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  string(130) "Effect of Prior Local Therapy on Response to First Line Systemic Therapy in Men with Metastatic Castrate Resistant Prostate Cancer"
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  string(689) "Preclinical or animal studies have shown that primary local therapy directed to prostate triggers some subcellular level changes in the prostate cancer cells. However, it is unknown whether these changes translate into any clinically meaningful difference in outcomes when systemic therapies are initiated after progression to a metastatic stage in patients treated with prior local therapy. We propose a combined analysis of ACIS, PREVAIL, COU-AA-302 which will provide robust evidence whether receipt of primary local therapy and the type of primary local therapy affect outcome including response to subsequent lines of therapy in men with metastatic castrate resistant prostate cancer."
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      string(33) "The Ottawa Hospital Cancer Centre"
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      string(223) "NCT00887198 - A Phase 3, Randomized, Double-blind, Placebo-Controlled Study of Abiraterone Acetate (CB7630) Plus Prednisone in Asymptomatic or Mildly Symptomatic Patients With Metastatic Castration-Resistant Prostate Cancer"
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  string(3322) "Background: Preclinical studies suggest that receipt of definitive local therapy (LT) to prostate might bear substantial effect on subsequent systemic therapy in metastatic prostate cancer. However, there is lack of concrete clinical evidence which shows differential impact of prior local therapy on subsequent lines of systemic therapy. This is highly relevant as patients with localized, locally advanced, and de novo metastatic hormone sensitive prostate cancer with limited metastatic burden receive prostate directed LT and a number of them eventually progress to metastatic castrate resistant prostate cancer (mCRPC) phase where androgen receptor axis targeted therapy (ARAT) remains the standard of care. It is unknown if receipt of prior local therapy affects response to first line ARAT in docetaxel naive mCRPC patients. Objectives: We plan to perform a pooled analysis of PREVAIL, ACIS and COU-AA-302 trial to compare the radiographic progression-free survival (rPFS) and overall survival (OS) in patients treated with prior LT compared to those who had no prior LT. We also plan to compare rPFS and time to progression in patient treated with prior radical prostatectomy (RP) versus those who were treated with prior radiation therapy (RT). Finally we plan to determine the surrogacy of rPFS for OS in docetaxel naive mCRPC patients.
Design and Participants: A pooled analysis with patients in the PREVAIL (NCT01212991), ACIS (NCT02257736) and COU-AA-302 (NCT00887198). Main outcome: The primary endpoint will be rPFS and OS. The secondary endpoints will include patient reported quality of life outcomes.
Main exposure variable: Receipt of prior LT vs no LT.
Statistical Plan: For rPFS and OS, separate multivariable Cox regression models will be applied to determine the adjusted effect of local therapy (radiation therapy or radical prostatectomy vs. no prior therapy) after adjustment for treatment arm, duration of androgen deprivation therapy (ADT), Gleason score, tumor stage, metastatic stage, and nodal stage at initial diagnosis, presence of visceral metastasis, number of skeletal metastasis, prostate-specifi c antigen (PSA) and alkaline phosphatase at the time of study entry, and receipt of ADT before start of protocol treatment. Trials will be added as a random effect. To determine the heterogeneity of treatment effect from fi rst line ARAT on rPFS, OS, we will fi t separate multivariable Cox regression models with interaction terms between the receipt of prior local therapy with randomized treatment regimen. Similar analyses will be done for type of prior local therapy (radical prostatectomy or radiation therapy versus no local therapy). HR-QoL will be scored using FACT-P and treatment effect on longitudinal changes in HR-QoL will be compared among patients with or without prior local therapy using linear mixed models with an interaction term between prior local therapy and treatment regimen. We will use both Prentice criteria and meta-analytic approach to investigate the surrogacy of rPFS for OS. The meta-analytic approach would mandate determining the patient level correlation between the surrogate endpoint and the true endpoint and a trial level correlation between the treatment effect on surrogate endpoint and a treatment effect on true endpoint." ["project_brief_bg"]=> string(3197) "Definitive treatment for men with localized prostate cancer often comprises local therapy (LT) (either radical prostatectomy [RP] or radiation therapy [RT]), with or without androgen deprivation therapy (ADT) based on patient and disease characteristics.(1, 2) Despite these curative intent treatments, a proportion of patients, particularly those with high-risk and. locally advanced disease, eventually develop recurrence and progression, including to metastatic castrate resistant prostate cancer (mCRPC).(3, 4) At this stage, systemic treatment including chemotherapy, androgen receptor axis targeted therapy (ARAT) remains the cornerstone of management.(5?11) Whether primary LT after diagnosis affects response to this subsequent treatment is unclear. Preclinical studies have shown that fractionated ionizing RT can induce neuroendocrine differentiation in prostate cancer by increasing the nuclear content of phospho-CREB and cytoplasmic accumulation of ATF2.(12) This has significant implications in progression of prostate cancer, androgen-independent growth, and it ultimately portends poor prognosis. In contrast, minimal residual disease after RP could give rise to treatment-resistant clones that can lead to poor response to adjuvant or salvage therapy.(13) In a small Japanese study, initial curative treatment modality was a significant predictor of castration resistance based on a multivariable regression.(14) In another Japanese retrospective study, prior LT was associated with a lower risk of overall mortality (hazard ratio [HR]: 0.56, 95% confidence interval [CI]: 0.40?0.79) in patients with CRPC.(15) Similarly, a retrospective study by Patel et al showed that patients with mCRPC who were previously treated with RP with/without postoperative RT had superior overall survival (HR: 0.70, 95% CI: 0.53-0.88) compared to those without prior LT.(16)
Three randomized controlled trials have investigated the role of first line ARAT in mCRPC. In COU-AA-302 trial (17), docetaxel naive mCRPC patients were randomized to receive placebo vs abiraterone while in PREVAIL trial (18), docetaxel naive mCRPC patients were randomized between placebo and Enzalutamide (18). ACIS (19) investigated the utility of dual ARATs (abiraterone plus apalutamide) compared to single ARAT (abiraterone) in these patients. Herein we propose a pooled analysis of PREVAIL, ACIS and COU-AA-302 to compare the outcome with second generation anti-androgen therapy in mCRPC based on receipt of prior local therapy. The response will be compared primarily in terms of rPFS, OS, and patient reported quality of life (QoL). Our findings will clarify whether the outcome and response to systemic therapy in mCRPC depends on the receipt of prior local therapy and the modality of prior local therapy. This will also provide important information on the fact if receipt of prior LT portend any poor prognosis. Furthermore, we also plan to determine if rPFS is a surrogate endpoint for OS which is the major endpoint in oncological trial. If proven as a surrogate, use of time rPFS will allow a quicker read out of the trials and would help patients to have faster access to life prolonging treatments." ["project_specific_aims"]=> string(1256) "Aim 1: if the response to first line androgen receptor axis targeted therapy (ARAT) in chemotherapy naive metastatic castrate resistant prostate cancer (mCRPC) vary based on receipt of prior local therapy (LT) to prostate? We propose to determine treatment effect from first line ARAT on rPFS, OS, and patient reported QoL from a pooled individual patient data from COU-AA-302, ACIS, and PREVAIL trial. We will determine if the effect of first line ARAT on these outcomes differ based on receipt of prior LT. Furthermore, we will also determine if the treatment effect on this outcome vary depending on type of prior LT (radical prostatectomy versus radiation therapy versus both).
Aim 2: Does receipt of prior LT has any association with oncologic outcome in patients with chemotherapy naive mCRPC? To investigate this, we will compare radiographic progression-free survival in patients treated with prior LT to prostate as compared to patients with no prior LT.
Aim 3: Is rPFS a strong surrogate for OS in chemotherapy naive mCRPC treated with first line ARAT? Using individual patient data from these three trials, we will determine if rPFS is a surrogate for OS. We will apply Prentice criteria and meta-analytic approach to address this." ["project_study_design"]=> array(2) { ["value"]=> string(7) "meta_an" ["label"]=> string(52) "Meta-analysis (analysis of multiple trials together)" } ["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(404) "Pooled analysis of individual patient data from ACIS trial (NCT02257736) dataset and COU-AA-302 (NCT00887198) and PREVAIL Trial (NCT 01212991). Please make note that the same proposal has been placed at the VIVLI platform (ID: 00008714). The data from ACIS and COU-AA-302 would come from YODA platform while the individual patient data from PREVAIL Trial will be provided by Pfizer at the VIVLI platform." ["project_main_outcome_measure"]=> string(710) "- Radiographic progression-free survival (rPFS), will be defined as time since randomization to radiographic progression or death from any cause
- Overall survival (OS) will be defined as time since randomization to death from any cause
- HR-QoL will be determined using FACT-P with specific focus on physical well-being, social well-being, emotional well-being, trial outcome index, prostate cancer sub scale, and total score.
Please make note that, the same proposal has been placed at the VIVLI platform (ID: 00008714). The data from ACIS and COU-AA-302 would come from YODA platform while the individual patient data from PREVAIL Trial will be provided by Pfizer at the VIVLI platform." ["project_main_predictor_indep"]=> string(504) "Receipt of prior local therapy (radical prostatectomy or radiotherapy to prostate) vs no local therapy. Additional subgroup analyses will be done to compare patients treated with radical prostatectomy and those treated with radiotherapy to prostate.
Of note, the same proposal has been placed at the VIVLI platform (ID: 00008714). The data from ACIS and COU-AA-302 would come from YODA platform while the individual patient data from PREVAIL Trial will be provided by Pfizer at the VIVLI platform." ["project_other_variables_interest"]=> string(1315) "Baseline Factors:
- Treatment arm: Categorical
- Race: Categorical
- Age, height, weight: Continuous
- Gleason Score at initial diagnosis: Ordinal
- Prior surgery i.e., prostatectomy: yes/no (categorical)
- Date of prior prostatectomy (if available)
- Prior radiation therapy: yes/no (categorical) to prostate with dates
- ECOG PS: Ordinal
- Date of randomization (date format) ? to calculate all endpoints
- Prior systemic treatment (ADT) ? yes/no (categorical)
- Tumor stage at diagnosis ? categorical
- Nodal stage at diagnosis ? categorical
- Metastatic stage at diagnosis ? Categorical
- PSA at diagnosis
- Time from initial diagnosis to randomization in years (continuous)
- Time from initiation of ADT or orchiectomy to randomization in years
- Site of visceral metastasis (categorical)
- No of skeletal metastasis (categorical)
Baseline and Post-Baseline Variables:
- PSA at time of study entry: continuous numeric variable
- - Baseline serum alkaline phosphatase level (continuous)
- Time of radiographic progression (date format)
- Time to death (date format) and cause of death
- Date of last tumor assessment and date of last follow-up" ["project_stat_analysis_plan"]=> string(3997) "Only three phase III randomized controlled trials have evaluated the role of first line ARAT as first line therapy in men with chemotherapy nave mCRPC. These are COU-AA-302, ACIS, and PREVAIL, respectively. Therefore, we propose a combined analysis of COU-AA-302, ACIS, and PREVAIL to determine if there is a difference in treatment effect from first line ARAT on rPFS, OS, and patient reported HR-QoL depending on receipt of prior lLT or type of prior LT. We will also determine the independent association of prior LT with rPFS, OS in mCRPC patients who are chemotherapy nave and treated with first line ARAT. Secondarily, we plan to determine the correlation of rPFS as a surrogate endpoint with OS as a true endpoint. Descriptive statistics will be used to characterize the data in the study, including means, medians, and analysis of variance and Wilcoxon signed rank for continuous variables and frequency tables and chi-square test for categorical variables. Radiographic progression-free survival, and overall survival will be estimated by Kaplan-Meier?s method. Separate multilevel multivariable cox proportional hazard regression models will be applied to estimate adjusted hazard ratios for receipt of local therapy (prostatectomy or radiation therapy or their combination) for each of the endpoints. For overall survival and radiographic progression-free survival, these multilevel multivariable Cox proportional hazard regression models will include the prior local therapy (radiation therapy or radical prostatectomy vs. no prior therapy), age at randomization, treatment arm, receipt of prior androgen deprivation therapy (ADT), Gleason score at initial diagnosis, tumor stage at initial diagnosis, nodal stage at initial diagnosis, number of skeletal metastasis at enrollment, PSA at the time of enrollment, ALP at the time of enrollment, duration of ADT before start of protocol treatment and the time interval between initial diagnosis to time to randomization. An interaction term will be introduced in these Cox models which will determine the heterogeneity of treatment effect from first line ARAT on OS and rPFS based on receipt of prior local therapy after adjustment for the covariables listed above. Individual trials will be added as a random effect in these multilevel multivariable Cox models. Proportionality assumption will be visually checked by Schoenfeld?s residuals and will be tested using Grambsch-Therneau?s test. To evaluate the robustness of our findings in presence of missing data, we plan to perform two sensitivity analyses with multivariable Cox regression. The first one will be a complete case analysis which will be restricted to patients with non-missing data on covariables. In the second sensitivity analysis, we will estimate pooled hazard ratios with pooled 95% confi dence intervals from multivariable Cox regression models in multiply imputed datasets. Trials will be added as a random effect in these sensitivity analyses. To model the changes in scores (relative to baseline) over time (random assignment to end of treatment (EOT)), we will apply linear mixed effects models. Baseline score, time from random assignment, treatment group, age, Eastern Cooperative Oncology Group (ECOG) performance status, receipt of prior local therapy, interaction between time of assessment and treatment group, and interaction between treatment group and LT will be treated as fixed covariates. Patients will be included as random intercepts. Patients with baseline and at least one post-baseline assessment will be included in the models. We will apply two approaches to determine the surrogacy of rPFS for OS, an intermediate clinical endpoint (ICE) - first, using the Prentice criteria and, second, using a two-stage meta-analytic approach. For the meta-meta-analytic strategy, we will premise our analysis on the following two conditions ? patient level correlation between the ICE and OS and trial level correlation of treatment effect on ICE and OS." ["project_timeline"]=> string(280) "- Project submission: January 2023
- Contract: February and March 2023
- Analysis: April 2023 to February 2024
- Abstract Submission (ASCO 2024 and ASTRO 2024): February 2024
- Paper Draft circulation: March-May 2024
- Paper Submission: May 2023" ["project_dissemination_plan"]=> string(236) "- Abstract presentation in ASCO 2023 and ASTRO 2023
- Submission of manuscript first-quartile oncology journals: Journal of Clinical Oncology, Journal of National Comprehensive Cancer Network, European Urology, Annals of Oncology" ["project_bibliography"]=> string(3712) "

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18. Beer T, Armstrong AJ, Rathkopf D, et al. Enzalutamide in Metastatic Prostate Cancer before Chemotherapy. N. Engl. J. Med. 2014;371:424-433.
19. Saad F, Efstathiou E, Attard G, et al. Apalutamide plus abiraterone acetate and prednisone versus placebo plus abiraterone and prednisone in metastatic, castration-resistant prostate cancer (ACIS): a randomised, placebo-controlled, double-blind, multinational, phase 3 study. Lancet Oncol. 2021;22:1541?1559.

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2023-5129

General Information

How did you learn about the YODA Project?: Scientific Publication

Conflict of Interest

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Associated Trial(s):
  1. NCT00887198 - A Phase 3, Randomized, Double-blind, Placebo-Controlled Study of Abiraterone Acetate (CB7630) Plus Prednisone in Asymptomatic or Mildly Symptomatic Patients With Metastatic Castration-Resistant Prostate Cancer
  2. NCT02257736 - A Phase 3 Randomized, Placebo-controlled Double-blind Study of JNJ-56021927 in Combination With Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone in Subjects With Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer (mCRPC)
What type of data are you looking for?: Individual Participant-Level Data, which includes Full CSR and all supporting documentation

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Data Request Status

Status: Withdrawn/Closed

Research Proposal

Project Title: Effect of Prior Local Therapy on Response to First Line Systemic Therapy in Men with Metastatic Castrate Resistant Prostate Cancer

Scientific Abstract: Background: Preclinical studies suggest that receipt of definitive local therapy (LT) to prostate might bear substantial effect on subsequent systemic therapy in metastatic prostate cancer. However, there is lack of concrete clinical evidence which shows differential impact of prior local therapy on subsequent lines of systemic therapy. This is highly relevant as patients with localized, locally advanced, and de novo metastatic hormone sensitive prostate cancer with limited metastatic burden receive prostate directed LT and a number of them eventually progress to metastatic castrate resistant prostate cancer (mCRPC) phase where androgen receptor axis targeted therapy (ARAT) remains the standard of care. It is unknown if receipt of prior local therapy affects response to first line ARAT in docetaxel naive mCRPC patients. Objectives: We plan to perform a pooled analysis of PREVAIL, ACIS and COU-AA-302 trial to compare the radiographic progression-free survival (rPFS) and overall survival (OS) in patients treated with prior LT compared to those who had no prior LT. We also plan to compare rPFS and time to progression in patient treated with prior radical prostatectomy (RP) versus those who were treated with prior radiation therapy (RT). Finally we plan to determine the surrogacy of rPFS for OS in docetaxel naive mCRPC patients.
Design and Participants: A pooled analysis with patients in the PREVAIL (NCT01212991), ACIS (NCT02257736) and COU-AA-302 (NCT00887198). Main outcome: The primary endpoint will be rPFS and OS. The secondary endpoints will include patient reported quality of life outcomes.
Main exposure variable: Receipt of prior LT vs no LT.
Statistical Plan: For rPFS and OS, separate multivariable Cox regression models will be applied to determine the adjusted effect of local therapy (radiation therapy or radical prostatectomy vs. no prior therapy) after adjustment for treatment arm, duration of androgen deprivation therapy (ADT), Gleason score, tumor stage, metastatic stage, and nodal stage at initial diagnosis, presence of visceral metastasis, number of skeletal metastasis, prostate-specifi c antigen (PSA) and alkaline phosphatase at the time of study entry, and receipt of ADT before start of protocol treatment. Trials will be added as a random effect. To determine the heterogeneity of treatment effect from fi rst line ARAT on rPFS, OS, we will fi t separate multivariable Cox regression models with interaction terms between the receipt of prior local therapy with randomized treatment regimen. Similar analyses will be done for type of prior local therapy (radical prostatectomy or radiation therapy versus no local therapy). HR-QoL will be scored using FACT-P and treatment effect on longitudinal changes in HR-QoL will be compared among patients with or without prior local therapy using linear mixed models with an interaction term between prior local therapy and treatment regimen. We will use both Prentice criteria and meta-analytic approach to investigate the surrogacy of rPFS for OS. The meta-analytic approach would mandate determining the patient level correlation between the surrogate endpoint and the true endpoint and a trial level correlation between the treatment effect on surrogate endpoint and a treatment effect on true endpoint.

Brief Project Background and Statement of Project Significance: Definitive treatment for men with localized prostate cancer often comprises local therapy (LT) (either radical prostatectomy [RP] or radiation therapy [RT]), with or without androgen deprivation therapy (ADT) based on patient and disease characteristics.(1, 2) Despite these curative intent treatments, a proportion of patients, particularly those with high-risk and. locally advanced disease, eventually develop recurrence and progression, including to metastatic castrate resistant prostate cancer (mCRPC).(3, 4) At this stage, systemic treatment including chemotherapy, androgen receptor axis targeted therapy (ARAT) remains the cornerstone of management.(5?11) Whether primary LT after diagnosis affects response to this subsequent treatment is unclear. Preclinical studies have shown that fractionated ionizing RT can induce neuroendocrine differentiation in prostate cancer by increasing the nuclear content of phospho-CREB and cytoplasmic accumulation of ATF2.(12) This has significant implications in progression of prostate cancer, androgen-independent growth, and it ultimately portends poor prognosis. In contrast, minimal residual disease after RP could give rise to treatment-resistant clones that can lead to poor response to adjuvant or salvage therapy.(13) In a small Japanese study, initial curative treatment modality was a significant predictor of castration resistance based on a multivariable regression.(14) In another Japanese retrospective study, prior LT was associated with a lower risk of overall mortality (hazard ratio [HR]: 0.56, 95% confidence interval [CI]: 0.40?0.79) in patients with CRPC.(15) Similarly, a retrospective study by Patel et al showed that patients with mCRPC who were previously treated with RP with/without postoperative RT had superior overall survival (HR: 0.70, 95% CI: 0.53-0.88) compared to those without prior LT.(16)
Three randomized controlled trials have investigated the role of first line ARAT in mCRPC. In COU-AA-302 trial (17), docetaxel naive mCRPC patients were randomized to receive placebo vs abiraterone while in PREVAIL trial (18), docetaxel naive mCRPC patients were randomized between placebo and Enzalutamide (18). ACIS (19) investigated the utility of dual ARATs (abiraterone plus apalutamide) compared to single ARAT (abiraterone) in these patients. Herein we propose a pooled analysis of PREVAIL, ACIS and COU-AA-302 to compare the outcome with second generation anti-androgen therapy in mCRPC based on receipt of prior local therapy. The response will be compared primarily in terms of rPFS, OS, and patient reported quality of life (QoL). Our findings will clarify whether the outcome and response to systemic therapy in mCRPC depends on the receipt of prior local therapy and the modality of prior local therapy. This will also provide important information on the fact if receipt of prior LT portend any poor prognosis. Furthermore, we also plan to determine if rPFS is a surrogate endpoint for OS which is the major endpoint in oncological trial. If proven as a surrogate, use of time rPFS will allow a quicker read out of the trials and would help patients to have faster access to life prolonging treatments.

Specific Aims of the Project: Aim 1: if the response to first line androgen receptor axis targeted therapy (ARAT) in chemotherapy naive metastatic castrate resistant prostate cancer (mCRPC) vary based on receipt of prior local therapy (LT) to prostate? We propose to determine treatment effect from first line ARAT on rPFS, OS, and patient reported QoL from a pooled individual patient data from COU-AA-302, ACIS, and PREVAIL trial. We will determine if the effect of first line ARAT on these outcomes differ based on receipt of prior LT. Furthermore, we will also determine if the treatment effect on this outcome vary depending on type of prior LT (radical prostatectomy versus radiation therapy versus both).
Aim 2: Does receipt of prior LT has any association with oncologic outcome in patients with chemotherapy naive mCRPC? To investigate this, we will compare radiographic progression-free survival in patients treated with prior LT to prostate as compared to patients with no prior LT.
Aim 3: Is rPFS a strong surrogate for OS in chemotherapy naive mCRPC treated with first line ARAT? Using individual patient data from these three trials, we will determine if rPFS is a surrogate for OS. We will apply Prentice criteria and meta-analytic approach to address this.

Study Design: Meta-analysis (analysis of multiple trials together)

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: Pooled analysis of individual patient data from ACIS trial (NCT02257736) dataset and COU-AA-302 (NCT00887198) and PREVAIL Trial (NCT 01212991). Please make note that the same proposal has been placed at the VIVLI platform (ID: 00008714). The data from ACIS and COU-AA-302 would come from YODA platform while the individual patient data from PREVAIL Trial will be provided by Pfizer at the VIVLI platform.

Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: - Radiographic progression-free survival (rPFS), will be defined as time since randomization to radiographic progression or death from any cause
- Overall survival (OS) will be defined as time since randomization to death from any cause
- HR-QoL will be determined using FACT-P with specific focus on physical well-being, social well-being, emotional well-being, trial outcome index, prostate cancer sub scale, and total score.
Please make note that, the same proposal has been placed at the VIVLI platform (ID: 00008714). The data from ACIS and COU-AA-302 would come from YODA platform while the individual patient data from PREVAIL Trial will be provided by Pfizer at the VIVLI platform.

Main Predictor/Independent Variable and how it will be categorized/defined for your study: Receipt of prior local therapy (radical prostatectomy or radiotherapy to prostate) vs no local therapy. Additional subgroup analyses will be done to compare patients treated with radical prostatectomy and those treated with radiotherapy to prostate.
Of note, the same proposal has been placed at the VIVLI platform (ID: 00008714). The data from ACIS and COU-AA-302 would come from YODA platform while the individual patient data from PREVAIL Trial will be provided by Pfizer at the VIVLI platform.

Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: Baseline Factors:
- Treatment arm: Categorical
- Race: Categorical
- Age, height, weight: Continuous
- Gleason Score at initial diagnosis: Ordinal
- Prior surgery i.e., prostatectomy: yes/no (categorical)
- Date of prior prostatectomy (if available)
- Prior radiation therapy: yes/no (categorical) to prostate with dates
- ECOG PS: Ordinal
- Date of randomization (date format) ? to calculate all endpoints
- Prior systemic treatment (ADT) ? yes/no (categorical)
- Tumor stage at diagnosis ? categorical
- Nodal stage at diagnosis ? categorical
- Metastatic stage at diagnosis ? Categorical
- PSA at diagnosis
- Time from initial diagnosis to randomization in years (continuous)
- Time from initiation of ADT or orchiectomy to randomization in years
- Site of visceral metastasis (categorical)
- No of skeletal metastasis (categorical)
Baseline and Post-Baseline Variables:
- PSA at time of study entry: continuous numeric variable
- - Baseline serum alkaline phosphatase level (continuous)
- Time of radiographic progression (date format)
- Time to death (date format) and cause of death
- Date of last tumor assessment and date of last follow-up

Statistical Analysis Plan: Only three phase III randomized controlled trials have evaluated the role of first line ARAT as first line therapy in men with chemotherapy nave mCRPC. These are COU-AA-302, ACIS, and PREVAIL, respectively. Therefore, we propose a combined analysis of COU-AA-302, ACIS, and PREVAIL to determine if there is a difference in treatment effect from first line ARAT on rPFS, OS, and patient reported HR-QoL depending on receipt of prior lLT or type of prior LT. We will also determine the independent association of prior LT with rPFS, OS in mCRPC patients who are chemotherapy nave and treated with first line ARAT. Secondarily, we plan to determine the correlation of rPFS as a surrogate endpoint with OS as a true endpoint. Descriptive statistics will be used to characterize the data in the study, including means, medians, and analysis of variance and Wilcoxon signed rank for continuous variables and frequency tables and chi-square test for categorical variables. Radiographic progression-free survival, and overall survival will be estimated by Kaplan-Meier?s method. Separate multilevel multivariable cox proportional hazard regression models will be applied to estimate adjusted hazard ratios for receipt of local therapy (prostatectomy or radiation therapy or their combination) for each of the endpoints. For overall survival and radiographic progression-free survival, these multilevel multivariable Cox proportional hazard regression models will include the prior local therapy (radiation therapy or radical prostatectomy vs. no prior therapy), age at randomization, treatment arm, receipt of prior androgen deprivation therapy (ADT), Gleason score at initial diagnosis, tumor stage at initial diagnosis, nodal stage at initial diagnosis, number of skeletal metastasis at enrollment, PSA at the time of enrollment, ALP at the time of enrollment, duration of ADT before start of protocol treatment and the time interval between initial diagnosis to time to randomization. An interaction term will be introduced in these Cox models which will determine the heterogeneity of treatment effect from first line ARAT on OS and rPFS based on receipt of prior local therapy after adjustment for the covariables listed above. Individual trials will be added as a random effect in these multilevel multivariable Cox models. Proportionality assumption will be visually checked by Schoenfeld?s residuals and will be tested using Grambsch-Therneau?s test. To evaluate the robustness of our findings in presence of missing data, we plan to perform two sensitivity analyses with multivariable Cox regression. The first one will be a complete case analysis which will be restricted to patients with non-missing data on covariables. In the second sensitivity analysis, we will estimate pooled hazard ratios with pooled 95% confi dence intervals from multivariable Cox regression models in multiply imputed datasets. Trials will be added as a random effect in these sensitivity analyses. To model the changes in scores (relative to baseline) over time (random assignment to end of treatment (EOT)), we will apply linear mixed effects models. Baseline score, time from random assignment, treatment group, age, Eastern Cooperative Oncology Group (ECOG) performance status, receipt of prior local therapy, interaction between time of assessment and treatment group, and interaction between treatment group and LT will be treated as fixed covariates. Patients will be included as random intercepts. Patients with baseline and at least one post-baseline assessment will be included in the models. We will apply two approaches to determine the surrogacy of rPFS for OS, an intermediate clinical endpoint (ICE) - first, using the Prentice criteria and, second, using a two-stage meta-analytic approach. For the meta-meta-analytic strategy, we will premise our analysis on the following two conditions ? patient level correlation between the ICE and OS and trial level correlation of treatment effect on ICE and OS.

Narrative Summary: Preclinical or animal studies have shown that primary local therapy directed to prostate triggers some subcellular level changes in the prostate cancer cells. However, it is unknown whether these changes translate into any clinically meaningful difference in outcomes when systemic therapies are initiated after progression to a metastatic stage in patients treated with prior local therapy. We propose a combined analysis of ACIS, PREVAIL, COU-AA-302 which will provide robust evidence whether receipt of primary local therapy and the type of primary local therapy affect outcome including response to subsequent lines of therapy in men with metastatic castrate resistant prostate cancer.

Project Timeline: - Project submission: January 2023
- Contract: February and March 2023
- Analysis: April 2023 to February 2024
- Abstract Submission (ASCO 2024 and ASTRO 2024): February 2024
- Paper Draft circulation: March-May 2024
- Paper Submission: May 2023

Dissemination Plan: - Abstract presentation in ASCO 2023 and ASTRO 2023
- Submission of manuscript first-quartile oncology journals: Journal of Clinical Oncology, Journal of National Comprehensive Cancer Network, European Urology, Annals of Oncology

Bibliography:

1. Mohler JL, Antonarakis ES, Armstrong AJ, et al. Prostate cancer, version 2.2019. JNCCN J. Natl. Compr. Cancer Netw. 2019;17:479?505.
2. Varlotto J, Schiff PB, Hu C-D, et al. Mechanistic insights into Molecular Targeting and Combined Modality Therapy for Aggressive, Localized Prostate Cancer. 2016;6:1.
3. Shore ND, Morgans AK, Ryan CJ. Resetting the Bar of Castration Resistance ? Understanding Androgen Dynamics in Therapy Resistance and Treatment Choice in Prostate Cancer. Clin. Genitourin. Cancer. 2021;19:199?207.
4. Burgess L, Roy S, Morgan S, et al. A Review on the Current Treatment Paradigm in High-Risk Prostate Cancer. Cancers 2021, Vol. 13, Page 4257. 2021;13:4257.
5. Lee C-H, Kantoff P. Treatment of Metastatic Prostate Cancer in 2018. JAMA Oncol. 2019;5:263?264.
6. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in Metastatic Prostate Cancer before Chemotherapy. N. Engl. J. Med. 2014;371:424?433.
7. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and Increased Survival in Metastatic Prostate Cancer. N. Engl. J. Med. 2011;364:1995?2005.
8. Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16:152?160.
9. Scher HI, Fizazi K, Saad F, et al. Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy Cabot RC, Harris NL, Rosenberg ES, et al., eds. N. Engl. J. Med. 2012;367:1187?1197.
10. Parker C, Nilsson S, Heinrich D, et al. Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer. n engl j med. 2013;369:213?236.
11. De Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial. Lancet. 2010;376:1147?1154.
12. Deng X, Liu H, Huang J, et al. Ionizing radiation induces prostate cancer neuroendocrine differentiation through interplay of CREB and ATF2: Implications for disease progression. Cancer Res. 2008;68:9663?9670.
13. Murray NP. Minimal residual disease in prostate cancer patients after primary treatment: Theoretical considerations, evidence and possible use in clinical management. Biol. Res. 2018;51:1?14.
14. Obata H, Shiota M, Akitake N, et al. Differential risk of castration resistance after initial radical prostatectomy or radiotherapy for prostate cancer. Anticancer Res. 2017;37:5631?5637.
15. Koura M, Shiota M, Ueda S, et al. Prognostic impact of prior local therapy in castration-resistant prostate cancer. Jpn. J. Clin. Oncol. 2021;51:1142?1148.
16. Patel DN, Jha S, Howard LE, et al. Impact of prior local therapy on overall survival in men with metastatic castration-resistant prostate cancer: Results from Shared Equal Access Regional Cancer Hospital. Int. J. Urol. 2018;25:998?1004.
17. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy. N. Engl. J. Med. 2013;368:138?148.
18. Beer T, Armstrong AJ, Rathkopf D, et al. Enzalutamide in Metastatic Prostate Cancer before Chemotherapy. N. Engl. J. Med. 2014;371:424-433.
19. Saad F, Efstathiou E, Attard G, et al. Apalutamide plus abiraterone acetate and prednisone versus placebo plus abiraterone and prednisone in metastatic, castration-resistant prostate cancer (ACIS): a randomised, placebo-controlled, double-blind, multinational, phase 3 study. Lancet Oncol. 2021;22:1541?1559.