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  string(147) "The relative efficacy and safety of enzalutamide, apalutamide, abiraterone, and darolutamide for nonmetastatic castration-resistant prostate cancer"
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  string(697) "Recently, there has been progress in research in nonmetastatic castration-resistant prostate cancer (nmCRPC) treatment, with the introduction of several promising drugs. The multitude of treatment options complicates decision-making, as little is known about the optimal drug therapy, which is reflected in the hesitance in clinical guidelines to recommend one drug over the others. With the comparative efficacy and safety of different drugs unclear, the costs of those drugs vary widely. In this study, we seek to compare the efficacy and safety of enzalutamide, apalutamide, abiraterone, and darolutamide for nmCRPC through network meta-analysis that incorporates individual patient trial data."
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  ["property_scientific_abstract"]=>
  string(1616) "Background: Recently, there has been progress in research in nonmetastatic castration-resistant prostate cancer (nmCRPC) treatment, with the introduction of four promising drugs, namely, apalutamide, enzalutamide, abiraterone , and darolutamide. The multitude of treatment options complicates decision-making, as little is known about the optimal drug therapy for each disease status, which is reflected in the hesitance in clinical guidelines to recommend one drug over the others. With the comparative efficacy and safety of different drugs unclear, the costs of those drugs vary widely. The monthly costs range from around $3,275 to $12,196 for different drugs
Objective: To compare the efficacy and safety of enzalutamide, apalutamide, abiraterone, and darolutamide for nmCRPC.
Study design: A systematic review and network meta-analysis of randomized controlled trials and single-arm trials, incorporating individual patient trial data. We will identify trials from searching bibliographic databases, trial registries, and regulatory documents.
Participants: nmCRPC patients
Main Outcome Measures: 1. Time to radiographic progression or death from any cause, which ever occurred first. 2. time to PSA progression. 3. overall survival.4. adverse events.
Statistical Analysis: Network meta-analysis by Bayesian hierarchical model using generalized linear modeling and Markov Chain Monte Carlo (MCMC) methods. We will estimate the relative treatment effect between any two drugs and use the Surface Under the Cumulative RAnking curve (SUCRA) as well as mean ranks to compare drugs." ["project_brief_bg"]=> string(1481) "Recently, there has been progress in research in nonmetastatic castration-resistant prostate cancer (nmCRPC) treatment, with the introduction of four promising drugs, namely, apalutamide, enzalutamide, abiraterone , and darolutamide.[1-8] The availability of these drugs has improved prostate cancer survival. Meanwhile, the multitude of treatment options complicates decision-making, as little is known about the optimal drug therapy, which is reflected in the hesitance in clinical guidelines to recommend one drug over the others.[9-11]
With the comparative efficacy and safety of different drugs unclear, the costs of those drugs vary widely. The monthly costs range from around $3,275 to $12,196 for different drugs. [12] Considering the huge disparity in costs, it is critical to evaluate the relative efficacy and safety of these drugs and inform value-based decision-making. Are higher costs justified by better treatment effects or a better safety profile? Or is there actually no difference, making abiraterone is the most economic choice?
In this study, we seek to compare the efficacy and safety of alternative drug therapies for nmCRPC in order to inform decision-making. We will identify, appraise, and synthesize data from clinical trials of drug therapies for nmCRPC with network meta-analysis that incorporates individual patient trial data, a state-ofart statistical method that has recently risen to prominence in comparative effectiveness research." ["project_specific_aims"]=> string(312) "Objective: To compare the efficacy and safety of enzalutamide, apalutamide, abiraterone, and darolutamide for nonmetastatic castration-resistant prostate cancer through network meta-analysis of clinical trial data.
Hypothesis: some drug therapies may be more efficacious or safer than other drug therapies." ["project_study_design"]=> string(0) "" ["project_study_design_exp"]=> string(0) "" ["project_purposes"]=> array(2) { [0]=> array(2) { ["value"]=> string(36) "Participant-level data meta-analysis" ["label"]=> string(36) "Participant-level data meta-analysis" } [1]=> array(2) { ["value"]=> string(69) "Meta-analysis using data from the YODA Project and other data sources" ["label"]=> string(69) "Meta-analysis using data from the YODA Project and other data sources" } } ["project_purposes_exp"]=> string(0) "" ["project_software_used"]=> array(2) { ["value"]=> string(7) "RStudio" ["label"]=> string(7) "RStudio" } ["project_software_used_exp"]=> string(0) "" ["project_research_methods"]=> string(846) "We will identify trials and obtain aggregated level trial data from searching bibliographic databases, trial registries, and regulatory documents. We will request individual patient trial data from trial data sharing websites including Vivli and YODA. Currently, we are in the process of requesting individual patient data of two trials (NCT00626548 and NCT01664923) from Vivli. The request ID is 00003762.
***IMPORTANT NOTES: For details of potential challenges in securing individual patient trial data and solutions, see the additional file uploaded
We will include nmCRPC patients from randomized controlled trials that compared apalutamide, enzalutamide, abiraterone, or darolutamide, in combination with androgen deprivation therapy with any comparators, or from single-arm trials that examined any of the four drug therapies." ["project_main_outcome_measure"]=> string(638) "Efficacy:
1. Primary outcome: time to radiographic progression (local or distant) or death from any cause, which ever occurred first.
2. Secondary outcome: time to PSA progression; overall survival.
For time-to-event outcomes, the number of patients who had the event, the median follow-up time, median survival, and the hazard ratio will be extracted.
Safety:
1. Number of patients included in safety analysis;
2. Any adverse events, serious adverse events, or treatment discontinuation due to adverse events.
For the dichotomous outcomes, the number of patients had the event will be extracted." ["project_main_predictor_indep"]=> string(92) "Drug therapy: apalutamide, enzalutamide, abiraterone, darolutamide, or placebo/no treatment." ["project_other_variables_interest"]=> string(230) "Age (continuous), serum prostate-specific antigen (PSA) level (continuous), PSA doubling time (continuous), Gleason category (categorical), previous local therapy for prostate cancer (categorical), performance status (continuous)." ["project_stat_analysis_plan"]=> string(657) "We will conduct network meta-analysis under a Bayesian framework using generalized linear modeling and Markov Chain Monte Carlo (MCMC) methods. The dichotomous outcomes will be determined by using an odds ratio (OR) with 95% credible intervals (CI). The time-to-event outcomes will be determined by using a hazard ratio (HR) with 95% CI. As the dosages for our alternative drug therapies are established, we expect little or no variation and will combine different dosage if necessary. We will estimate the relative treatment effect between any two drugs and use the Surface Under the Cumulative RAnking curve (SUCRA) as well as mean ranks to compare drugs." ["project_timeline"]=> string(220) "Anticipated project start date: June 2019
Analysis completion date: June 2020
Manuscript drafted: December 2020
First submission: January 2021
Results reported back to the YODA project: March 2021" ["project_dissemination_plan"]=> string(202) "Products: A manuscript to be published in major oncology journals (Journal of Clinical Oncology, JAMA Oncology, etc).
Audiences: Clinicians, patients, health policy makers, and health researchers." ["project_bibliography"]=> string(2292) "

1. Smith MR, Antonarakis ES, Ryan CJ, et al. Phase 2 study of the safety and antitumor activity of apalutamide (ARN-509), a potent androgen receptor antagonist, in the high-risk nonmetastatic castration-resistant prostate cancer cohort. European urology 2016;70:963-70.
2. Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. New England journal of medicine 2018;378:1408-18.
3. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. New England journal of medicine 2018;378:2465-74.
4. Virgo KS, Basch E, Loblaw DA, et al. Second-line hormonal therapy for men with chemotherapy-nave, castration-resistant prostate cancer: American Society of Clinical Oncology Provisional Clinical Opinion. Journal of clinical oncology 2017;35:1952-64.
5. Ryan CJ, Crawford ED, Shore ND, et al. The IMAAGEN study: effect of abiraterone acetate and prednisone on prostate specific antigen and radiographic disease progression in patients with nonmetastatic castration resistant prostate vancer. The journal of urology 2018;200:344-52.
6. Castration-resistant prostate cancer. Published 2013. Updated 2018. https://www.auanet.org/guidelines/prostate-cancer-castration-resistant-(2013-amended-2018.
7. Izumi K, Mizokami A, Namiki M, et al. Enzalutamide versus abiraterone as a first-line endocrine therapy for castration-resistant prostate cancer (ENABLE study for PCa): a study protocol for a multicenter randomized phase III trial. BMC cancer 2017;17:677.
8. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. New England journal of medicine 2019;380:1235-1246.
9. Prostate cancer (Version 4.2018). https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
10. Alpajaro SIR, Harris JAK, Evans CP. Non-metastatic castration resistant prostate cancer: a review of current and emerging medical therapies. Prostate cancer and prostatic diseases 2019;22:16-23.
11. Mateo J, Fizazi K, Gillessen S, et al. Managing monmetastatic castration-resistant prostate cancer. European urology 2019;75:285-93.
12. Drug Price Information. https://www.drugs.com/price-guide/

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2019-3886

General Information

How did you learn about the YODA Project?: Conference

Conflict of Interest

Request Clinical Trials

Associated Trial(s):
  1. NCT01314118 - A Multicenter, Open-label, Single-arm, Phase 2 Study of Abiraterone Acetate Plus Prednisone in Subjects With Advanced Prostate Cancer Without Radiographic Evidence of Metastatic Disease
What type of data are you looking for?:

Request Clinical Trials

Data Request Status

Status: Published

Research Proposal

Project Title: The relative efficacy and safety of enzalutamide, apalutamide, abiraterone, and darolutamide for nonmetastatic castration-resistant prostate cancer

Scientific Abstract: Background: Recently, there has been progress in research in nonmetastatic castration-resistant prostate cancer (nmCRPC) treatment, with the introduction of four promising drugs, namely, apalutamide, enzalutamide, abiraterone , and darolutamide. The multitude of treatment options complicates decision-making, as little is known about the optimal drug therapy for each disease status, which is reflected in the hesitance in clinical guidelines to recommend one drug over the others. With the comparative efficacy and safety of different drugs unclear, the costs of those drugs vary widely. The monthly costs range from around $3,275 to $12,196 for different drugs
Objective: To compare the efficacy and safety of enzalutamide, apalutamide, abiraterone, and darolutamide for nmCRPC.
Study design: A systematic review and network meta-analysis of randomized controlled trials and single-arm trials, incorporating individual patient trial data. We will identify trials from searching bibliographic databases, trial registries, and regulatory documents.
Participants: nmCRPC patients
Main Outcome Measures: 1. Time to radiographic progression or death from any cause, which ever occurred first. 2. time to PSA progression. 3. overall survival.4. adverse events.
Statistical Analysis: Network meta-analysis by Bayesian hierarchical model using generalized linear modeling and Markov Chain Monte Carlo (MCMC) methods. We will estimate the relative treatment effect between any two drugs and use the Surface Under the Cumulative RAnking curve (SUCRA) as well as mean ranks to compare drugs.

Brief Project Background and Statement of Project Significance: Recently, there has been progress in research in nonmetastatic castration-resistant prostate cancer (nmCRPC) treatment, with the introduction of four promising drugs, namely, apalutamide, enzalutamide, abiraterone , and darolutamide.[1-8] The availability of these drugs has improved prostate cancer survival. Meanwhile, the multitude of treatment options complicates decision-making, as little is known about the optimal drug therapy, which is reflected in the hesitance in clinical guidelines to recommend one drug over the others.[9-11]
With the comparative efficacy and safety of different drugs unclear, the costs of those drugs vary widely. The monthly costs range from around $3,275 to $12,196 for different drugs. [12] Considering the huge disparity in costs, it is critical to evaluate the relative efficacy and safety of these drugs and inform value-based decision-making. Are higher costs justified by better treatment effects or a better safety profile? Or is there actually no difference, making abiraterone is the most economic choice?
In this study, we seek to compare the efficacy and safety of alternative drug therapies for nmCRPC in order to inform decision-making. We will identify, appraise, and synthesize data from clinical trials of drug therapies for nmCRPC with network meta-analysis that incorporates individual patient trial data, a state-ofart statistical method that has recently risen to prominence in comparative effectiveness research.

Specific Aims of the Project: Objective: To compare the efficacy and safety of enzalutamide, apalutamide, abiraterone, and darolutamide for nonmetastatic castration-resistant prostate cancer through network meta-analysis of clinical trial data.
Hypothesis: some drug therapies may be more efficacious or safer than other drug therapies.

Study Design:

What is the purpose of the analysis being proposed? Please select all that apply.: Participant-level data meta-analysis Meta-analysis using data from the YODA Project and other data sources

Software Used: RStudio

Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: We will identify trials and obtain aggregated level trial data from searching bibliographic databases, trial registries, and regulatory documents. We will request individual patient trial data from trial data sharing websites including Vivli and YODA. Currently, we are in the process of requesting individual patient data of two trials (NCT00626548 and NCT01664923) from Vivli. The request ID is 00003762.
***IMPORTANT NOTES: For details of potential challenges in securing individual patient trial data and solutions, see the additional file uploaded
We will include nmCRPC patients from randomized controlled trials that compared apalutamide, enzalutamide, abiraterone, or darolutamide, in combination with androgen deprivation therapy with any comparators, or from single-arm trials that examined any of the four drug therapies.

Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: Efficacy:
1. Primary outcome: time to radiographic progression (local or distant) or death from any cause, which ever occurred first.
2. Secondary outcome: time to PSA progression; overall survival.
For time-to-event outcomes, the number of patients who had the event, the median follow-up time, median survival, and the hazard ratio will be extracted.
Safety:
1. Number of patients included in safety analysis;
2. Any adverse events, serious adverse events, or treatment discontinuation due to adverse events.
For the dichotomous outcomes, the number of patients had the event will be extracted.

Main Predictor/Independent Variable and how it will be categorized/defined for your study: Drug therapy: apalutamide, enzalutamide, abiraterone, darolutamide, or placebo/no treatment.

Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: Age (continuous), serum prostate-specific antigen (PSA) level (continuous), PSA doubling time (continuous), Gleason category (categorical), previous local therapy for prostate cancer (categorical), performance status (continuous).

Statistical Analysis Plan: We will conduct network meta-analysis under a Bayesian framework using generalized linear modeling and Markov Chain Monte Carlo (MCMC) methods. The dichotomous outcomes will be determined by using an odds ratio (OR) with 95% credible intervals (CI). The time-to-event outcomes will be determined by using a hazard ratio (HR) with 95% CI. As the dosages for our alternative drug therapies are established, we expect little or no variation and will combine different dosage if necessary. We will estimate the relative treatment effect between any two drugs and use the Surface Under the Cumulative RAnking curve (SUCRA) as well as mean ranks to compare drugs.

Narrative Summary: Recently, there has been progress in research in nonmetastatic castration-resistant prostate cancer (nmCRPC) treatment, with the introduction of several promising drugs. The multitude of treatment options complicates decision-making, as little is known about the optimal drug therapy, which is reflected in the hesitance in clinical guidelines to recommend one drug over the others. With the comparative efficacy and safety of different drugs unclear, the costs of those drugs vary widely. In this study, we seek to compare the efficacy and safety of enzalutamide, apalutamide, abiraterone, and darolutamide for nmCRPC through network meta-analysis that incorporates individual patient trial data.

Project Timeline: Anticipated project start date: June 2019
Analysis completion date: June 2020
Manuscript drafted: December 2020
First submission: January 2021
Results reported back to the YODA project: March 2021

Dissemination Plan: Products: A manuscript to be published in major oncology journals (Journal of Clinical Oncology, JAMA Oncology, etc).
Audiences: Clinicians, patients, health policy makers, and health researchers.

Bibliography:

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