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  string(1798) "Background
Accumulated data suggest that the anti-tumor effect of the combination of abiraterone acetate (AA) and androgen deprivation therapy (ADT) is, in part, driven by the modulation of the gut microbiota, characterized by the promotion of vitamin K2-producing Akkermansia muciniphila. In contrast, the use of proton pump inhibitors (PPIs) has been associated with decreased A. muciniphila abundance in the gut microbiota.
Objective
To investigate the impact of PPI use in patients with advanced prostate cancer receiving AA.
Study design
Post-hoc analysis of patients participating in randomized controlled trials
Participants
Patients with advanced prostate cancer who were enrolled in COU-AA-301 (phase 3 randomized controlled trial [RCT] of AA vs. placebo in chemotherapy-resistant metastatic castration-resistant prostate cancer [mCRPC], N = 1195), COU-AA-302 (phase 3 RCT of AA vs. placebo in chemotherapy-naive mCRPC, N = 1088), and LATITUDE (phase 3 RCT of AA vs. placebo in treatment-nave metastatic castration-sensitive prostate cancer, N = 1199).
Main Outcome Measures
Progression-free survival is defined as the time from randomization to disease progression in bone and/or soft tissue or death, whichever occurred first. In addition, overall survival and prostate-specific antigen progression-free survival will be determined.
Statistical Analysis
Inverse probability of weighting (IPW) is used to adjust patient characteristics. The IPW-adjusted Kaplan-Meier method will be applied to evaluate the survival distribution. The association between PPI use and outcomes will be evaluated using IPW-adjusted univariable Cox regression models. The interaction terms within these models will also be evaluated." ["project_brief_bg"]=> string(1967) "It has been reported that gut microbiota participates in hormone metabolism in the host.[1] Furthermore, androgen precursors can reportedly be converted into active androgens, suggesting their involvement in the pathophysiology of prostate cancer.[2]
AA is a selective inhibitor of androgen biosynthesis that potently blocks cytochrome P450 c17 and is widely used to treat locally advanced prostate cancer.[3?5] AA exhibits limited solubility. Reportedly, 50% of the unaltered parent compound from an administered dose undergoes fecal excretion, indicating that a high amount of AA is exposed to the gut microbiota.[6] A recent study has reported that AA + ADT can promote the growth of Akkermansia muciniphila, resulting in increased bacterial biosynthesis of vitamin K2.[7] Vitamin K2 inhibits the growth of androgen-dependent and androgen-independent prostate cancer cells in vitro, and its dietary intake is associated with the risk of advanced prostate cancer.[8,9] Collectively, the effectiveness of AA + ADT may be partly driven by its ability to alter the composition of the gut microbiota and increase microbially synthesized vitamin K2.
Proton pump inhibitors (PPIs) are among the most commonly used drug classes, and once initiated, they are continuously used without clear therapeutic intent. In addition, it has been reported that 20 to 50% of patients who receive cancer treatment also utilize PPIs.[10] Like AA, previous studies have indicated that PPI use can be associated with significant changes in gut microbiota.[11,12] Furthermore, PPI use has been associated with a decreased abundance of A. muciniphila, thus suggesting that PPIs might oppose the effect of AA.[13]
Collectively, this study highlights the importance of PPI use in patients with prostate cancer treated with AA + ADT, and given the newly available treatment options for patients with advanced prostate cancer, the results may help guide treatment selection." ["project_specific_aims"]=> string(430) "Increasing evidence suggested that PPI use was associated with the effectiveness of anti-tumor therapeutics.[14,15] This study specifically aims to study the potential role of PPI use on the effectiveness of AA + ADT. Our first hypothesis is that PPI use is associated with worse treatment response, measured by radiographic and overall survival, of AA + ADT. Our second hypothesis is that this association was treatment-specific." ["project_study_design"]=> string(0) "" ["project_study_design_exp"]=> string(0) "" ["project_purposes"]=> array(0) { } ["project_purposes_exp"]=> string(0) "" ["project_software_used"]=> string(0) "" ["project_software_used_exp"]=> string(0) "" ["project_research_methods"]=> string(601) "1. A Study of Abiraterone Acetate Plus Low-Dose Prednisone Plus Androgen Deprivation Therapy (ADT) Versus ADT Alone in Newly Diagnosed Participants With High-Risk, Metastatic Hormone-Naive Prostate Cancer (mHNPC) (NCT01715285)
2. Abiraterone Acetate in Asymptomatic or Mildly Symptomatic Patients With Metastatic Castration-Resistant Prostate Cancer (NCT00887198)
3. Abiraterone Acetate in Castration-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Chemotherapy (NCT00638690)
Inclusion criteria: all patients in the trials
Exclusion criteria: missing data" ["project_main_outcome_measure"]=> string(141) "Outcome measures that will be defined include progression-free survival and overall survival, as indicated in the original publications.[3?5]" ["project_main_predictor_indep"]=> string(173) "The primary assessed variable is any PPI use within 30 days before and 30 days after treatment initiation. PPI use will be categorized as a dichotomous variable (yes or no)." ["project_other_variables_interest"]=> string(520) "Age (categorized), race, Eastern Cooperative Oncology Group (ECOG) performance status (0 or ?1), baseline prostate-specific antigen (PSA) (categorized), baseline body mass index (categorized), Gleason score at diagnosis (categorized), reported pain scale (categorized), prior taxane (no or yes), castration status (castration-sensitive or castration-resistance), disease extent (categorized), number of bone metastases (categorized), presence of visceral metastasis (no or yes), other concurrent drug use (no or yes)." ["project_stat_analysis_plan"]=> string(925) "Descriptive statistics will be used to describe patient characteristics. Inverse probability of weighting (IPW) will be used for the adjustment of covariates. Unweighted and weighted patient characteristics will be stratified according to PPI use.
The association between PPI use and patient characteristics will be assessed using an unweighted logistic regression model. IPW-adjusted Kaplan-Meier curves will be calculated to compare survival between PPI users and non-users. The IPW-adjusted Cox regression model will be used to evaluate the hazard ratio for PPI use on clinical outcomes. Furthermore, heterogeneity of treatment effects according to patient characteristics and treatment (AA or ADT) will be examined by testing the interaction terms within the IPW-adjusted Cox regression models. The association between PPI use and adverse events or complications that occur during treatment will also be evaluated." ["project_timeline"]=> string(191) "Day 0: Approval of the project
Day30: Data transfer
Day 60: Data processing
Day 90: Data analysis
Day 120: Manuscript writing
Day 180: Manuscript submission" ["project_dissemination_plan"]=> string(232) "The findings of this project are expected to result in the development of a manuscript suitable for publication in a urologic oncology journal. In addition, the results will be presented at appropriate urologic oncology conferences." ["project_bibliography"]=> string(3907) "

[1] Neuman H, Debelius JW, Knight R, Koren O. Microbial endocrinology: the interplay between the microbiota and the endocrine system. FEMS Microbiology Reviews 2015;39:509?21. https://doi.org/10.1093/femsre/fuu010.
[2] Pernigoni N, Zagato E, Calcinotto A, Troiani M, Mestre RP, Cal B, et al. Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis. Science 2021:10. https://doi.org/10.1126/science.abf8403.
[3] Bono JS de, North S, Saad F, Flaig TW, Hainsworth JD, Flchon A, et al. Abiraterone and Increased Survival in Metastatic Prostate Cancer. N Engl j Med 2011:11.
[4] Ryan CJ, Smith MR, Bono JS de, Molina A, Logothetis CJ, Souza P de, et al. Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy. New England Journal of Medicine 2013;368:138?48. https://doi.org/10.1056/NEJMoa1209096.
[5] Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. New England Journal of Medicine 2017;377:352?60. https://doi.org/10.1056/NEJMoa1704174.
[6] Acharya M, Gonzalez M, Mannens G, De Vries R, Lopez C, Griffin T, et al. A phase I, open-label, single-dose, mass balance study of 14C-labeled abiraterone acetate in healthy male subjects. Xenobiotica 2013;43:379?89. https://doi.org/10.3109/00498254.2012.721022.
[7] Daisley BA, Chanyi RM, Abdur-Rashid K, Al KF, Gibbons S, Chmiel JA, et al. Abiraterone acetate preferentially enriches for the gut commensal Akkermansia muciniphila in castrate-resistant prostate cancer patients. Nature Communications 2020;11:4822. https://doi.org/10.1038/s41467-020-18649-5.
[8] Nimptsch K, Rohrmann S, Linseisen J. Dietary intake of vitamin K and risk of prostate cancer in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg). The American Journal of Clinical Nutrition 2008;87:985?92. https://doi.org/10.1093/ajcn/87.4.985.
[9] Samykutty A, Shetty AV, Dakshinamoorthy G, Kalyanasundaram R, Zheng G, Chen A, et al. Vitamin K2, a Naturally Occurring Menaquinone, Exerts Therapeutic Effects on Both Hormone-Dependent and Hormone-Independent Prostate Cancer Cells. Evidence-Based Complementary and Alternative Medicine 2013;2013:1?5. https://doi.org/10.1155/2013/287358.
[10] Smelick GS, Heffron TP, Chu L, Dean B, West DA, DuVall SL, et al. Prevalence of Acid-Reducing Agents (ARA) in Cancer Populations and ARA DrugDrug Interaction Potential for Molecular Targeted Agents in Clinical Development. Molecular Pharmaceutics 2013;10:4055?62. https://doi.org/10.1021/mp400403s.
[11] Imhann F, Bonder MJ, Vich Vila A, Fu J, Mujagic Z, Vork L, et al. Proton pump inhibitors affect the gut microbiome. Gut 2016;65:740?8. https://doi.org/10.1136/gutjnl-2015-310376.
[12] Reveles KR, Ryan CN, Chan L, Cosimi RA, Haynes WL. Proton pump inhibitor use associated with changes in gut microbiota composition. Gut 2018;67:1369?70. https://doi.org/10.1136/gutjnl-2017-315306.
[13] Davis JA, Collier F, Mohebbi M, Stuart AL, Loughman A, Pasco JA, et al. Obesity, Akkermansia muciniphila, and Proton Pump Inhibitors: Is there a Link? Obesity Research & Clinical Practice 2020;14:524?30. https://doi.org/10.1016/j.orcp.2020.10.006.
[14] Hopkins AM, Kichenadasse G, Karapetis CS, Rowland A, Sorich MJ. Concomitant Proton Pump Inhibitor Use and Survival in Urothelial Carcinoma Treated with Atezolizumab. Clinical Cancer Research 2020. https://doi.org/10.1158/1078-0432.CCR-20-1876.
[15] Del Re M, Omarini C, Diodati L, Palleschi M, Meattini I, Crucitta S, et al. Drug-drug interactions between palbociclib and proton pump inhibitors may significantly affect clinical outcome of metastatic breast cancer patients. ESMO Open 2021;6:100231. https://doi.org/10.1016/j.esmoop.2021.100231.

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2021-4813

Research Proposal

Project Title: Association between proton pump inhibitor use and survival of patients with prostate cancer receiving abiraterone acetate plus prednisone

Scientific Abstract: Background
Accumulated data suggest that the anti-tumor effect of the combination of abiraterone acetate (AA) and androgen deprivation therapy (ADT) is, in part, driven by the modulation of the gut microbiota, characterized by the promotion of vitamin K2-producing Akkermansia muciniphila. In contrast, the use of proton pump inhibitors (PPIs) has been associated with decreased A. muciniphila abundance in the gut microbiota.
Objective
To investigate the impact of PPI use in patients with advanced prostate cancer receiving AA.
Study design
Post-hoc analysis of patients participating in randomized controlled trials
Participants
Patients with advanced prostate cancer who were enrolled in COU-AA-301 (phase 3 randomized controlled trial [RCT] of AA vs. placebo in chemotherapy-resistant metastatic castration-resistant prostate cancer [mCRPC], N = 1195), COU-AA-302 (phase 3 RCT of AA vs. placebo in chemotherapy-naive mCRPC, N = 1088), and LATITUDE (phase 3 RCT of AA vs. placebo in treatment-nave metastatic castration-sensitive prostate cancer, N = 1199).
Main Outcome Measures
Progression-free survival is defined as the time from randomization to disease progression in bone and/or soft tissue or death, whichever occurred first. In addition, overall survival and prostate-specific antigen progression-free survival will be determined.
Statistical Analysis
Inverse probability of weighting (IPW) is used to adjust patient characteristics. The IPW-adjusted Kaplan-Meier method will be applied to evaluate the survival distribution. The association between PPI use and outcomes will be evaluated using IPW-adjusted univariable Cox regression models. The interaction terms within these models will also be evaluated.

Brief Project Background and Statement of Project Significance: It has been reported that gut microbiota participates in hormone metabolism in the host.[1] Furthermore, androgen precursors can reportedly be converted into active androgens, suggesting their involvement in the pathophysiology of prostate cancer.[2]
AA is a selective inhibitor of androgen biosynthesis that potently blocks cytochrome P450 c17 and is widely used to treat locally advanced prostate cancer.[3?5] AA exhibits limited solubility. Reportedly, 50% of the unaltered parent compound from an administered dose undergoes fecal excretion, indicating that a high amount of AA is exposed to the gut microbiota.[6] A recent study has reported that AA + ADT can promote the growth of Akkermansia muciniphila, resulting in increased bacterial biosynthesis of vitamin K2.[7] Vitamin K2 inhibits the growth of androgen-dependent and androgen-independent prostate cancer cells in vitro, and its dietary intake is associated with the risk of advanced prostate cancer.[8,9] Collectively, the effectiveness of AA + ADT may be partly driven by its ability to alter the composition of the gut microbiota and increase microbially synthesized vitamin K2.
Proton pump inhibitors (PPIs) are among the most commonly used drug classes, and once initiated, they are continuously used without clear therapeutic intent. In addition, it has been reported that 20 to 50% of patients who receive cancer treatment also utilize PPIs.[10] Like AA, previous studies have indicated that PPI use can be associated with significant changes in gut microbiota.[11,12] Furthermore, PPI use has been associated with a decreased abundance of A. muciniphila, thus suggesting that PPIs might oppose the effect of AA.[13]
Collectively, this study highlights the importance of PPI use in patients with prostate cancer treated with AA + ADT, and given the newly available treatment options for patients with advanced prostate cancer, the results may help guide treatment selection.

Specific Aims of the Project: Increasing evidence suggested that PPI use was associated with the effectiveness of anti-tumor therapeutics.[14,15] This study specifically aims to study the potential role of PPI use on the effectiveness of AA + ADT. Our first hypothesis is that PPI use is associated with worse treatment response, measured by radiographic and overall survival, of AA + ADT. Our second hypothesis is that this association was treatment-specific.

Study Design:

What is the purpose of the analysis being proposed? Please select all that apply.:

Software Used:

Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: 1. A Study of Abiraterone Acetate Plus Low-Dose Prednisone Plus Androgen Deprivation Therapy (ADT) Versus ADT Alone in Newly Diagnosed Participants With High-Risk, Metastatic Hormone-Naive Prostate Cancer (mHNPC) (NCT01715285)
2. Abiraterone Acetate in Asymptomatic or Mildly Symptomatic Patients With Metastatic Castration-Resistant Prostate Cancer (NCT00887198)
3. Abiraterone Acetate in Castration-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Chemotherapy (NCT00638690)
Inclusion criteria: all patients in the trials
Exclusion criteria: missing data

Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: Outcome measures that will be defined include progression-free survival and overall survival, as indicated in the original publications.[3?5]

Main Predictor/Independent Variable and how it will be categorized/defined for your study: The primary assessed variable is any PPI use within 30 days before and 30 days after treatment initiation. PPI use will be categorized as a dichotomous variable (yes or no).

Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: Age (categorized), race, Eastern Cooperative Oncology Group (ECOG) performance status (0 or ?1), baseline prostate-specific antigen (PSA) (categorized), baseline body mass index (categorized), Gleason score at diagnosis (categorized), reported pain scale (categorized), prior taxane (no or yes), castration status (castration-sensitive or castration-resistance), disease extent (categorized), number of bone metastases (categorized), presence of visceral metastasis (no or yes), other concurrent drug use (no or yes).

Statistical Analysis Plan: Descriptive statistics will be used to describe patient characteristics. Inverse probability of weighting (IPW) will be used for the adjustment of covariates. Unweighted and weighted patient characteristics will be stratified according to PPI use.
The association between PPI use and patient characteristics will be assessed using an unweighted logistic regression model. IPW-adjusted Kaplan-Meier curves will be calculated to compare survival between PPI users and non-users. The IPW-adjusted Cox regression model will be used to evaluate the hazard ratio for PPI use on clinical outcomes. Furthermore, heterogeneity of treatment effects according to patient characteristics and treatment (AA or ADT) will be examined by testing the interaction terms within the IPW-adjusted Cox regression models. The association between PPI use and adverse events or complications that occur during treatment will also be evaluated.

Narrative Summary: Accumulated evidence suggests that the combination of abiraterone acetate (AA) and androgen deprivation therapy (ADT) exhibits an anti-tumor effect by modifying the gut microbiota. Previous studies have also indicated that proton pump inhibitors (PPIs) can cause significant changes in the gut microbiota; however, the association between PPI use and the effectiveness of AA + ADT remains elusive. Therefore, the objective of this study was to investigate the impact of PPI use on the effectiveness of AA + ADT in patients with advanced prostate cancer. The results could be employed to improve clinical decision-making for the systemic treatment of advanced prostate cancer.

Project Timeline: Day 0: Approval of the project
Day30: Data transfer
Day 60: Data processing
Day 90: Data analysis
Day 120: Manuscript writing
Day 180: Manuscript submission

Dissemination Plan: The findings of this project are expected to result in the development of a manuscript suitable for publication in a urologic oncology journal. In addition, the results will be presented at appropriate urologic oncology conferences.

Bibliography:

[1] Neuman H, Debelius JW, Knight R, Koren O. Microbial endocrinology: the interplay between the microbiota and the endocrine system. FEMS Microbiology Reviews 2015;39:509?21. https://doi.org/10.1093/femsre/fuu010.
[2] Pernigoni N, Zagato E, Calcinotto A, Troiani M, Mestre RP, Cal B, et al. Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis. Science 2021:10. https://doi.org/10.1126/science.abf8403.
[3] Bono JS de, North S, Saad F, Flaig TW, Hainsworth JD, Flchon A, et al. Abiraterone and Increased Survival in Metastatic Prostate Cancer. N Engl j Med 2011:11.
[4] Ryan CJ, Smith MR, Bono JS de, Molina A, Logothetis CJ, Souza P de, et al. Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy. New England Journal of Medicine 2013;368:138?48. https://doi.org/10.1056/NEJMoa1209096.
[5] Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. New England Journal of Medicine 2017;377:352?60. https://doi.org/10.1056/NEJMoa1704174.
[6] Acharya M, Gonzalez M, Mannens G, De Vries R, Lopez C, Griffin T, et al. A phase I, open-label, single-dose, mass balance study of 14C-labeled abiraterone acetate in healthy male subjects. Xenobiotica 2013;43:379?89. https://doi.org/10.3109/00498254.2012.721022.
[7] Daisley BA, Chanyi RM, Abdur-Rashid K, Al KF, Gibbons S, Chmiel JA, et al. Abiraterone acetate preferentially enriches for the gut commensal Akkermansia muciniphila in castrate-resistant prostate cancer patients. Nature Communications 2020;11:4822. https://doi.org/10.1038/s41467-020-18649-5.
[8] Nimptsch K, Rohrmann S, Linseisen J. Dietary intake of vitamin K and risk of prostate cancer in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg). The American Journal of Clinical Nutrition 2008;87:985?92. https://doi.org/10.1093/ajcn/87.4.985.
[9] Samykutty A, Shetty AV, Dakshinamoorthy G, Kalyanasundaram R, Zheng G, Chen A, et al. Vitamin K2, a Naturally Occurring Menaquinone, Exerts Therapeutic Effects on Both Hormone-Dependent and Hormone-Independent Prostate Cancer Cells. Evidence-Based Complementary and Alternative Medicine 2013;2013:1?5. https://doi.org/10.1155/2013/287358.
[10] Smelick GS, Heffron TP, Chu L, Dean B, West DA, DuVall SL, et al. Prevalence of Acid-Reducing Agents (ARA) in Cancer Populations and ARA DrugDrug Interaction Potential for Molecular Targeted Agents in Clinical Development. Molecular Pharmaceutics 2013;10:4055?62. https://doi.org/10.1021/mp400403s.
[11] Imhann F, Bonder MJ, Vich Vila A, Fu J, Mujagic Z, Vork L, et al. Proton pump inhibitors affect the gut microbiome. Gut 2016;65:740?8. https://doi.org/10.1136/gutjnl-2015-310376.
[12] Reveles KR, Ryan CN, Chan L, Cosimi RA, Haynes WL. Proton pump inhibitor use associated with changes in gut microbiota composition. Gut 2018;67:1369?70. https://doi.org/10.1136/gutjnl-2017-315306.
[13] Davis JA, Collier F, Mohebbi M, Stuart AL, Loughman A, Pasco JA, et al. Obesity, Akkermansia muciniphila, and Proton Pump Inhibitors: Is there a Link? Obesity Research & Clinical Practice 2020;14:524?30. https://doi.org/10.1016/j.orcp.2020.10.006.
[14] Hopkins AM, Kichenadasse G, Karapetis CS, Rowland A, Sorich MJ. Concomitant Proton Pump Inhibitor Use and Survival in Urothelial Carcinoma Treated with Atezolizumab. Clinical Cancer Research 2020. https://doi.org/10.1158/1078-0432.CCR-20-1876.
[15] Del Re M, Omarini C, Diodati L, Palleschi M, Meattini I, Crucitta S, et al. Drug-drug interactions between palbociclib and proton pump inhibitors may significantly affect clinical outcome of metastatic breast cancer patients. ESMO Open 2021;6:100231. https://doi.org/10.1016/j.esmoop.2021.100231.