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  string(696) "Advanced prostate cancer has been plagued by the lack of an optimal endpoint to rapidly assess the anti-tumor activity of new drugs due to the presence of mostly bone metastases.  Unfortunately, bone metastases are not possible to accurately measure in contrast to measurable metastases in other organs like the lung, lymph nodes and liver.  Since, current improved CT scan technology is more frequently detecting measurable tumors, we propose to study the COU-AA-301 dataset (and AA-302 trial when available) to validate the association between response of measurable tumors and survival. The validation of this association will expedite drug development and will represent an important advance."
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      string(233) "NCT00638690 - A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Abiraterone Acetate (CB7630) Plus Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer Who Have Failed Docetaxel-Based Chemotherapy"
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  string(1611) "Background: Objective RECIST (Response Evaluation Criteria in Solid Tumors) criteria have not been generally applicable to metastatic castration-resistant prostate cancer (mCRPC) due to mostly non-measurable bone metastases. Given the more frequent detection of measurable disease with current CT imaging technology, the accrual of mCRPC patients with measurable tumors in phase II trials to assess RECIST changes may provide a more objective signal of efficacy of new drugs. The COU-AA-302 and COU-AA-301 phase III trials, which evaluated abiraterone, were both ?positive? for extension of overall survival (OS), and afford a unique opportunity to study the surrogacy of RECIST response to predict OS. The surrogacy of RECIST changes may then be examined across other agents to confirm universal applicability. Such a development will allow the objective determination of activity of agents in phase II trials and resources will be better utilized since the most suitable agents will be selected for phase III development.
Objectives: To study RECIST response as a surrogate for OS
Study design and participants: The COU-AA-302 will be employed as the discovery dataset and COU-AA-301 as the validation dataset.
Outcome measures: The association RECIST changes with OS will be studied.
Statistical analysis: Univariable and multivariable Cox regression analyses will evaluate the prognostic ability of RECIST changes. A landmark analysis will be performed using day 90 as the landmark time. RECIST changes will be evaluated as potential surrogates using the likelihood reduction factor." ["project_brief_bg"]=> string(3108) "Intermediate endpoints correlating with survival in men with mCRPC:
mCRPC has been historically plagued by the lack of an optimal intermediate endpoint correlating with survival due to the presence of mostly bone metastases and lack of measurable disease [1-9]. PSA declines and radiographic progression are associated with survival, but are not validated across different drugs and have subjective components. Although circulating tumor cell (CTC) changes carry prognostic value, all patients do not have detectable CTCs and costs may be a barrier [10-13].
Objective measurable disease response:
Measurable disease response by WHO criteria was associated with OS in the setting of chemotherapy as shown in the TAX327 trial[14]. Partial responders demonstrated longer median OS (29.0 months) than patients with SD (22.1 months) or those with PD (10.8 months) or those who were not assessed (12.7 months). Radiologic response remained a significant but modest post-treatment prognostic factor for OS after adjusting for treatment, pain response, and ? 30% PSA decline (P = 0.009), and remained significant based on landmark analyses. Recently, response by RECIST criteria was examined for association with OS in the VENICE dataset of patients receiving docetaxel-based chemotherapy (confidential; data submitted to GU ASCO symposium 2015)[15]. To briefly summarize the findings, 363 of 612 patients (59.3%) who received docetaxel-prednisone had measurable lesions. Objective changes in tumor size by RECIST within 90 days were robustly associated with OS in patients with mCRPC receiving first-line docetaxel-based chemotherapy.
COU-AA-302 and AA-301 trials:
The COU-AA-301 (N=1195) and AA-302 (N=1088) phase III trials are randomized trials that showed an extension of survival as well as multiple secondary endpoints (including RECIST response) with abiraterone + prednisone compared to placebo + prednisone in the post-docetaxel and pre-docetaxel settings, respectively [16, 17].
Statement of project significance:
Given the limitations of objectively measuring tumor burden in bone and more frequent detection of measurable disease with current imaging, the accrual of patients with measurable tumors in phase II trials to assess RECIST changes may provide a more robust and objective signal of efficacy of new drugs compared to currently used intermediate endpoints. The COU-AA-302 and AA-301 trial datasets offer the opportunity to validate the association between RECIST response and survival in the setting of abiraterone plus prednisone. It is proposed that COU-AA-302 be employed as the discovery dataset and AA-301 be employed as the validation dataset. If RECIST changes show at least moderate surrogacy for OS using these datasets, the surrogacy of RECIST changes may then be examined across other agents to confirm universal applicability. Such a development will allow the objective determination of activity of agents in phase II trials and resources will be better utilized since the most suitable agents will be selected for phase III development." ["project_specific_aims"]=> string(1287) "Given the limitations of objectively measuring tumor burden in bone in men with metastatic castration prostate cancer (mCRPC) and more frequent detection of measurable disease with current imaging, the accrual of men with measurable tumors in phase II trials to assess RECIST changes may be hypothesized to provide a more robust and objective signal of efficacy of new drugs compared to endpoints such as PSA response and radiographic progression-free survival.
1. To study the association of RECIST response with survival in docetaxel-nave and post-docetaxel men with mCRPC receiving prednisone combined with placebo or abiraterone
Cox regression analyses of COU-AA-301 and COU-AA-302 trials will evaluate the prognostic ability of RECIST changes to predict survival after adjusting for previously reported baseline prognostic factors. The impact of RECIST changes independent of PSA response will be studied.
2. To evaluate RECIST response as a surrogate endpoint in docetaxel-nave and post-docetaxel men with mCRPC receiving prednisone combined with placebo or abiraterone
RECIST changes will be evaluated as potential surrogates for OS using COU-AA-302 as the discovery dataset and COU-AA-301 as the validation dataset, using the likelihood reduction factor." ["project_study_design"]=> string(0) "" ["project_study_design_exp"]=> string(0) "" ["project_purposes"]=> array(1) { [0]=> array(2) { ["value"]=> string(114) "New research question to examine treatment effectiveness on secondary endpoints and/or within subgroup populations" ["label"]=> string(114) "New research question to examine treatment effectiveness on secondary endpoints and/or within subgroup populations" } } ["project_purposes_exp"]=> string(0) "" ["project_software_used"]=> string(0) "" ["project_software_used_exp"]=> string(0) "" ["project_research_methods"]=> string(3143) "Retrospective analyses of COU-AA-302 and AA-301 will be conducted to assess the association of RECIST changes with OS. The suitability of RECIST response as a surrogate endpoint will be assessed. COU-AA-302, the pre-docetaxel trial, will be employed as the discovery dataset and AA-301, the post-docetaxel trial, will be employed as the validation dataset. Clinical data (deidentified) will be requested from the COU-AA-302 and AA-301 trials. The following clinical and laboratory variables are requested:
1. Age
2. Therapy arm
3. Trial (AA-301 and AA-302)
4. ECOG-PS
5. Metastatic sites (PCWG2 subtype)
6. Pain
7. Hb
8. Alkaline phosphatase
9. PSA-DT
10. PSA
11. Testosterone level
12. Gleason score
13. Albumin
14. Date of therapy start
15. Date of protocol-defined progression on trial
16. Type of progression: Radiographic progression (measurable disease or bone scan), PSA progression, skeletal-related event, pain progression, and radiotherapy for symptoms or death
17. Date of last follow-up
18. Survival at last follow-up
19. Neutrophil count (baseline)
20. Lymphocyte count (baseline)
21. Measurable tumor
22. RECIST response status and % decline in RECIST dimension by day 90
23. PSA response
COU-AA-302 will be employed as the discovery dataset and AA-301 will be employed as the validation dataset. The AA-302 (NCT00887198) dataset has been requested and is expected to be available soon through the YODA project; however, in the event the NCT00887198 dataset is not available within 2-3 months, analysis and internal validation of the association of RECIST changes and OS will be conducted in the available NCT00638690 (AA-301) trial. Univariable and multivariable Cox regression analyses will evaluate the prognostic ability (with primary endpoint of overall survival and secondary endpoint of radiographic PFS) of RECIST changes (PR, SD, PD) and the previously reported prognostic factors(performance status, pain, visceral metastasis, anemia, PSA, alkaline phosphatase, neutrophil/lymphocyte ratio, PSA response) [17-24]. The impact of RECIST changes independent of PSA declines will be studied. Since there is the potential of a time-bias when using RECIST changes, a landmark analysis will be performed using day 90 as the landmark time. The Kaplan-Meier method will be used for to estimate OS within selected subgroups. Validation of factors hypothesized to be prognostic (performance status, pain, visceral metastasis, anemia, PSA, alkaline phosphatase, neutrophil/lymphocyte ratio, PSA response) will be initially examined in the discovery dataset, and then validated in the validation dataset. Results will be reported using a combination of hazard ratios, overall survival estimation, c-statistics, discrimination plots, tables, descriptive statistics and confidence intervals. RECIST changes will be evaluated as potential surrogates using the likelihood reduction factor [25]. All analyses will be two-sided and statistical significance will be defined at ?=0.05 level." ["project_main_outcome_measure"]=> string(0) "" ["project_main_predictor_indep"]=> string(0) "" ["project_other_variables_interest"]=> string(0) "" ["project_stat_analysis_plan"]=> string(0) "" ["project_timeline"]=> string(285) "1. Completion of contract- 11/2014
2. Obtain deidentified dataset-12/2014
3. Analysis and report submitted to YODA- 1/2014
4. Circulation of abstract targeting ASCO 2015 to YODA - 1/2014
5. Circulation of paper to YODA targeting JCO, Lancet Oncol or CCR- 2/2014" ["project_dissemination_plan"]=> string(128) "1. Circulation of abstract targeting ASCO 2015 - 1/2014
2. Circulation of paper targeting JCO, Lancet Oncol or CCR- 2/2014" ["project_bibliography"]=> string(7099) "

[1] Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008 Mar 1: 26:1148-59
[2] Dennis ER, Jia X, Mezheritskiy IS, et al. Bone scan index: a quantitative treatment response biomarker for castration-resistant metastatic prostate cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012 Feb 10: 30:519-24
[3] Ulmert D, Kaboteh R, Fox JJ, et al. A novel automated platform for quantifying the extent of skeletal tumour involvement in prostate cancer patients using the Bone Scan Index. European urology. 2012 Jul: 62:78-84
[4] Petrylak DP, Ankerst DP, Jiang CS, et al. Evaluation of prostate-specific antigen declines for surrogacy in patients treated on SWOG 99-16. Journal of the National Cancer Institute. 2006 Apr 19: 98:516-21
[5] Armstrong AJ, Garrett-Mayer E, Ou Yang YC, et al. Prostate-specific antigen and pain surrogacy analysis in metastatic hormone-refractory prostate cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007 Sep 1: 25:3965-70
[6] Hussain M, Goldman B, Tangen C, et al. Prostate-specific antigen progression predicts overall survival in patients with metastatic prostate cancer: data from Southwest Oncology Group Trials 9346 (Intergroup Study 0162) and 9916. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2009 May 20: 27:2450-6
[7] Armstrong AJ, Garrett-Mayer E, de Wit R, Tannock I, Eisenberger M. Prediction of survival following first-line chemotherapy in men with castration-resistant metastatic prostate cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. Jan 1: 16:203-11
[8] Sonpavde G, Pond GR, Armstrong AJ, et al. Radiographic progression by Prostate Cancer Working Group (PCWG)-2 criteria as an intermediate endpoint for drug development in metastatic castration-resistant prostate cancer. BJU international. 2013 Dec 3:
[9] Ryan CJ MM, Molina A, Piulats JR, De Souza P, Li J, et al. Association of radiographic progression-free survival adapted from Prostate Cancer Working Group-2 consensus criteria with overall survival in patients wuth metastatic castration-resistant prostate cancer. ESMO Congress September 2012, Vienna, Austria, abstract 8940.
[10] Scher H HG, Molina A, Kheoh T, Attard G, Moreira J, Sandhu S, Parker C, Logothetis C, McCormack R, Fizazi K, Anand A, Danila D, Fleisher M, Olmos D, Haqq C, De Bono J. Evaluation of circulating tumor cell (CTC) enumeration as an efficacy response biomarker of overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC): Planned final analysis (FA) of COU-AA-301, a randomized double-blind, placebo-controlled phase III study of abiraterone acetate (AA) plus low-dose prednisone (P) post docetaxel. J Clin Oncol 29: 2011 (suppl; abstr LBA4517^). 2011:
[11] de Bono JS, Scher HI, Montgomery RB, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2008 Oct 1: 14:6302-9
[12] Beer TM, Lalani AS, Lee S, et al. C-reactive protein as a prognostic marker for men with androgen-independent prostate cancer: results from the ASCENT trial. Cancer. 2008 Jun: 112:2377-83
[13] Prins RC, Rademacher BL, Mongoue-Tchokote S, et al. C-reactive protein as an adverse prognostic marker for men with castration-resistant prostate cancer (CRPC): Confirmatory results. Urologic oncology. Mar 5:
[14] Sonpavde G, Pond GR, Berry WR, et al. The association between radiographic response and overall survival in men with metastatic castration-resistant prostate cancer receiving chemotherapy. Cancer. Mar 1:
[15] Tannock IF, Fizazi K, Ivanov S, et al. Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial. The lancet oncology. 2013 Jul: 14:760-8
[16] de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. The New England journal of medicine. 2011 May: 364:1995-2005
[17] Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. The New England journal of medicine. 2013 Jan 10: 368:138-48
[18] Smaletz O, Scher HI, Small EJ, et al. Nomogram for overall survival of patients with progressive metastatic prostate cancer after castration. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2002 Oct 1: 20:3972-82
[19] Halabi S, Small EJ, Kantoff PW, et al. Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2003 Apr 1: 21:1232-7
[20] Armstrong AJ, Garrett-Mayer ES, Yang YC, de Wit R, Tannock IF, Eisenberger M. A contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: a TAX327 study analysis. Clin Cancer Res. 2007 Nov: 13:6396-403
[21] Armstrong AJ, Garrett-Mayer E, de Wit R, Tannock I, Eisenberger M. Prediction of survival following first-line chemotherapy in men with castration-resistant metastatic prostate cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2010 Jan: 16:203-11
[22] Armstrong AJ, Tannock IF, de Wit R, George DJ, Eisenberger M, Halabi S. The development of risk groups in men with metastatic castration-resistant prostate cancer based on risk factors for PSA decline and survival. European journal of cancer. 2010 Feb: 46:517-25
[23] Halabi S, Lin CY, Kelly WK, et al. Updated prognostic model for predicting overall survival in first-line chemotherapy for patients with metastatic castration-resistant prostate cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014 Mar 1: 32:671-7
[24] Halabi S, Lin CY, Small EJ, et al. Prognostic model predicting metastatic castration-resistant prostate cancer survival in men treated with second-line chemotherapy. Journal of the National Cancer Institute. 2013 Nov 20: 105:1729-37
[25] Omlin A, Pezaro C, Mukherji D, et al. Improved survival in a cohort of trial participants with metastatic castration-resistant prostate cancer demonstrates the need for updated prognostic nomograms. European urology. 2013 Aug: 64:300-6
[26] O’Quigley J, Flandre P. Quantification of the prentice criteria for surrogate endpoints. Biometrics. 2006 Mar: 62:297-300

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2014-0333

General Information

How did you learn about the YODA Project?:

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Associated Trial(s):
  1. NCT00638690 - A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Abiraterone Acetate (CB7630) Plus Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer Who Have Failed Docetaxel-Based Chemotherapy
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Status: Unknown - Revoked

Research Proposal

Project Title: RECIST response as a surrogate endpoint in metastatic castration-resistant prostate cancer: Retrospective analysis of COU-AA-302 and COU-AA-301

Scientific Abstract: Background: Objective RECIST (Response Evaluation Criteria in Solid Tumors) criteria have not been generally applicable to metastatic castration-resistant prostate cancer (mCRPC) due to mostly non-measurable bone metastases. Given the more frequent detection of measurable disease with current CT imaging technology, the accrual of mCRPC patients with measurable tumors in phase II trials to assess RECIST changes may provide a more objective signal of efficacy of new drugs. The COU-AA-302 and COU-AA-301 phase III trials, which evaluated abiraterone, were both ?positive? for extension of overall survival (OS), and afford a unique opportunity to study the surrogacy of RECIST response to predict OS. The surrogacy of RECIST changes may then be examined across other agents to confirm universal applicability. Such a development will allow the objective determination of activity of agents in phase II trials and resources will be better utilized since the most suitable agents will be selected for phase III development.
Objectives: To study RECIST response as a surrogate for OS
Study design and participants: The COU-AA-302 will be employed as the discovery dataset and COU-AA-301 as the validation dataset.
Outcome measures: The association RECIST changes with OS will be studied.
Statistical analysis: Univariable and multivariable Cox regression analyses will evaluate the prognostic ability of RECIST changes. A landmark analysis will be performed using day 90 as the landmark time. RECIST changes will be evaluated as potential surrogates using the likelihood reduction factor.

Brief Project Background and Statement of Project Significance: Intermediate endpoints correlating with survival in men with mCRPC:
mCRPC has been historically plagued by the lack of an optimal intermediate endpoint correlating with survival due to the presence of mostly bone metastases and lack of measurable disease [1-9]. PSA declines and radiographic progression are associated with survival, but are not validated across different drugs and have subjective components. Although circulating tumor cell (CTC) changes carry prognostic value, all patients do not have detectable CTCs and costs may be a barrier [10-13].
Objective measurable disease response:
Measurable disease response by WHO criteria was associated with OS in the setting of chemotherapy as shown in the TAX327 trial[14]. Partial responders demonstrated longer median OS (29.0 months) than patients with SD (22.1 months) or those with PD (10.8 months) or those who were not assessed (12.7 months). Radiologic response remained a significant but modest post-treatment prognostic factor for OS after adjusting for treatment, pain response, and ? 30% PSA decline (P = 0.009), and remained significant based on landmark analyses. Recently, response by RECIST criteria was examined for association with OS in the VENICE dataset of patients receiving docetaxel-based chemotherapy (confidential; data submitted to GU ASCO symposium 2015)[15]. To briefly summarize the findings, 363 of 612 patients (59.3%) who received docetaxel-prednisone had measurable lesions. Objective changes in tumor size by RECIST within 90 days were robustly associated with OS in patients with mCRPC receiving first-line docetaxel-based chemotherapy.
COU-AA-302 and AA-301 trials:
The COU-AA-301 (N=1195) and AA-302 (N=1088) phase III trials are randomized trials that showed an extension of survival as well as multiple secondary endpoints (including RECIST response) with abiraterone + prednisone compared to placebo + prednisone in the post-docetaxel and pre-docetaxel settings, respectively [16, 17].
Statement of project significance:
Given the limitations of objectively measuring tumor burden in bone and more frequent detection of measurable disease with current imaging, the accrual of patients with measurable tumors in phase II trials to assess RECIST changes may provide a more robust and objective signal of efficacy of new drugs compared to currently used intermediate endpoints. The COU-AA-302 and AA-301 trial datasets offer the opportunity to validate the association between RECIST response and survival in the setting of abiraterone plus prednisone. It is proposed that COU-AA-302 be employed as the discovery dataset and AA-301 be employed as the validation dataset. If RECIST changes show at least moderate surrogacy for OS using these datasets, the surrogacy of RECIST changes may then be examined across other agents to confirm universal applicability. Such a development will allow the objective determination of activity of agents in phase II trials and resources will be better utilized since the most suitable agents will be selected for phase III development.

Specific Aims of the Project: Given the limitations of objectively measuring tumor burden in bone in men with metastatic castration prostate cancer (mCRPC) and more frequent detection of measurable disease with current imaging, the accrual of men with measurable tumors in phase II trials to assess RECIST changes may be hypothesized to provide a more robust and objective signal of efficacy of new drugs compared to endpoints such as PSA response and radiographic progression-free survival.
1. To study the association of RECIST response with survival in docetaxel-nave and post-docetaxel men with mCRPC receiving prednisone combined with placebo or abiraterone
Cox regression analyses of COU-AA-301 and COU-AA-302 trials will evaluate the prognostic ability of RECIST changes to predict survival after adjusting for previously reported baseline prognostic factors. The impact of RECIST changes independent of PSA response will be studied.
2. To evaluate RECIST response as a surrogate endpoint in docetaxel-nave and post-docetaxel men with mCRPC receiving prednisone combined with placebo or abiraterone
RECIST changes will be evaluated as potential surrogates for OS using COU-AA-302 as the discovery dataset and COU-AA-301 as the validation dataset, using the likelihood reduction factor.

Study Design:

What is the purpose of the analysis being proposed? Please select all that apply.: New research question to examine treatment effectiveness on secondary endpoints and/or within subgroup populations

Software Used:

Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: Retrospective analyses of COU-AA-302 and AA-301 will be conducted to assess the association of RECIST changes with OS. The suitability of RECIST response as a surrogate endpoint will be assessed. COU-AA-302, the pre-docetaxel trial, will be employed as the discovery dataset and AA-301, the post-docetaxel trial, will be employed as the validation dataset. Clinical data (deidentified) will be requested from the COU-AA-302 and AA-301 trials. The following clinical and laboratory variables are requested:
1. Age
2. Therapy arm
3. Trial (AA-301 and AA-302)
4. ECOG-PS
5. Metastatic sites (PCWG2 subtype)
6. Pain
7. Hb
8. Alkaline phosphatase
9. PSA-DT
10. PSA
11. Testosterone level
12. Gleason score
13. Albumin
14. Date of therapy start
15. Date of protocol-defined progression on trial
16. Type of progression: Radiographic progression (measurable disease or bone scan), PSA progression, skeletal-related event, pain progression, and radiotherapy for symptoms or death
17. Date of last follow-up
18. Survival at last follow-up
19. Neutrophil count (baseline)
20. Lymphocyte count (baseline)
21. Measurable tumor
22. RECIST response status and % decline in RECIST dimension by day 90
23. PSA response
COU-AA-302 will be employed as the discovery dataset and AA-301 will be employed as the validation dataset. The AA-302 (NCT00887198) dataset has been requested and is expected to be available soon through the YODA project; however, in the event the NCT00887198 dataset is not available within 2-3 months, analysis and internal validation of the association of RECIST changes and OS will be conducted in the available NCT00638690 (AA-301) trial. Univariable and multivariable Cox regression analyses will evaluate the prognostic ability (with primary endpoint of overall survival and secondary endpoint of radiographic PFS) of RECIST changes (PR, SD, PD) and the previously reported prognostic factors(performance status, pain, visceral metastasis, anemia, PSA, alkaline phosphatase, neutrophil/lymphocyte ratio, PSA response) [17-24]. The impact of RECIST changes independent of PSA declines will be studied. Since there is the potential of a time-bias when using RECIST changes, a landmark analysis will be performed using day 90 as the landmark time. The Kaplan-Meier method will be used for to estimate OS within selected subgroups. Validation of factors hypothesized to be prognostic (performance status, pain, visceral metastasis, anemia, PSA, alkaline phosphatase, neutrophil/lymphocyte ratio, PSA response) will be initially examined in the discovery dataset, and then validated in the validation dataset. Results will be reported using a combination of hazard ratios, overall survival estimation, c-statistics, discrimination plots, tables, descriptive statistics and confidence intervals. RECIST changes will be evaluated as potential surrogates using the likelihood reduction factor [25]. All analyses will be two-sided and statistical significance will be defined at ?=0.05 level.

Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study:

Main Predictor/Independent Variable and how it will be categorized/defined for your study:

Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study:

Statistical Analysis Plan:

Narrative Summary: Advanced prostate cancer has been plagued by the lack of an optimal endpoint to rapidly assess the anti-tumor activity of new drugs due to the presence of mostly bone metastases. Unfortunately, bone metastases are not possible to accurately measure in contrast to measurable metastases in other organs like the lung, lymph nodes and liver. Since, current improved CT scan technology is more frequently detecting measurable tumors, we propose to study the COU-AA-301 dataset (and AA-302 trial when available) to validate the association between response of measurable tumors and survival. The validation of this association will expedite drug development and will represent an important advance.

Project Timeline: 1. Completion of contract- 11/2014
2. Obtain deidentified dataset-12/2014
3. Analysis and report submitted to YODA- 1/2014
4. Circulation of abstract targeting ASCO 2015 to YODA - 1/2014
5. Circulation of paper to YODA targeting JCO, Lancet Oncol or CCR- 2/2014

Dissemination Plan: 1. Circulation of abstract targeting ASCO 2015 - 1/2014
2. Circulation of paper targeting JCO, Lancet Oncol or CCR- 2/2014

Bibliography:

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