetate and enzalutamide have different hormonal mechanisms against prostate cancer as mentioned above, which agent should be introduced first was one of the most important clinical problems. Therefor we investigated our chemotherapy naive CRPC cohort and we released the multi-institutional real-world analysis about the difference of survival outcome between abiraterone acetate and enzalutamide as first line setting. (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) We concluded that enzalutamide induction correlated with significant better survival outcome in our multi-institutional retrospective study. In our real world analysis, included the cases with reduced induction dose in both abiraterone acetate and enzalutamide. However, it was reported that reduced induction dose of ARSI correlated with reduced efficacy. (\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e–\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) Therefore we need to compare full dose induction cohort to analyze the true difference of efficacy between abiraterone acetate and enzalutamide. In this study, we analyzed full dose induction subgroups in our overall cohort and investigated difference of efficacy between abiraterone acetate and enzalutamide.\u003c/p\u003e "},{"header":"Patients and methods","content":"\u003cp\u003eA total of 242 chemotherapy-naïve CRPC patients introduced first-line abiraterone or enzalutamide between June 2014 and December 2016 at Jikei University Hospital and its affiliated institutions were included in our previous analysis, with a data cut-off date of November 2021. (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) And we reanalyzed full dose induction subgroups from overall cohort. Induction dose was 160 mg daily in enzalutamide or 1000 mg daily in abiraterone acetate (plus 10mg/daily of prednisolone). However, dose was reduced or treatment agent was stopped temporarily, according to a patient’s medical condition during clinical course if needed. Abiraterone acetate and enzalutamide are approved against both non-metastatic and metastatic CRPC in this country. Therefore, both non-metastatic and metastatic CRPC cases were included in this study. And all patients with or without subsequent therapy were included in the study.\u003c/p\u003e\u003cp\u003eParameters included in this analysis were initial PSA, Gleason score at diagnosis of prostate cancer, age, Eastern Corporative Oncology Group performance status (PS), PSA at induction of ARSI, white blood cell (WBC) count, hemoglobin (Hb), alkaline phosphate (ALP), lactate dehydrogenase (LDH), C-reactive protein (CRP) (values \u0026lt; 0.04 or \u0026lt; 0.01 mg/dl were defined as 0.04 or 0.01 mg/dl, respectively), metastasis at the time of initiating ARAT, primary ADT duration, time to introduction of ARAT from the diagnosis of CRPC, and sequential treatment after failure of first-line ARAT. The outcome measures were PSA response rate, PSA decline ≥ 90%, PSA progression free survival (PSA-PFS), treatment failure free survival (TFF), cancer specific survival (CSS) and overall survival (OS). PSA failure was defined according to the PCWC2 criteria. TFF was defined as the time to discontinue the agent due to clinical progression, the patient’s medical condition, or the physician’s judgment. TTF was the same as the treatment duration.\u003c/p\u003e\u003cp\u003e This study was approved Jikei university Institutional Review Board (34–189).\u003c/p\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eWe performed the Mann–Whitney U test, t-test, or Fischer test to evaluate the differences between the groups. Survival rates were estimated using the Kaplan–Meier method, and survival distributions were compared using the log-rank test. A Cox proportional hazards model was used for univariate and multivariate analyses. Multiple imputation method was used to complete the data. And inverse probability of treatment weighting (IPTW) approach was introduced to balance observable characteristics between the groups. Statistical significance was defined as a threshold p-value of \u0026lt; 0.05. All statistical analyses were performed using R (The R Foundation for Statistical Computing, Vienna, Austria) and EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003ePSA response and survival outcome\u003c/p\u003e \u003cp\u003ePatient demographics of full dose induction subgroups are summarized in Supplementary Table\u0026nbsp;1. Abiraterone acetate and enzalutamide was introduced as first-line ARSI for 58 and 162 patients, respectively. The median follow-up duration was 24.0 months (range: 1\u0026ndash;85 months).\u003c/p\u003e \u003cp\u003eSurvival outcome (PSA-PFS, TTF, CSS and OS) stratified by the level of PSA decline are shown in Supplementary Fig.\u0026nbsp;1(a-d). Levels of PSA decline correlated survival outcome significantly. (Median PSA-PFS : PSA decline\u0026thinsp;\u0026lt;\u0026thinsp;0%: 1m (95%CI: 0\u0026ndash;2), 0\u0026ndash;90%: 6m (95%CI: 4\u0026ndash;8), \u0026ge;\u0026thinsp;90%: 11m (95%CI: 8\u0026ndash;15), p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001. Median TFF: PSA decline\u0026thinsp;\u0026lt;\u0026thinsp;0%: 2m (95%CI: 1\u0026ndash;4), 0\u0026ndash;50%: 9m (95%CI: 6\u0026ndash;11), \u0026ge;\u0026thinsp;90%: 25m (95%CI: 20\u0026ndash;30), p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, Median CSS : PSA decline\u0026thinsp;\u0026lt;\u0026thinsp;0%: 43m (95%CI: 21\u0026ndash;51), 0\u0026ndash;90%: 68m (95%CI: 48-NR), \u0026ge;\u0026thinsp;90%: not reached (NR) (95%CI: NR-NR), p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001. Median OS : PSA decline\u0026thinsp;\u0026lt;\u0026thinsp;0%: 22m (95%CI: 15\u0026ndash;47), 0\u0026ndash;50%: 53m (95%CI: 45-NR), \u0026ge;\u0026thinsp;90%: NR (95%CI: NR-NR), p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) PSA response rate (PSA-RR) significantly correlated with PSA-PFS (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), TFF (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), CSS (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and OS (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e(a-d)) A better PSA response correlated with a better survival outcome.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePatient demographics of abiraterone acetate versus enzalutamide\u003c/p\u003e \u003cp\u003ePatient demographics (abiraterone acetate versus enzalutamide) are shown in Table\u0026nbsp;1. There was no significant difference in the baseline parameters at the time of diagnosis of prostate cancer and at the time of treatment initiation between the two groups, except for the visceral metastasis rate (19.0% [A] vs. 5.6% [E]; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Regarding sequential treatment, 2nd line treatment induction rate was 82.2% [A] and 74.6% [E] (p\u0026thinsp;=\u0026thinsp;0.408) after primary ARSI failure. There were no significant differences in induction rate of 2nd line ARAT and docetaxel between the groups. And in terms of other 2nd line life prolonging agent, 2nd line \u003csup\u003e223\u003c/sup\u003eRa was introduced one case in abiraterone acetate group, and 2nd line \u003csup\u003e223\u003c/sup\u003eRa, bicalutamide, flutamide, estramustine phosphate and ethinylestradiol were introduced 2, 1, 1, 1 and 1 case in enzalutamide group, respectively.\u003c/p\u003e \u003cp\u003ePSA responses of first-line abiraterone acetate versus enzalutamide\u003c/p\u003e \u003cp\u003eIn terms of PSA response rate, the median PSA responses rates were \u0026minus;\u0026thinsp;65.4% [A] and \u0026minus;\u0026thinsp;81.5% [E] (p\u0026thinsp;=\u0026thinsp;0.0252) (Supplementary Fig.\u0026nbsp;2a). A waterfall plot of the best PSA response in this cohort is shown in Supplementary Fig.\u0026nbsp;2b. PSA decline of \u0026ge;\u0026thinsp;90% were 22.4% [A] and 37.0% [E] (p\u0026thinsp;=\u0026thinsp;0.0478). PSA responses were not available in 4 cases each, in both groups.\u003c/p\u003e \u003cp\u003eSurvival outcome\u003c/p\u003e \u003cp\u003eWe investigated PSA-PFS, TTF, CSS and OS in this study. The Kaplan\u0026ndash;Meier curves of PSA-PFS, TTF, CSS and OS with respect to abiraterone acetate versus enzalutamide are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e(a-d). The median PSA-PFS (4 months [A] and 7 months [E]; p\u0026thinsp;=\u0026thinsp;0.00833), median TFF (6 months [A] and 15 months [E]; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), median CSS (45 months [A] and not reached (NR) [E]; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), median OS (34 months [A] and 80 months [E]; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were better in the enzalutamide group.\u003c/p\u003e \u003cp\u003eAnalyses of survival outcome using IPTW method\u003c/p\u003e \u003cp\u003eIPTW method was used to minimize patients\u0026rsquo; demographics. After IPTW adjustment, all absolute value of standardized mean difference (SMD) in weighted comparisons were \u0026lt;\u0026thinsp;0.10 except for LDH (SMD\u0026thinsp;=\u0026thinsp;0.13(CSS) and \u0026minus;\u0026thinsp;0.12 (OS)) which indicated that distribution of baseline factors was similar between abiraterone acetate and enzalutamide group. (Supplementary Table. 2a, b) IPTW- adjusted Kaplan-Meier curves show that median CSS and OS was significantly longer in enzalutamide group (41 months and 80 months [E], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 (CSS), and 34 months [A] and 80 months [E], p\u0026thinsp;=\u0026thinsp;0.011 (OS)). (Figure. 2a, b)\u003c/p\u003e \u003cp\u003eUnivariate and multivariate analyses for OS and CSS\u003c/p\u003e \u003cp\u003eUnivariate and multivariate analyses for CSS and OS are shown in Table\u0026nbsp;2(a,b). In univariate analysis for CSS, age, PSA, Hb, ALP, ARSI (p\u0026thinsp;=\u0026thinsp;0.0461, \u0026lt;\u0026thinsp;0.0001, 0.017, \u0026lt;\u0026thinsp;0.001 and \u0026lt;\u0026thinsp;0.001, respectively) were significant. In the multivariate analysis for CSS, ALP (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and ARSI (enzalutamide vs. abiraterone acetate, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) were significant factors. (Table\u0026nbsp;2a) In univariate analysis for OS, age, PS, metastasis, PSA, Hb, ALP, LDH and ARSI (p\u0026thinsp;=\u0026thinsp;0.012, 0.0024, 0.023, \u0026lt;\u0026thinsp;0.001, \u0026lt;\u0026thinsp;0.0001, 0.0045, \u0026lt;\u0026thinsp;0.001 and 0.00126, respectively) were significant factors. And in the multivariate analysis for OS, Hb (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and ARSI (enzalutamide vs. abiraterone acetate, p\u0026thinsp;=\u0026thinsp;0.0155) were significant factors. (Table\u0026nbsp;2b)\u003c/p\u003e \u003cp\u003e2nd line treatment and survival outcome\u003c/p\u003e \u003cp\u003eCorrelation between 2nd line treatment and survival outcome were analyzed. In ARSI-ARSI seqent cohort, overall survival was not different between the groups (median OS was 51 months [A] and 59 months [E] (p\u0026thinsp;=\u0026thinsp;0.33). (Supplementary Fig.\u0026nbsp;3a) In ARSI-docetaxelcohort, although it did not reach significant difference (p\u0026thinsp;=\u0026thinsp;0.0541), OS trended better in enzalutamide group (median OS was 27 months [A] and 63 months [E] (p\u0026thinsp;=\u0026thinsp;0.0541). (Supplementary Fig.\u0026nbsp;3b) And in the cohort without subsequent therapy after failure of primary ARSI, although it did not reach significant difference (p\u0026thinsp;=\u0026thinsp;0.0997), OS of enzalutamide group might be better (median OS was 29.5 months [A] and 61 months [E]. (Supplementary Fig.\u0026nbsp;3c)\u003c/p\u003e \u003cp\u003eSurvival outcome of nmCRPC and mCRPC\u003c/p\u003e \u003cp\u003eOS of nmCRPC and mCRPC are shown in Supplementary Fig.\u0026nbsp;4 (a, b) Median OS of non-metastatic disease was 68 months (abirtaterone) and 80 months (enzalutamide) (p\u0026thinsp;=\u0026thinsp;0.0733), median OS of metastatic disease was 28 months (abiraterone) and 59 months (enzalutamide) (p\u0026thinsp;=\u0026thinsp;0.00577).\u003c/p\u003e \u003cp\u003eSubgroup analysis\u003c/p\u003e \u003cp\u003eForrest plot of HR for PSA-PFS, TFF, CSS and OS are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e (a-d). HR of each subgroups are shifted to enzalutamide better in all survival outcome.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSome reports showed that induction dose of ARSI correlates oncological outcome. (\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) Tsuzuki et al. reported that reduced induction dose of enzalutamide correlated lower PSA response significantly. (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) PSA response was \u0026minus;\u0026thinsp;87.4% (standard dose) and \u0026minus;\u0026thinsp;66.3% (reduced dose) (p\u0026thinsp;=\u0026thinsp;0.02). Median PFS was 12.1 months (standard dose) and 7.2 months (reduced dose) (p\u0026thinsp;=\u0026thinsp;0.038). Yokomizo et al. reported reduced induction dose of enzalutamide correlated shorter time to PSA progression in nmCRPC cohort. (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) And Yamada et al. reported dose reduction was significant prognostic factor for progression free survival (PFS) in multivariate analysis. (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) Median PFS was 12.1 months (standard dose) and 7.2 months (reduced dose) (p\u0026thinsp;=\u0026thinsp;0.038). Recently we reported the difference of efficacy between ARSI (abiraterone acetate and enzalutamide) against chemo-na\u0026iuml;ve CRPC in real world setting and concluded that introducing enzalutamide first correlates better survival outcome. (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) Although induction dose correlates oncological outcome mentioned above, our cohort included both full (standard) dose and reduced dose induction cases. Therefor we reanalyzed full dose induction subgroups from our overall cohort to compare true difference of efficacy of ARSI against chemo-na\u0026iuml;ve CRPC in this study. We showed the results as below, 1. PSA decline correlated survival outcome (PSA-PFS, TFF, CSS and OS). 2. PSA responses was better in enzalutamide group. 3. Therefore, survival outcome (PSA-PFS, TFF, CSS and OS) was better in enzalutamide group. Advantages of enzalutamide were also proved in multivariate analysis, IPTW method and subgroup analysis in this study.\u003c/p\u003e \u003cp\u003ePSA response correlates survival outcome (\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) and better PSA response in enzalutamide were proved in randomized prospective trial previously. (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) In terms of comparison of survival outcome between ARSI, although phase 2 randomized prospective ARSI cross over trial showed same OS (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e), some meta-analyses studies and two retrospective large cohort studies showed survival benefit with induction enzalutamide first. (\u003cspan additionalcitationids=\"CR22 CR23 CR24\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) Although, these results were almost same as our overall cohort (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), true difference of efficacy was shown in this full dose induction analysis.\u003c/p\u003e \u003cp\u003eIn this study, we focused the efficacy of ARSI against chemo-na\u0026iuml;ve CRPC. However, ARSI is introduced upfront setting (against metastatic hormone sensitive prostate cancer: mHSPC) nowadays after survival benefit were proved in randomized controlled trial (\u003cspan additionalcitationids=\"CR27 CR28 CR29\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Although the induction timing of ARSI is different between conventional setting and upfront setting, the biological feature of prostate cancer would be same at the failure of first line ARSI. Therefore, our results could be referred when consider using ARSI as upfront setting against mHSPC. Because there is no published prospective trial comparing the survival benefit between ARSI against mHSPC, our results would be informative to select the treatment agent. Biologically, time to CRPC in upfront setting might be same as time to progression after introduction of first ARSI in conventional setting. In our study, enzalutamide induction correlated better PSA-PFS and TFF. Therefore, enzalutamide induction in upfront setting would correlate better survival outcome also. Although we could not mention about apalutamide because it is not approved against mCRPC, anti-androgen agent might have more benefit than androgen synthesis inhibitor against mHSPC.\u003c/p\u003e \u003cp\u003eThis study has some limitations. They are same as our overall cohort study. (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) First, this was a retrospective analysis, the follow-up regimen was not standardized, and the cohort size was relatively small. Moreover, the number of cases in the abiraterone acetate and enzalutamide groups were unbalanced. This was because enzalutamide was approved earlier than abiraterone acetate in Japan.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe results of this study indicate that the PSA response, PSA-PFS, TFF, CSS and OS were better with full dose enzalutamide induction first than full dose abiraterone acetate induction. Direct inhibition of AR signaling by enzalutamide was associated with better PSA decline and longer survival outcome (PSA-PFS, TFF, CSS, and OS).\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eT.S: data analysis and writing manuscript. K.M, K.Y, A.M, W.F, T.Y, K.H, M.M, Y.K and F.U: data collection. J.M and H.Y: supervision. T.K: edit manuscript and supervision.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eEthics Statement:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study received Institutional Review Board approval (Jikei University School of Medicine, Tokyo, IRB No. 34-189).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003econflict of interest \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTakahiro Kimura is a paid consultant/advisor of Astellas, Bayer, Janssen, and Sanofi.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e\u003cspan\u003eFerlay J, Autier P, Boniol M, et al. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol. 2007;18(3):581\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eSiegel R, DeSantis C, Virgo K, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012;62(4):220\u0026ndash;41\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eMottet N, Bellmunt J, Bolla M, et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2011;59(4):572\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eTran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 2009; 324:787\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eLeibowitz-Amit R, Joshua AM. Targeting the androgen receptor in the management of castration-resistant prostate cancer: rationale, progress and future directions. Curr Oncol 2012;19(Suppl 3):S22-31.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eCheng J, Wu Y, Mohler JL, Ip C. The transcriptomics of de novo androgen biosynthesis in prostate cancer cells following androgen reduction. Cancer Biol Ther 2010; 9:1033\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eFizazi K, Scher HI, Molina A, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2012; 13:983\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eSonpavde G, Attard G, Bellmunt J, et al. The role of abiraterone acetate in the management of prostate cancer: a critical analysis of the literature. Eur Urol 2011; 60:270\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eScher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367:1187\u0026ndash;97.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eBeer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371:424\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eRyan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2015; 16:152\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eShimomura T, Mori K, Yasue K, et al. Survival outcome of chemotherapy-na\u0026iuml;ve castration-resistant prostate cancer treated with new-generation androgen receptor axis-targeted agents in real-world analysis. Int J Clin Oncol. 2024;29(2):213\u0026ndash;221\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eTsuzuki S, Nakanishi S, Tamaki M, et al. Initial dose reduction of enzalutamide does not decrease the incidence of adverse events in castration-resistant prostate cancer. PLOS ONE \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e|https://doi.org/10.1371/journal.pone.0258160\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eYokomizo A, Yonese J, Egawa S, et al. Real -world use of enzalutamide in men with nonmetastatic castration-resistant prostate cancer in Japan. International Journal of Clinical Oncology (2022) 27:418\u0026ndash;426\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eYamada S, Shiota M, Blas L et al. Prognostic impact of dose reduction in androgen receptor pathway inhibitors for castration-resistant prostate cancer. Prostate International 10 (2022) 50\u0026ndash;55\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eKanda Y.: Investigation of the freely-available easy-to-use software \u0026ldquo;EZR\u0026rdquo; (Easy R) for medical statistics. : Bone Marrow Transplant. 2013:48,452\u0026ndash;458.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eRescigno P, Lorente D, Bianchini D, et.al Prostate-specific Antigen Decline After 4 Weeks of Treatment with Abiraterone Acetate and Overall Survival in Patients with Metastatic Castration-resistant Prostate Cancer. European Urology 2016;70(5):724\u0026ndash;731\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eArmstrong AJ, Lin P, Higano CS, et.al Prognostic Association of Prostate-specific Antigen Decline with Clinical Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Treated with Enzalutamide in a Randomized Clinical Trial. European Urology Oncology 2019;2:677\u0026ndash;684\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eXu XS, Ryan CJ, Stuyckens K, et.al Correlation between Prostate-Specific Antigen Kinetics and Overall Survival in Abiraterone Acetate\u0026ndash;Treated Castration-Resistant Prostate Cancer Patients. Clin Cancer Res 2015;21(14), 3170\u0026ndash;3177\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eKhalaf DJ, Annala M, Taavitsainen S, et.al Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial. The lancet oncology 2019;20:1730\u0026ndash;1739\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eFang M, Nakazawa M, Antonarakis ES, et.al Efficacy of Abiraterone and Enzalutamide in Pre- and Postdocetaxel Castration-Resistant Prostate Cancer: A Trial-Level Meta-Analysis. Hindawi Prostate Cancer Volume 2017, Article ID 8560827\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eChopra A, Georgieva M, Lopes G, et.al Abiraterone or Enzalutamide in Advanced Castration-Resistant Prostate Cancer: An Indirect Comparison. The Prostate 2017;77:639\u0026ndash;646\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eMcCool R, Fleetwood K, Glanville J, et.al Systematic Review and Network Meta-Analysis of Treatments for Chemotherapy-Naive Patients with Asymptomatic/Mildly Symptomatic Metastatic Castration-Resistant Prostate Cancer. Value in health 2018;21: 1259\u0026ndash;1268\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eTagawa ST, Ramaswamy K, Huang A, et.al Survival outcomes in patients with chemotherapy-naive metastatic castration-resistant prostate cancer treated with enzalutamide or abiraterone acetate. Prostate Cancer and Prostatic Diseases 2021;24, 1032\u0026ndash;1040\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eScailteux LM, Campillo-Gimenez B, Kerbrat S, et.al Overall Survival Among Chemotherapy-Naive Patients With Castration-Resistant Prostate Cancer Under Abiraterone Versus Enzalutamide: A Direct Comparison Based on a 2014\u0026ndash;2018 French Population Study (theSPEAR Cohort). Am J Epidemiol. 2021;190(3):413\u0026ndash;422\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eFizazi K, Tran NP, Fein L, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med 2017; 377:352\u0026ndash;360\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eDavis ID, Martin AJ, Stockler MR, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med 2019; 381:121\u0026ndash;131\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eArmstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. Journal of Clinical Oncology, Volume 37, Number 32\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eChi KN, Agarwal N, Bjartell A, et al. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med 2019; 381:13\u0026ndash;24\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eJames ND, de Bono JS, Spears MR et al. Abiraterone for prostate cancer \u003cspan\u003enot previously treated with hormone therapy. N Engl J Med 2017; 377: 338\u0026ndash;51\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"chemotherapy naïve CRPC, ARSI, PSA response, survival outcome, metastatic and non-metastatic CRPC","lastPublishedDoi":"10.21203/rs.3.rs-4235921/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4235921/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003ePurpose\u003c/b\u003e\u003c/p\u003e \u003cp\u003eWe recently released the multi-institutional real-world analysis about the difference of survival outcome between abiraterone acetate and enzalutamide against chemo-na\u0026iuml;ve castration resistant prostate cancer as first line setting. Although reduced dose induction cases were included in that analysis, induction dose reduction might correlate reduced efficacy. In this study, we analyzed full dose induction subgroups from our overall cohort and investigated true difference of efficacy between these agents.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eA total of 220 chemotherapy-na\u0026iuml;ve CRPC cases treated with full dose induction of first-line ARSI were analyzed. Outcome measures were PSA response, PSA progression-free survival (PSA-PFS), treatment failure free survival (TFF), cancer specific survival (CSS) and overall survival (OS).\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAbiraterone acetate (A) and enzalutamide (E) were administered to 58 and 162 patients, respectively. The median PSA response rate (\u0026minus;\u0026thinsp;65.4% [A] and \u0026minus;\u0026thinsp;81.5% [E], p\u0026thinsp;=\u0026thinsp;0.0252), PSA decline\u0026thinsp;\u0026ge;\u0026thinsp;90% (22.4% [A] and 37.0% [E], p\u0026thinsp;=\u0026thinsp;0.0478), PSA-PFS (median 4 months [A] and 7 months [E], p\u0026thinsp;=\u0026thinsp;0.00833), TFF (median 6 months [A] and 15 months [E], p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), CSS (median 45 months [A] and not reached [E], p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and OS (median 34 months [A] and 80 months [E], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were significantly better in the enzalutamide group.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis study showed that PSA response, PSA-PFS, TTF, CSS and OS were better with first-line enzalutamide administration. Direct inhibition of androgen receptor signaling by enzalutamide is associated with better clinical outcomes in full dose induction cohort.\u003c/p\u003e","manuscriptTitle":"Abiraterone acetate versus enzalutamide against chemo-naïve castration resistant prostate cancer with full dose induction","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-18 18:48:00","doi":"10.21203/rs.3.rs-4235921/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1c5eb0e5-68ea-4558-9be9-44e8d74c3879","owner":[],"postedDate":"April 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-04-18T18:48:02+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-18 18:48:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4235921","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4235921","identity":"rs-4235921","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}