Association between concomitant proton pump inhibitor use and survival of patients with metastatic prostate cancer receiving abiraterone acetate: a post-hoc analysis of pooled data from three randomized controlled trials

Association between concomitant proton pump inhibitor use and survival of patients with metastatic prostate cancer receiving abiraterone acetate: a post-hoc analysis of pooled data from three randomized controlled trials | 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 Help Center Sign In Submit a Preprint Cite Share Download PDF Article Association between concomitant proton pump inhibitor use and survival of patients with metastatic prostate cancer receiving abiraterone acetate: a post-hoc analysis of pooled data from three randomized controlled trials Wataru Fukuokaya, Keiichiro Mori, Takafumi Yanagisawa, Kohei Akazawa, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2834713/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Jul, 2023 Read the published version in Prostate Cancer and Prostatic Diseases → Version 1 posted 13 You are reading this latest preprint version Abstract Background Evidence suggests proton pump inhibitor (PPI) use may attenuate the effect of abiraterone acetate plus prednisone (AAP) in metastatic prostate cancer via the modification of gut microbiota. This study aimed to examine whether concomitant PPI use is associated with survival in patients with metastatic prostate cancer treated with androgen deprivation therapy (ADT) and AAP. Methods Post-hoc analysis was conducted in patients with metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC) treated in the LATITUDE, COU-AA-301, and COU-AA-302 trials (ADT vs. ADT plus AAP). PPI users and non-users were compared for restricted mean overall survival time (RMOST) and restricted mean progression-free survival time (RMPFST) based on inverse probability of treatment weight (IPTW)-adjusted Kaplan-Meier curves. IPTW-adjusted Cox regression models were used to assess heterogeneity of treatment effect. Results In patients treated with AAP, PPI use was associated with inferior RMOST [difference (95% confidence interval): -4.2 (-7.0 to -1.4)] and RMPFST [-3.5 (-6.6 to -0.4)] compared with non-users. However, RMOST and RMPFST were similar between PPI users and non-users in patients treated with ADT alone [RMOST, -2.6 (-5.8 to 0.6); RMPFST, -1.7 (-4.8 to 1.4)]. Interaction term analyses did not show evidence of heterogeneity in treatment effect between AAP and ADT, despite the prominent treatment effect shown in mCSPC vs. mCRPC. Conclusions PPI use may be associated with inferior survival in patients with metastatic prostate cancer who receive ADT plus AAP. Discontinuing unnecessary PPI use might improve those outcomes. Health sciences/Medical research/Outcomes research Health sciences/Diseases/Cancer/Urological cancer Figures Figure 1 Figure 2 Figure 3 Introduction Three international randomized controlled trials (RCTs) (LATITUDE, COU-AA-302, and COU-AA-301) have investigated the efficacy of abiraterone acetate (AA), with results showing that AA improved overall survival (OS) in patients with metastatic castration-sensitive prostate cancer (mCSPC) and castration-resistant prostate cancer (mCRPC). 1 – 3 However, even with such treatment, prognosis is poor for these patients, and improving their treatment outcomes remains a major challenge. The gut microbiota are known to affect hormone metabolism in the host. 4 , 5 Interestingly, a recent pre-clinical study has suggested that androgen deprivation therapy (ADT), an important component of therapy in metastatic prostate cancer (mPCa), acts to alter the gut microbiota composition and can increase castration resistance through bacterial androgen biosynthesis. 6 AA is a selective inhibitor of androgen biosynthesis that blocks cytochrome P450 17A1. 7 This substance has limited solubility, so that half of the administered AA dose is excreted through the feces as unaltered parent compound, 8 suggesting that a high amount of AA is exposed to the gut microbiota. A recent study reported that the administration of AA induces treatment-specific alterations in gut microbiota including Akkermansia muciniphila. 9 These alterations can lead to increased bacterial biosynthesis of vitamin K2, a potential growth inhibitor of prostate cancer. 9 In another clinical study, the use of androgen receptor axis-targeted agents such as AA, bicalutamide, and enzalutamide was associated with higher levels of A. muciniphila. 10 Taken together, these data suggest that the effectiveness of AA treatment may be partly driven by the modulation of gut microbiota. Proton pump inhibitors (PPIs) are among the most commonly used drug classes, and once initiated, their use is often continued without clear therapeutic intent. 11 In particular, 20–50% of patients receiving cancer treatment are reported to also use PPIs, 12 and evidence indicates that PPI use can be associated with the alteration of gut microbiota. 13 , 14 Data from male participants suggests that such use was associated with decreased levels of A. muciniphila in the gut microbiota, 15 indicating that PPI use might reduce the effects of AA. In this study we performed post-hoc analysis of pooled data, collected from RCTs investigating the efficacy of AA plus prednisone on mPCa, to evaluate the association between PPI use and oncologic outcomes in patients with mPCa treated with ADT and AA plus prednisone or with ADT alone. Subjects And Methods Data Sources We harmonized individual participant data from the randomized controlled trials LATITUDE (NCT01715285), COU-AA-302 (NCT00887198), and COU-AA-301 (NCT00638690). LATITUDE was a multicenter, double-blind RCT to evaluate the efficacy and safety of the addition of AA (1000 mg once daily) plus prednisone (5 mg once daily) versus dual placebo on ADT in patients with high-risk mCSPC. COU-AA-301 and COU-AA-302 were multicenter, double-blind RCTs to assess the efficacy and safety of AA (1000 mg once daily) plus prednisone (5 mg twice daily) plus ADT versus prednisone (5 mg twice daily) plus ADT in patients with chemotherapy-treated and chemotherapy-naive mCRPC. The results of data from these three trials were published previously. 1 – 3 This study utilized the final dataset from LATITUDE (data cutoff, Aug 15, 2018), COU-AA-302 (data cutoff, Mar 31, 2014), and COU-AA-301 (data cutoff, Sept 20, 2010). 16 – 18 Data were analyzed from November 2, 2021, to June 13, 2022. Exposures and Variable Definitions Pooled individual participant data from the 3 trials were analyzed. Overall, analysis involved 99.6% (1194 of 1199), 99.2% (1185 of 1195), and 99.4% (1081 of 1088) of patients from LATITUDE, COU-AA-301, and COU-AA-302, with the available follow-up data. In addition to the established prognostic factors and characteristics of mPCa, 19 data on metformin use and statin use were collected because those uses have previously been shown to be associated with treatment outcomes in patients with mCRPC participating in COU-AA-301 and COU-AA-302. 20 Given the difference in survival of participants among the trials, 16 – 18 the proportion of patients participating from each trial was also used as a baseline characteristic. Concomitant use of drugs such as PPI, metformin, and statin was defined as any administration during the interval between 30 days before and 30 days after randomization. This interval was based on previously published research. 21 , 22 Outcomes The outcomes were OS and radiographic progression-free survival (rPFS). OS was defined as the time from randomization to the date of death from any cause. Detailed criteria for rPFS were published previously. 1 – 3 In brief, rPFS was defined as the freedom from all-cause mortality; the freedom from progression in soft-tissue lesions assessed by computed tomography or magnetic resonance imaging, defined as per Response Evaluation Criteria in Solid Tumors (RECIST) criteria; 23 or progression on bone scan based on criteria adapted from the Prostate Cancer Working Group 2 criteria. 24 Statistical Analyses Descriptive statistics were used to compare patient characteristics between PPI users and non-users. Because of the skewed distribution of raw laboratory data, a natural logarithmic transformation was applied to prostate-specific antigen (PSA) and lactate dehydrogenase (LDH) levels to achieve a more normal distribution. Multiple imputation by chained equations was performed to deal with missing data. 25 Ten imputed data sets were generated, and Rubin’s rules were applied to pool the effect estimates and variances across all multiply imputed data sets. 26 Each element of imputed data was individually stratified by treatment (abiraterone acetate plus prednisone [AAP] or ADT) to evaluate the effect of PPI use on treatment effectiveness. Stabilized inverse probability of treatment weights (IPTWs) based on propensity scores was calculated within each treatment group to balance patient characteristics. The three multivariable logistic regression models were fitted to estimate IPTWs in the total cohort, the AAP cohorts (patients treated with ADT plus AA plus prednisone), and the ADT cohorts (patients treated with ADT alone or plus prednisone) to assess the clinical impact of PPI use based on treatment. The covariates used in multivariable logistic regression models are listed in Supplemental Table 1. The post-weighting balance in patient characteristics was evaluated using standardized mean differences (SMDs); SMDs > 0.1 (10%) indicated an imbalance in patient characteristics. 27 The association between PPI use and other patient characteristics was assessed based on multivariable logistic regression models. The results were described as odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). IPTW-adjusted Kaplan-Meier estimates were used to visualize survival distribution with the corresponding 95% CIs based on PPI use, and the distributions were compared by restricted mean survival time (RMST) based on the crude and IPTW-adjusted Kaplan-Meier curves. RMST for OS and rPFS was defined as restricted mean overall survival time (RMOST) and restricted mean progression-free survival time (RMPFST), respectively. The last observed or censored survival time was used as the truncation time. 28 Curves based on the RMST difference with the simultaneous 95% CI bands as a function of truncation time were depicted to visualize the change in RMST difference during the follow-up period. 29 IPTW-adjusted Cox regression models were used to estimate the hazard ratios (HRs) and the corresponding 95% CIs for PPI use. Finally, the heterogeneity of treatment effect in relation to treatment (AA + prednisone vs. ADT) and castration resistance (mCSPC vs. mCRPC) was tested by the interaction term within the IPTW-adjusted Cox regression model based on the total cohort. In the sensitivity analysis, the E-value of HR for all-cause mortality and radiographic progression was calculated to estimate the degree of potential unmeasured confounding. In this analysis, HRs were calculated based on the IPTW-adjusted Cox regression models. The E-value is the minimum strength of association between a possible unmeasured confounder or set of confounders, and both the treatment and outcome that are needed to cancel an association. 30 All statistical analyses were conducted using R statistics, version 4.1.3 (R Foundation for Statistical Computing). Two-sided statistical significance was defined as P < 0.05. Results Study population The total cohort (N = 3460) consisted of patients treated with ADT plus AA plus prednisone (AAP cohort; N = 1930) and patients treated with ADT plus placebo with or without prednisone (ADT cohort; N = 1530). Baseline patient characteristics, accumulated for three cohorts based on PPI use, are summarized in Supplemental Tables 2 and 4. Overall, 475 patients (24.6%) used PPI in the AAP cohort, and 300 (19.6%) in the ADT cohort. Baseline characteristics were comparable before and after imputation. PPI use is listed in Supplemental Table 5. Omeprazole was the most widely used drug in the total cohort (N = 327 [42.2%]). The details of PPI use were similar between the AAP cohort and the ADT cohort. After applying IPTW, patient characteristics were balanced between PPI users and non-users in all cohorts (Supplemental Table 2 to Supplemental Table 4). The distributions of estimated propensity scores were shown in Supplemental Fig. 1. Association between PPI use and patient characteristics Multivariable logistic regression analysis showed the following characteristics to be significantly associated with PPI use in the total cohort: performance status (OR: 2.05, 95% CI: 1.29 to 3.25), history of gastrointestinal disorder (OR: 4.05, 95% CI: 3.36 to 4.87), history of cardiovascular disorder (OR: 1.29, 95% CI: 1.05 to 1.58), statin use (OR: 1.29, 95% CI: 1.05 to 1.58), lymph node metastasis (OR: 0.79, 95% CI: 0.66 to 0.95), and trial (LATITUDE vs. COU-AA-301, OR: 2.51, 95% CI: 1.74 to 3.62; LATITUDE vs. COU-AA-302, OR: 1.78, 95% CI: 1.27 to 2.50) (Supplemental Table 6). Treatment effectiveness of AA plus prednisone and ADT based on PPI use Median follow-up was 49.3 months (interquartile range: 38.7 to 54.9) for the AAP cohort and 49.8 months (interquartile range: 39.4 to 54.0). During follow-up in the AAP cohort, radiographic progression developed in 1396 patients (72.3%) and all-cause mortality in 1274 (66.0%). In the ADT cohort, those numbers were 1186 (77.5%) and 1058 (69.2%), respectively. The crude Kaplan-Meier curves showed that AA treatment was associated with improved survival of patients enrolled in LATITUDE, COU-AA-301, and COU-AA-302 compared with placebo, irrespective of PPI use (Supplemental Fig. 2 to 3). The crude Kaplan-Meier curves for the 2 cohorts, based on PPI use, are shown in Fig. 1 . Crude data from the AAP cohort showed that PPI users had a shorter RMOST (difference: -10.5 months, 95% CI: -12.6 to -8.4) and RMPFST (difference: -8.5 months, 95% CI: -10.7 to -6.3) than non-users (Table 1). After IPTW adjustment, PPI users continued to show shorter RMOST (difference: -4.2 months, 95% CI: -7.0 to -1.4) and RMPFST (difference: -3.5 months, 95% CI: -6.6 to -0.4) compared with non-users. Furthermore, the RMST difference curves showed that the differences in RMOST and RMPFST increased over time until truncation at 63.5 months (Fig. 2 ). PPI use was associated with higher HRs for all-cause mortality (HR: 1.25, 95% CI: 1.08 to 1.45) and radiographic progression (HR: 1.20, 95% CI: 1.03 to 1.39), respectively. Similar associations were observed between PPI use and treatment outcomes from the crude data of the ADT cohort (RMOST, difference: -8.3 months, 95% CI: -10.6 to -5.9; RMPFST, difference: -4.7 months, 95% CI: -6.8 to -2.5). However, the differences in RMOST (difference: -2.6 months, 95% CI: -5.8 to 0.6) and RMPFST (difference: -1.7 months, 95% CI: -4.8 to 1.3) were no longer significant after applying IPTW (Table 1). The RMST difference curves in the ADT cohort also showed that the differences in RMOST and RMPFST remained non-significant until the truncation time (Fig. 3 ). The IPTW-adjusted Cox regression model did not show a significant association between PPI use and treatment outcomes in the ADT cohort (HR for all-cause mortality: 1.18, 95% CI: 0.99 to 1.41; HR for radiographic progression: 1.11, 95% CI: 0.92 to 1.33). Interaction term analysis showed no evidence of significant interaction with treatment (AAP vs. ADT/ADTP, HR: 0.90, 95% CI: 0.72 to 1.13, P for interaction = 0.36). However, PPI notably affected mCSPC (mCRPC vs. mCSPC, HR: 1.48, 95% CI: 1.14 to 1.91, P for interaction = 0.003). Sensitivity analysis Sensitivity analysis based on the E-value was performed to assess the degree of possible unmeasured confounding within this study. In the ADT cohort and the AAP cohort, the E-values of HRs for all-cause mortality were 1.61 and 1.53, respectively, and for radiographic progression were 1.49 and 1.36, respectively. Discussion Despite several studies showing the potential association between PPI use and oncological outcomes in patients with prostate cancer, 31 , 32 evidence remains scarce for the association between PPI use and effects on treatment with AAP in mPCa. This study used pooled data from LATITUDE, COU-AA-301, and COU-AA-302 to show that PPI use was associated with inferior survival in patients with mPCa treated with ADT plus AA plus prednisone. On average, life expectancy in the AAP cohort was 4.2 months shorter for PPI users than for non-users, and radiographic progression occurred as much as 3.5 months sooner. Although no similar associations were observed in the ADT cohort, interaction term analysis showed that the heterogeneity of treatment effect was not statistically significant. The multivariable logistic regression model showed not only an association between PPI use and previous history of gastrointestinal disorder, but also between such use and higher ORs for previous history of cardiovascular disorder and statin use. Despite the paucity of available data on PPI use, these findings suggested that PPI might partially prevent gastrointestinal bleeding in patients with cardiovascular disease who take anti-platelet therapy. 33 Of note, our results indicated that PPI use affected patients with mCSPC more than those with mCRPC. A pre-clinical study has suggested that supplementation with PPIs such as omeprazole, lansoprazole, and esomeprazole increased cell proliferation and survival of CSPC cell lines but not of CRPC cell lines, suggesting that PPI use directly attenuated the anti-tumor effect of AA. 34 In contrast, patient characteristics showed that PPI users were more likely than non-users to receive glucocorticoid (41.5% vs. 21.3%) and participate in the COU-AA-301 trial (64.0% vs. 33.5%), which evaluated the efficacy of AA in mCRPC previously treated with docetaxel. 3 Similar to PPI, evidence showed that glucocorticoid, which is concomitantly used with docetaxel, was associated with alterations in the gut microbiota. 35 , 36 Taken together, the gut microbiota in patients with mCRPC might be modified by prior anti-cancer treatments. Although the IPTW adjustment balanced the proportion of glucocorticoid users, the difference in baseline composition of gut microbiota between patients with mCSPC and mCRPC might explain the significantly heterogeneous treatment effect of PPI use. Despite the lack of clinically acceptable proof, these mechanisms may account for our findings. Our findings should be interpreted within the context of a post-hoc study design. Although IPTW adjustment achieved balance in patient characteristics between PPI users and non-users, potential unmeasured confounders might influence the results. Of note, results from sensitivity analyses showed that the E-values of HRs for all-cause mortality and radiographic progression were modest, suggesting that there were possible residual confounding factors that affect both the decision to initiate or continue PPI use and the clinical outcomes of patients participating in LATITUDE, COU-AA-301, and COU-AA-302. Given the study population in the present study, the treatment effects remain unclear for the use of ADT plus AA plus prednisone in PPI users with mPCa who are ineligible for a clinical trial. This study did not address such issues as duration of treatment and type of PPI used in the analysis. Importantly, we were unable to assess data on the association of PPI use and the alteration of gut microbiota. Future mechanistic studies are warranted to elucidate the association between PPI use and the treatment effects of ADT plus AA plus prednisone on such alteration. Conclusions PPI use was associated with worse survival in patients with mPCa treated with ADT plus AA plus prednisone. The results of this hypothesis-generating study must be validated in a prospective phase 3 trial before they can be applied in clinical practice. Discontinuing unnecessary PPI prescriptions might improve patient outcomes. Declarations Conflict of interest disclosure statements Wataru Fukuokaya certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Takahiro Kimura is a paid consultant/advisor of Astellas, Bayer, Janssen, and Sanofi. The other authors declare no conflicts of interest associated with this manuscript. Financial support This work was supported by JSPS KAKENHI Grant Number JP 20K18102. Acknowledgments This study, carried out under YODA Project # 2021-4813, used data obtained from the Yale University Open Data Access Project, which has an agreement with JANSSEN RESEARCH & DEVELOPMENT, L.L.C. The interpretation and reporting of research using these data are solely the responsibility of the authors and does not necessarily represent the official views of the Yale University Open Data Access Project or JANSSEN RESEARCH & DEVELOPMENT, L.L.C. English-language editorial support was provided by Seaman Medical, Inc., Bellingham WA USA. Data availability statement Data are available at https://yoda.yale.edu/ upon reasonable request. References Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med 2017; 377 : 352–360. Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P et al. Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy. N Engl J Med 2013; 368 : 138–148. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L et al. Abiraterone and Increased Survival in Metastatic Prostate Cancer. N Engl J Med 2011; 364 : 1995–2005. 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Proton pump inhibitors promote the growth of androgen-sensitive prostate cancer cells through ErbB2, ERK1/2, PI3K/Akt, GSK-3β signaling and inhibition of cellular prostatic acid phosphatase. Cancer Letters 2019; 449 : 252–262. Qiu D, Xia Z, Deng J, Jiao X, Liu L, Li J. Glucorticoid‐induced obesity individuals have distinct signatures of the gut microbiome. BioFactors 2019; 45 : 892–901. Wu T, Yang L, Jiang J, Ni Y, Zhu J, Zheng X et al. Chronic glucocorticoid treatment induced circadian clock disorder leads to lipid metabolism and gut microbiota alterations in rats. Life Sciences 2018; 192 : 173–182. Table Table 1 is available in the Supplementary Files section. Additional Declarations Yes there is potential conflict of interest. Supplementary Files supplfigure1.pdf Supplemental Figure 1 The distributions of propensity scores based on PPI use supplfigure2.pdf Supplemental Figure 2 Kaplan-Meier curves based on study treatment in PPI users supplfigure3.pdf Supplemental Figure 3 Kaplan-Meier curves based on study treatment in non-users suppltable1.xlsx suppltable2.xlsx suppltable3.xlsx suppltable4.xlsx suppltable5.xlsx suppltable6.xlsx table1.xlsx Cite Share Download PDF Status: Published Journal Publication published 18 Jul, 2023 Read the published version in Prostate Cancer and Prostatic Diseases → Version 1 posted Editorial decision: revise 23 May, 2023 Review # 4 received at journal 13 May, 2023 Review # 1 received at journal 13 May, 2023 Reviewer # 4 agreed at journal 04 May, 2023 Reviewer # 3 agreed at journal 03 May, 2023 Review # 2 received at journal 30 Apr, 2023 Reviewer # 2 agreed at journal 28 Apr, 2023 Reviewer # 1 agreed at journal 24 Apr, 2023 Reviewers invited by journal 21 Apr, 2023 Submission checks completed at journal 20 Apr, 2023 First submitted to journal 19 Apr, 2023 Editor assigned by journal 19 Apr, 2023 Unknown event 19 Apr, 2023 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies 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-2834713","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":194027886,"identity":"122522cc-467e-4288-95e3-c279f6d9a8f0","order_by":0,"name":"Wataru Fukuokaya","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4ElEQVRIiWNgGAWjYDAC5gPMQDIBzAISEjKEtbAlwLSwgQgJHlK08BiA+IS1GBzjMTbmqUiTNzh+5vOrGzUWPAzsh49uIKQlmedMjuGGM7nbrHOOAR3Gk5Z2A58Ws/s9xod52yoYNxzI3WacwwbUIsFjhl8L0BaQFvsN5988M875R6SWZN62nMQNN3KYH+e2EaHF/hhbseGcM2nJM288M2PO7ZPgYSPkF8k25s0SbyqSbfvOJz/+nPOtTo6f/fAxvFrgQOEAA5sEiMFGlHIQkG9gYP5AtOpRMApGwSgYUQAAzdJIjAZ7hZkAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-1044-912X","institution":"The Jikei University School of Medicine","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Wataru","middleName":"","lastName":"Fukuokaya","suffix":""},{"id":194027887,"identity":"5f67911a-4252-4e69-86c2-dd7e53ac9a70","order_by":1,"name":"Keiichiro Mori","email":"","orcid":"","institution":"Medical University of Vienna","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Keiichiro","middleName":"","lastName":"Mori","suffix":""},{"id":194027888,"identity":"c617eb95-88b6-4190-830a-dfd8d6f0de75","order_by":2,"name":"Takafumi Yanagisawa","email":"","orcid":"https://orcid.org/0000-0002-7410-0712","institution":"Medical University of Vienna","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Takafumi","middleName":"","lastName":"Yanagisawa","suffix":""},{"id":194027889,"identity":"712a0b76-fa75-4df9-8ae4-aa808667e1d4","order_by":3,"name":"Kohei Akazawa","email":"","orcid":"","institution":"Niigata University Medical and Dental Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kohei","middleName":"","lastName":"Akazawa","suffix":""},{"id":194027890,"identity":"e862142b-69f8-45dc-a605-b3b3d51278fb","order_by":4,"name":"Tatsuya Shimomura","email":"","orcid":"","institution":"The Jikei University School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tatsuya","middleName":"","lastName":"Shimomura","suffix":""},{"id":194027891,"identity":"ff31c39b-1d4f-4969-9e0f-fe6e9774b49c","order_by":5,"name":"Takahiro Kimura","email":"","orcid":"https://orcid.org/0000-0002-5673-1553","institution":"The Jikei University School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Takahiro","middleName":"","lastName":"Kimura","suffix":""}],"badges":[],"createdAt":"2023-04-19 05:00:42","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2834713/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2834713/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41391-023-00695-x","type":"published","date":"2023-07-18T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":36286503,"identity":"a64797b1-9082-414c-90bb-614b6dc10452","added_by":"auto","created_at":"2023-04-25 16:49:49","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":99195,"visible":true,"origin":"","legend":"\u003cp\u003eCrude Kaplan-Meier curves in the AAP cohort and the ADT cohort\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-2834713/v1/e12d1a2be4a8e5164663fdc4.png"},{"id":36286756,"identity":"d2489b28-2071-489a-b3ae-55a4357cba29","added_by":"auto","created_at":"2023-04-25 16:57:50","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":144941,"visible":true,"origin":"","legend":"\u003cp\u003eInverse probability of treatment weight-adjusted Kaplan-Meier curves in the AAP cohort. (A and B). Dynamic restricted mean survival time difference curves for restricted mean progression-free survival time and restricted mean overall survival time based on proton pump inhibitor use in the AAP cohort. (C and D)\u003c/p\u003e\n\u003cp\u003eBlue lines indicate the difference in restricted mean survival time (RMST) between proton pump inhibitor (PPI) users and non-users. (C and D) RMST differences were calculated as RMST [PPI users] minus RMST [non-users]. An RMST difference of more than 0 indicates that the RMST of PPI users was longer than that of non-users. Light blue bands indicate the corresponding 95% confidence intervals.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-2834713/v1/16192b5144d30b78442fd5d4.png"},{"id":36286755,"identity":"5e64580c-0870-426e-9c68-5f56f67c85e4","added_by":"auto","created_at":"2023-04-25 16:57:50","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":144260,"visible":true,"origin":"","legend":"\u003cp\u003eInverse probability of treatment weight-adjusted Kaplan-Meier curves in the ADT cohort. (A and B). Dynamic restricted mean survival time difference curves for restricted mean progression-free survival time and restricted mean overall survival time based on proton pump inhibitor use in the ADT cohort. (C and D)\u003c/p\u003e\n\u003cp\u003eBlue lines indicate the difference in restricted mean survival time (RMST) between proton pump inhibitor (PPI) users and non-users. (C and D) RMST differences were calculated as RMST [PPI users] minus RMST [non-users]. An RMST difference of more than 0 indicates that the RMST of PPI users was longer than that of non-users. Light blue bands indicate the corresponding 95% confidence intervals.\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-2834713/v1/18ab8dfba5a521827ae55b2c.png"},{"id":40357130,"identity":"94a20e57-0df7-412d-91c0-1e422c16c6ae","added_by":"auto","created_at":"2023-07-21 07:25:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1135616,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2834713/v1/a6a2b5a2-f2c6-4ca2-9436-b843ddfe23a2.pdf"},{"id":36286506,"identity":"9dbe5092-b044-49ca-ae05-064e01ad4474","added_by":"auto","created_at":"2023-04-25 16:49:50","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":51284,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplemental Figure 1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe distributions of propensity scores based on PPI use\u003c/p\u003e","description":"","filename":"supplfigure1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2834713/v1/336da42ba88f47fa0f75f2a1.pdf"},{"id":36286504,"identity":"345a1702-f85d-4adf-94ab-2c4583cb0453","added_by":"auto","created_at":"2023-04-25 16:49:50","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":32138,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplemental Figure 2\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKaplan-Meier curves based on study treatment in PPI users\u003c/p\u003e","description":"","filename":"supplfigure2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2834713/v1/0b0c0e9eb8583a7cea552c48.pdf"},{"id":36286514,"identity":"af3dceca-288a-43e9-ab25-989ae4e49950","added_by":"auto","created_at":"2023-04-25 16:49:50","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":77571,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplemental Figure 3\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKaplan-Meier curves based on study treatment in non-users\u003c/p\u003e","description":"","filename":"supplfigure3.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2834713/v1/131d7ef9fa84d17343247fb4.pdf"},{"id":36286758,"identity":"6799b291-493f-4731-a540-a7bc5e6600b0","added_by":"auto","created_at":"2023-04-25 16:57:50","extension":"xlsx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":10112,"visible":true,"origin":"","legend":"","description":"","filename":"suppltable1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-2834713/v1/54bf0dc900c77f8661873a2d.xlsx"},{"id":36286508,"identity":"3db3a318-d7ae-440e-b143-668756b58033","added_by":"auto","created_at":"2023-04-25 16:49:50","extension":"xlsx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":15540,"visible":true,"origin":"","legend":"","description":"","filename":"suppltable2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-2834713/v1/6ffc545e9023eb654f5487cb.xlsx"},{"id":36286512,"identity":"1b2e4fcb-81b5-4e73-968c-17817d205494","added_by":"auto","created_at":"2023-04-25 16:49:50","extension":"xlsx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":15064,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"suppltable3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-2834713/v1/63ef19a6418eb0ad34add034.xlsx"},{"id":36286513,"identity":"9a3826f1-ec3d-4aea-9893-e4a36213d2b7","added_by":"auto","created_at":"2023-04-25 16:49:50","extension":"xlsx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":15061,"visible":true,"origin":"","legend":"","description":"","filename":"suppltable4.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-2834713/v1/2509309a35180f016a493ef7.xlsx"},{"id":36286515,"identity":"46487dd6-90fb-4c27-ac91-c850293b615f","added_by":"auto","created_at":"2023-04-25 16:49:50","extension":"xlsx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":9843,"visible":true,"origin":"","legend":"","description":"","filename":"suppltable5.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-2834713/v1/d5758f00d19c522f5b1561bb.xlsx"},{"id":36286510,"identity":"c5152a49-1862-4a30-83fa-1e45a3351ee7","added_by":"auto","created_at":"2023-04-25 16:49:50","extension":"xlsx","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":11386,"visible":true,"origin":"","legend":"","description":"","filename":"suppltable6.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-2834713/v1/ad20ab5afa24a9f34c9062d6.xlsx"},{"id":36287088,"identity":"b4cd781d-ad3a-46f4-b8f2-4a3a97c5c2da","added_by":"auto","created_at":"2023-04-25 17:05:50","extension":"xlsx","order_by":10,"title":"","display":"","copyAsset":false,"role":"supplement","size":10488,"visible":true,"origin":"","legend":"","description":"","filename":"table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-2834713/v1/e7f502ea1a58508a14ea18ba.xlsx"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential conflict of interest.","formattedTitle":"Association between concomitant proton pump inhibitor use and survival of patients with metastatic prostate cancer receiving abiraterone acetate: a post-hoc analysis of pooled data from three randomized controlled trials","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThree international randomized controlled trials (RCTs) (LATITUDE, COU-AA-302, and COU-AA-301) have investigated the efficacy of abiraterone acetate (AA), with results showing that AA improved overall survival (OS) in patients with metastatic castration-sensitive prostate cancer (mCSPC) and castration-resistant prostate cancer (mCRPC).\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e However, even with such treatment, prognosis is poor for these patients, and improving their treatment outcomes remains a major challenge.\u003c/p\u003e \u003cp\u003eThe gut microbiota are known to affect hormone metabolism in the host.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Interestingly, a recent pre-clinical study has suggested that androgen deprivation therapy (ADT), an important component of therapy in metastatic prostate cancer (mPCa), acts to alter the gut microbiota composition and can increase castration resistance through bacterial androgen biosynthesis.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAA is a selective inhibitor of androgen biosynthesis that blocks cytochrome P450 17A1.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e This substance has limited solubility, so that half of the administered AA dose is excreted through the feces as unaltered parent compound,\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e suggesting that a high amount of AA is exposed to the gut microbiota. A recent study reported that the administration of AA induces treatment-specific alterations in gut microbiota including Akkermansia muciniphila.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e These alterations can lead to increased bacterial biosynthesis of vitamin K2, a potential growth inhibitor of prostate cancer.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e In another clinical study, the use of androgen receptor axis-targeted agents such as AA, bicalutamide, and enzalutamide was associated with higher levels of A. muciniphila.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Taken together, these data suggest that the effectiveness of AA treatment may be partly driven by the modulation of gut microbiota.\u003c/p\u003e \u003cp\u003eProton pump inhibitors (PPIs) are among the most commonly used drug classes, and once initiated, their use is often continued without clear therapeutic intent.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e In particular, 20\u0026ndash;50% of patients receiving cancer treatment are reported to also use PPIs,\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e and evidence indicates that PPI use can be associated with the alteration of gut microbiota.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Data from male participants suggests that such use was associated with decreased levels of A. muciniphila in the gut microbiota,\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e indicating that PPI use might reduce the effects of AA.\u003c/p\u003e \u003cp\u003eIn this study we performed post-hoc analysis of pooled data, collected from RCTs investigating the efficacy of AA plus prednisone on mPCa, to evaluate the association between PPI use and oncologic outcomes in patients with mPCa treated with ADT and AA plus prednisone or with ADT alone.\u003c/p\u003e"},{"header":"Subjects And Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData Sources\u003c/h2\u003e \u003cp\u003eWe harmonized individual participant data from the randomized controlled trials LATITUDE (NCT01715285), COU-AA-302 (NCT00887198), and COU-AA-301 (NCT00638690). LATITUDE was a multicenter, double-blind RCT to evaluate the efficacy and safety of the addition of AA (1000 mg once daily) plus prednisone (5 mg once daily) versus dual placebo on ADT in patients with high-risk mCSPC. COU-AA-301 and COU-AA-302 were multicenter, double-blind RCTs to assess the efficacy and safety of AA (1000 mg once daily) plus prednisone (5 mg twice daily) plus ADT versus prednisone (5 mg twice daily) plus ADT in patients with chemotherapy-treated and chemotherapy-naive mCRPC. The results of data from these three trials were published previously.\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e This study utilized the final dataset from LATITUDE (data cutoff, Aug 15, 2018), COU-AA-302 (data cutoff, Mar 31, 2014), and COU-AA-301 (data cutoff, Sept 20, 2010).\u003csup\u003e\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e Data were analyzed from November 2, 2021, to June 13, 2022.\u003c/p\u003e \u003cp\u003eExposures and Variable Definitions\u003c/p\u003e \u003cp\u003ePooled individual participant data from the 3 trials were analyzed. Overall, analysis involved 99.6% (1194 of 1199), 99.2% (1185 of 1195), and 99.4% (1081 of 1088) of patients from LATITUDE, COU-AA-301, and COU-AA-302, with the available follow-up data. In addition to the established prognostic factors and characteristics of mPCa,\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e data on metformin use and statin use were collected because those uses have previously been shown to be associated with treatment outcomes in patients with mCRPC participating in COU-AA-301 and COU-AA-302.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e Given the difference in survival of participants among the trials,\u003csup\u003e\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e the proportion of patients participating from each trial was also used as a baseline characteristic. Concomitant use of drugs such as PPI, metformin, and statin was defined as any administration during the interval between 30 days before and 30 days after randomization. This interval was based on previously published research.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes\u003c/h2\u003e \u003cp\u003eThe outcomes were OS and radiographic progression-free survival (rPFS). OS was defined as the time from randomization to the date of death from any cause. Detailed criteria for rPFS were published previously.\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e In brief, rPFS was defined as the freedom from all-cause mortality; the freedom from progression in soft-tissue lesions assessed by computed tomography or magnetic resonance imaging, defined as per Response Evaluation Criteria in Solid Tumors (RECIST) criteria;\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e or progression on bone scan based on criteria adapted from the Prostate Cancer Working Group 2 criteria.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analyses\u003c/h2\u003e \u003cp\u003eDescriptive statistics were used to compare patient characteristics between PPI users and non-users. Because of the skewed distribution of raw laboratory data, a natural logarithmic transformation was applied to prostate-specific antigen (PSA) and lactate dehydrogenase (LDH) levels to achieve a more normal distribution. Multiple imputation by chained equations was performed to deal with missing data.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e Ten imputed data sets were generated, and Rubin\u0026rsquo;s rules were applied to pool the effect estimates and variances across all multiply imputed data sets.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e Each element of imputed data was individually stratified by treatment (abiraterone acetate plus prednisone [AAP] or ADT) to evaluate the effect of PPI use on treatment effectiveness. Stabilized inverse probability of treatment weights (IPTWs) based on propensity scores was calculated within each treatment group to balance patient characteristics. The three multivariable logistic regression models were fitted to estimate IPTWs in the total cohort, the AAP cohorts (patients treated with ADT plus AA plus prednisone), and the ADT cohorts (patients treated with ADT alone or plus prednisone) to assess the clinical impact of PPI use based on treatment. The covariates used in multivariable logistic regression models are listed in Supplemental Table\u0026nbsp;1. The post-weighting balance in patient characteristics was evaluated using standardized mean differences (SMDs); SMDs\u0026thinsp;\u0026gt;\u0026thinsp;0.1 (10%) indicated an imbalance in patient characteristics.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe association between PPI use and other patient characteristics was assessed based on multivariable logistic regression models. The results were described as odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). IPTW-adjusted Kaplan-Meier estimates were used to visualize survival distribution with the corresponding 95% CIs based on PPI use, and the distributions were compared by restricted mean survival time (RMST) based on the crude and IPTW-adjusted Kaplan-Meier curves. RMST for OS and rPFS was defined as restricted mean overall survival time (RMOST) and restricted mean progression-free survival time (RMPFST), respectively. The last observed or censored survival time was used as the truncation time.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e Curves based on the RMST difference with the simultaneous 95% CI bands as a function of truncation time were depicted to visualize the change in RMST difference during the follow-up period.\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e IPTW-adjusted Cox regression models were used to estimate the hazard ratios (HRs) and the corresponding 95% CIs for PPI use. Finally, the heterogeneity of treatment effect in relation to treatment (AA\u0026thinsp;+\u0026thinsp;prednisone vs. ADT) and castration resistance (mCSPC vs. mCRPC) was tested by the interaction term within the IPTW-adjusted Cox regression model based on the total cohort.\u003c/p\u003e \u003cp\u003eIn the sensitivity analysis, the E-value of HR for all-cause mortality and radiographic progression was calculated to estimate the degree of potential unmeasured confounding. In this analysis, HRs were calculated based on the IPTW-adjusted Cox regression models. The E-value is the minimum strength of association between a possible unmeasured confounder or set of confounders, and both the treatment and outcome that are needed to cancel an association.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAll statistical analyses were conducted using R statistics, version 4.1.3 (R Foundation for Statistical Computing). Two-sided statistical significance was defined as P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eThe total cohort (N\u0026thinsp;=\u0026thinsp;3460) consisted of patients treated with ADT plus AA plus prednisone (AAP cohort; N\u0026thinsp;=\u0026thinsp;1930) and patients treated with ADT plus placebo with or without prednisone (ADT cohort; N\u0026thinsp;=\u0026thinsp;1530). Baseline patient characteristics, accumulated for three cohorts based on PPI use, are summarized in Supplemental Tables\u0026nbsp;2 and 4. Overall, 475 patients (24.6%) used PPI in the AAP cohort, and 300 (19.6%) in the ADT cohort. Baseline characteristics were comparable before and after imputation. PPI use is listed in Supplemental Table\u0026nbsp;5. Omeprazole was the most widely used drug in the total cohort (N\u0026thinsp;=\u0026thinsp;327 [42.2%]). The details of PPI use were similar between the AAP cohort and the ADT cohort.\u003c/p\u003e \u003cp\u003eAfter applying IPTW, patient characteristics were balanced between PPI users and non-users in all cohorts (Supplemental Table\u0026nbsp;2 to Supplemental Table\u0026nbsp;4). The distributions of estimated propensity scores were shown in Supplemental Fig.\u0026nbsp;1.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eAssociation between PPI use and patient characteristics\u003c/h2\u003e \u003cp\u003eMultivariable logistic regression analysis showed the following characteristics to be significantly associated with PPI use in the total cohort: performance status (OR: 2.05, 95% CI: 1.29 to 3.25), history of gastrointestinal disorder (OR: 4.05, 95% CI: 3.36 to 4.87), history of cardiovascular disorder (OR: 1.29, 95% CI: 1.05 to 1.58), statin use (OR: 1.29, 95% CI: 1.05 to 1.58), lymph node metastasis (OR: 0.79, 95% CI: 0.66 to 0.95), and trial (LATITUDE vs. COU-AA-301, OR: 2.51, 95% CI: 1.74 to 3.62; LATITUDE vs. COU-AA-302, OR: 1.78, 95% CI: 1.27 to 2.50) (Supplemental Table\u0026nbsp;6).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eTreatment effectiveness of AA plus prednisone and ADT based on PPI use\u003c/h2\u003e \u003cp\u003eMedian follow-up was 49.3 months (interquartile range: 38.7 to 54.9) for the AAP cohort and 49.8 months (interquartile range: 39.4 to 54.0). During follow-up in the AAP cohort, radiographic progression developed in 1396 patients (72.3%) and all-cause mortality in 1274 (66.0%). In the ADT cohort, those numbers were 1186 (77.5%) and 1058 (69.2%), respectively.\u003c/p\u003e \u003cp\u003eThe crude Kaplan-Meier curves showed that AA treatment was associated with improved survival of patients enrolled in LATITUDE, COU-AA-301, and COU-AA-302 compared with placebo, irrespective of PPI use (Supplemental Fig.\u0026nbsp;2 to 3). The crude Kaplan-Meier curves for the 2 cohorts, based on PPI use, are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eCrude data from the AAP cohort showed that PPI users had a shorter RMOST (difference: -10.5 months, 95% CI: -12.6 to -8.4) and RMPFST (difference: -8.5 months, 95% CI: -10.7 to -6.3) than non-users (Table\u0026nbsp;1). After IPTW adjustment, PPI users continued to show shorter RMOST (difference: -4.2 months, 95% CI: -7.0 to -1.4) and RMPFST (difference: -3.5 months, 95% CI: -6.6 to -0.4) compared with non-users. Furthermore, the RMST difference curves showed that the differences in RMOST and RMPFST increased over time until truncation at 63.5 months (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). PPI use was associated with higher HRs for all-cause mortality (HR: 1.25, 95% CI: 1.08 to 1.45) and radiographic progression (HR: 1.20, 95% CI: 1.03 to 1.39), respectively.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSimilar associations were observed between PPI use and treatment outcomes from the crude data of the ADT cohort (RMOST, difference: -8.3 months, 95% CI: -10.6 to -5.9; RMPFST, difference: -4.7 months, 95% CI: -6.8 to -2.5). However, the differences in RMOST (difference: -2.6 months, 95% CI: -5.8 to 0.6) and RMPFST (difference: -1.7 months, 95% CI: -4.8 to 1.3) were no longer significant after applying IPTW (Table\u0026nbsp;1). The RMST difference curves in the ADT cohort also showed that the differences in RMOST and RMPFST remained non-significant until the truncation time (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The IPTW-adjusted Cox regression model did not show a significant association between PPI use and treatment outcomes in the ADT cohort (HR for all-cause mortality: 1.18, 95% CI: 0.99 to 1.41; HR for radiographic progression: 1.11, 95% CI: 0.92 to 1.33).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eInteraction term analysis showed no evidence of significant interaction with treatment (AAP vs. ADT/ADTP, HR: 0.90, 95% CI: 0.72 to 1.13, P for interaction\u0026thinsp;=\u0026thinsp;0.36). However, PPI notably affected mCSPC (mCRPC vs. mCSPC, HR: 1.48, 95% CI: 1.14 to 1.91, P for interaction\u0026thinsp;=\u0026thinsp;0.003).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analysis\u003c/h2\u003e \u003cp\u003eSensitivity analysis based on the E-value was performed to assess the degree of possible unmeasured confounding within this study. In the ADT cohort and the AAP cohort, the E-values of HRs for all-cause mortality were 1.61 and 1.53, respectively, and for radiographic progression were 1.49 and 1.36, respectively.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eDespite several studies showing the potential association between PPI use and oncological outcomes in patients with prostate cancer,\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e evidence remains scarce for the association between PPI use and effects on treatment with AAP in mPCa.\u003c/p\u003e \u003cp\u003eThis study used pooled data from LATITUDE, COU-AA-301, and COU-AA-302 to show that PPI use was associated with inferior survival in patients with mPCa treated with ADT plus AA plus prednisone. On average, life expectancy in the AAP cohort was 4.2 months shorter for PPI users than for non-users, and radiographic progression occurred as much as 3.5 months sooner. Although no similar associations were observed in the ADT cohort, interaction term analysis showed that the heterogeneity of treatment effect was not statistically significant. The multivariable logistic regression model showed not only an association between PPI use and previous history of gastrointestinal disorder, but also between such use and higher ORs for previous history of cardiovascular disorder and statin use. Despite the paucity of available data on PPI use, these findings suggested that PPI might partially prevent gastrointestinal bleeding in patients with cardiovascular disease who take anti-platelet therapy.\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOf note, our results indicated that PPI use affected patients with mCSPC more than those with mCRPC. A pre-clinical study has suggested that supplementation with PPIs such as omeprazole, lansoprazole, and esomeprazole increased cell proliferation and survival of CSPC cell lines but not of CRPC cell lines, suggesting that PPI use directly attenuated the anti-tumor effect of AA.\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e In contrast, patient characteristics showed that PPI users were more likely than non-users to receive glucocorticoid (41.5% vs. 21.3%) and participate in the COU-AA-301 trial (64.0% vs. 33.5%), which evaluated the efficacy of AA in mCRPC previously treated with docetaxel.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Similar to PPI, evidence showed that glucocorticoid, which is concomitantly used with docetaxel, was associated with alterations in the gut microbiota.\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e Taken together, the gut microbiota in patients with mCRPC might be modified by prior anti-cancer treatments. Although the IPTW adjustment balanced the proportion of glucocorticoid users, the difference in baseline composition of gut microbiota between patients with mCSPC and mCRPC might explain the significantly heterogeneous treatment effect of PPI use. Despite the lack of clinically acceptable proof, these mechanisms may account for our findings.\u003c/p\u003e \u003cp\u003eOur findings should be interpreted within the context of a post-hoc study design. Although IPTW adjustment achieved balance in patient characteristics between PPI users and non-users, potential unmeasured confounders might influence the results. Of note, results from sensitivity analyses showed that the E-values of HRs for all-cause mortality and radiographic progression were modest, suggesting that there were possible residual confounding factors that affect both the decision to initiate or continue PPI use and the clinical outcomes of patients participating in LATITUDE, COU-AA-301, and COU-AA-302. Given the study population in the present study, the treatment effects remain unclear for the use of ADT plus AA plus prednisone in PPI users with mPCa who are ineligible for a clinical trial. This study did not address such issues as duration of treatment and type of PPI used in the analysis. Importantly, we were unable to assess data on the association of PPI use and the alteration of gut microbiota. Future mechanistic studies are warranted to elucidate the association between PPI use and the treatment effects of ADT plus AA plus prednisone on such alteration.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003ePPI use was associated with worse survival in patients with mPCa treated with ADT plus AA plus prednisone. The results of this hypothesis-generating study must be validated in a prospective phase 3 trial before they can be applied in clinical practice. Discontinuing unnecessary PPI prescriptions might improve patient outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch3\u003e\u003cstrong\u003eConflict of interest disclosure statements\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eWataru Fukuokaya certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Takahiro Kimura is a paid consultant/advisor of Astellas, Bayer, Janssen, and Sanofi. The other authors declare no conflicts of interest associated with this manuscript.\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003eFinancial support\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eThis work was supported by JSPS KAKENHI Grant Number JP 20K18102.\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eThis study, carried out under YODA Project # 2021-4813, used data obtained from the Yale University Open Data Access Project, which has an agreement with JANSSEN RESEARCH \u0026amp; DEVELOPMENT, L.L.C. The interpretation and reporting of research using these data are solely the responsibility of the authors and does not necessarily represent the official views of the Yale University Open Data Access Project or JANSSEN RESEARCH \u0026amp; DEVELOPMENT, L.L.C. English-language editorial support was provided by Seaman Medical, Inc., Bellingham WA USA.\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eData are available at https://yoda.yale.edu/ upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY \u003cem\u003eet al.\u003c/em\u003e Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. \u003cem\u003eN Engl J Med\u003c/em\u003e 2017; \u003cstrong\u003e377\u003c/strong\u003e: 352\u0026ndash;360.\u003c/li\u003e\n\u003cli\u003eRyan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P \u003cem\u003eet al.\u003c/em\u003e Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy. \u003cem\u003eN Engl J Med\u003c/em\u003e 2013; \u003cstrong\u003e368\u003c/strong\u003e: 138\u0026ndash;148.\u003c/li\u003e\n\u003cli\u003ede Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L \u003cem\u003eet al.\u003c/em\u003e Abiraterone and Increased Survival in Metastatic Prostate Cancer. \u003cem\u003eN Engl J Med\u003c/em\u003e 2011; \u003cstrong\u003e364\u003c/strong\u003e: 1995\u0026ndash;2005.\u003c/li\u003e\n\u003cli\u003eNeuman H, Debelius JW, Knight R, Koren O. 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Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. \u003cem\u003eStatist Med\u003c/em\u003e 2009; \u003cstrong\u003e28\u003c/strong\u003e: 3083\u0026ndash;3107.\u003c/li\u003e\n\u003cli\u003eUno H, Claggett B, Tian L, Fu H, Huang B, Kim DH \u003cem\u003eet al.\u003c/em\u003e Adding a new analytical procedure with clinical interpretation in the tool box of survival analysis. \u003cem\u003eAnnals of Oncology\u003c/em\u003e 2018; \u003cstrong\u003e29\u003c/strong\u003e: 1092\u0026ndash;1094.\u003c/li\u003e\n\u003cli\u003eLiao JJZ, Liu GF, Wu W-C. Dynamic RMST curves for survival analysis in clinical trials. \u003cem\u003eBMC Med Res Methodol\u003c/em\u003e 2020; \u003cstrong\u003e20\u003c/strong\u003e: 218.\u003c/li\u003e\n\u003cli\u003eVanderWeele TJ, Ding P. 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Antiplatelet Therapy and Proton Pump Inhibition: Clinician Update. \u003cem\u003eCirculation\u003c/em\u003e 2012; \u003cstrong\u003e125\u003c/strong\u003e: 375\u0026ndash;380.\u003c/li\u003e\n\u003cli\u003eGesmundo I, Di Blasio L, Banfi D, Villanova T, Fanciulli A, Favaro E \u003cem\u003eet al.\u003c/em\u003e Proton pump inhibitors promote the growth of androgen-sensitive prostate cancer cells through ErbB2, ERK1/2, PI3K/Akt, GSK-3\u0026beta; signaling and inhibition of cellular prostatic acid phosphatase. \u003cem\u003eCancer Letters\u003c/em\u003e 2019; \u003cstrong\u003e449\u003c/strong\u003e: 252\u0026ndash;262.\u003c/li\u003e\n\u003cli\u003eQiu D, Xia Z, Deng J, Jiao X, Liu L, Li J. Glucorticoid‐induced obesity individuals have distinct signatures of the gut microbiome. \u003cem\u003eBioFactors\u003c/em\u003e 2019; \u003cstrong\u003e45\u003c/strong\u003e: 892\u0026ndash;901.\u003c/li\u003e\n\u003cli\u003eWu T, Yang L, Jiang J, Ni Y, Zhu J, Zheng X \u003cem\u003eet al.\u003c/em\u003e Chronic glucocorticoid treatment induced circadian clock disorder leads to lipid metabolism and gut microbiota alterations in rats. \u003cem\u003eLife Sciences\u003c/em\u003e 2018; \u003cstrong\u003e192\u003c/strong\u003e: 173\u0026ndash;182.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"prostate-cancer-and-prostatic-diseases","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"pcan","sideBox":"Learn more about [Prostate Cancer and Prostatic Diseases](http://www.nature.com/pcan/)","snPcode":"41391","submissionUrl":"https://mts-pcan.nature.com/cgi-bin/main.plex","title":"Prostate Cancer and Prostatic Diseases","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-2834713/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2834713/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch3\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eEvidence suggests proton pump inhibitor (PPI) use may attenuate the effect of abiraterone acetate plus prednisone (AAP) in metastatic prostate cancer via the modification of gut microbiota. This study aimed to examine whether concomitant PPI use is associated with survival in patients with metastatic prostate cancer treated with androgen deprivation therapy (ADT) and AAP.\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003ePost-hoc analysis was conducted in patients with metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC) treated in the LATITUDE, COU-AA-301, and COU-AA-302 trials (ADT vs. ADT plus AAP). PPI users and non-users were compared for restricted mean overall survival time (RMOST) and restricted mean progression-free survival time (RMPFST) based on inverse probability of treatment weight (IPTW)-adjusted Kaplan-Meier curves. IPTW-adjusted Cox regression models were used to assess heterogeneity of treatment effect.\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eIn patients treated with AAP, PPI use was associated with inferior RMOST [difference (95% confidence interval): -4.2 (-7.0 to -1.4)] and RMPFST [-3.5 (-6.6 to -0.4)] compared with non-users. However, RMOST and RMPFST were similar between PPI users and non-users in patients treated with ADT alone [RMOST, -2.6 (-5.8 to 0.6); RMPFST, -1.7 (-4.8 to 1.4)]. Interaction term analyses did not show evidence of heterogeneity in treatment effect between AAP and ADT, despite the prominent treatment effect shown in mCSPC vs. mCRPC.\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003ePPI use may be associated with inferior survival in patients with metastatic prostate cancer who receive ADT plus AAP. Discontinuing unnecessary PPI use might improve those outcomes.\u003c/p\u003e","manuscriptTitle":"Association between concomitant proton pump inhibitor use and survival of patients with metastatic prostate cancer receiving abiraterone acetate: a post-hoc analysis of pooled data from three randomized controlled trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-04-25 16:49:45","doi":"10.21203/rs.3.rs-2834713/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2023-05-23T15:41:30+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2023-05-13T18:58:11+00:00","index":4,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2023-05-13T07:15:56+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2023-05-04T07:31:36+00:00","index":4,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2023-05-03T21:08:47+00:00","index":3,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2023-04-30T09:25:53+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2023-04-28T17:05:06+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2023-04-24T07:43:01+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2023-04-21T17:21:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-04-20T08:58:18+00:00","index":"","fulltext":""},{"type":"submitted","content":"Prostate Cancer and Prostatic Diseases","date":"2023-04-19T13:40:53+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-04-19T13:40:53+00:00","index":"","fulltext":""},{"type":"checksFailed","content":"","date":"2023-04-19T10:25:36+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"prostate-cancer-and-prostatic-diseases","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"pcan","sideBox":"Learn more about [Prostate Cancer and Prostatic Diseases](http://www.nature.com/pcan/)","snPcode":"41391","submissionUrl":"https://mts-pcan.nature.com/cgi-bin/main.plex","title":"Prostate Cancer and Prostatic Diseases","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"92628be5-40b8-4e3e-9b02-bf394475c6c2","owner":[],"postedDate":"April 25th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":20908654,"name":"Health sciences/Medical research/Outcomes research"},{"id":20908655,"name":"Health sciences/Diseases/Cancer/Urological cancer"}],"tags":[],"updatedAt":"2023-07-21T07:25:44+00:00","versionOfRecord":{"articleIdentity":"rs-2834713","link":"https://doi.org/10.1038/s41391-023-00695-x","journal":{"identity":"prostate-cancer-and-prostatic-diseases","isVorOnly":false,"title":"Prostate Cancer and Prostatic Diseases"},"publishedOn":"2023-07-18 04:00:00","publishedOnDateReadable":"July 18th, 2023"},"versionCreatedAt":"2023-04-25 16:49:45","video":"","vorDoi":"10.1038/s41391-023-00695-x","vorDoiUrl":"https://doi.org/10.1038/s41391-023-00695-x","workflowStages":[]},"version":"v1","identity":"rs-2834713","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2834713","identity":"rs-2834713","version":["v1"]},"buildId":"oE6Zbj460LM0Up2FdVbMZ","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}