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  ["project_title"]=>
  string(144) "Effect of systemic therapy in Patients with Metastatic Castrate Resistant Prostate Cancer Previously Treated with or without Prior Local Therapy"
  ["project_narrative_summary"]=>
  string(687) "NARRATIVE SUMMARY:
Preclinical or animal studies have shown that primary local therapy directed to prostate triggers changes at cellular level 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 these patients treated with prior local therapy. This secondary analysis ofCOU-AA-302 will clarify this ambiguity and will provide robust evidence whether receipt of prior local therapy affect overall outcome including response to subsequent lines of therapy in men with metastatic castrate resistant prostate cancer." ["project_learn_source"]=> string(12) "scien_public" ["project_learn_source_exp"]=> string(0) "" ["project_key_personnel"]=> array(1) { [0]=> array(6) { ["p_pers_f_name"]=> string(9) "Soumyajit" ["p_pers_l_name"]=> string(3) "Roy" ["p_pers_degree"]=> string(10) "MBBS, MSc." ["p_pers_pr_affil"]=> string(30) "Rush University Medical Center" ["p_pers_scop_id"]=> string(19) "0000-0002-7784-6309" ["requires_data_access"]=> string(0) "" } } ["project_ext_grants"]=> array(2) { ["value"]=> string(2) "no" ["label"]=> string(68) "No external grants or funds are being used to support this research." } ["project_funding_source"]=> string(0) "" ["project_assoc_trials"]=> array(1) { [0]=> object(WP_Post)#3822 (24) { ["ID"]=> int(1568) ["post_author"]=> string(4) "1363" ["post_date"]=> string(19) "2016-10-31 14:30:00" ["post_date_gmt"]=> string(19) "2016-10-31 14:30:00" ["post_content"]=> string(0) "" ["post_title"]=> 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" ["post_excerpt"]=> string(0) "" ["post_status"]=> string(7) "publish" ["comment_status"]=> string(4) "open" ["ping_status"]=> string(4) "open" ["post_password"]=> string(0) "" ["post_name"]=> string(193) "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-re" ["to_ping"]=> string(0) "" ["pinged"]=> string(0) "" ["post_modified"]=> string(19) "2024-03-26 10:20:09" ["post_modified_gmt"]=> string(19) "2024-03-26 14:20:09" ["post_content_filtered"]=> string(0) "" ["post_parent"]=> int(0) ["guid"]=> string(242) "https://dev-yoda.pantheonsite.io/clinical-trial/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-re/" ["menu_order"]=> int(0) ["post_type"]=> string(14) "clinical_trial" ["post_mime_type"]=> string(0) "" ["comment_count"]=> string(1) "0" ["filter"]=> string(3) "raw" } } ["project_date_type"]=> string(18) "full_crs_supp_docs" ["property_scientific_abstract"]=> string(2144) "Background: Preclinical studies suggest that receipt of definitive local therapy at the time of diagnosis 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.
Objectives: We plan to perform a secondary analysis of COU-AA-302 trial to determine the heterogeneity of treatment effect on radiographic progression-free survival (rPFS) and overall survival (OS) in patients with metastatic castrate resistant prostate cancer (mCRPC) and compare the radiographic progression-free survival (rPFS) and overall survival (OS) in patients treated with prior local therapy compared to those who had no prior local therapy. Secondarily we would like to investigate if receipt of prior local therapy plays any effect modifying role on the treatment effect (abiraterone vs. placebo) on these endpoints.
Design and Participants: Secondary analysis with patients in the COU-AA-302 trial (NCT00887198).
Main outcome measures: The primary endpoint will be rPFS. The secondary endpoints will include overall survival (OS).
Main exposure variable: Receipt of prior local therapy (RP or RT) vs no local therapy.
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 ADT, Gleason score, tumor stage, metastatic stage, and nodal stage at initial diagnosis, presence of visceral metastasis, number of skeletal metastasis, PSA at the time of study entry, duration of ADT before start of protocol treatment and the time interval between initial diagnosis to time to randomization. An interaction term between the treatment arm and local therapy will be incorporated into the Cox models which will provide information on presence of any significant effect modification by local therapy on the effect of randomized treatment on these endpoints." ["project_brief_bg"]=> string(3198) "Definitive treatment for men with localized prostate cancer often comprises local therapy (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 local therapy after diagnosis affects response to this subsequent treatment is unclear. Preclinical studies have shown that use of 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 local therapy 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 local therapy (16).
In COU-AA-302, a phase III randomized controlled trial, 1088 patients with mCRPC were randomly assigned to receive abiraterone acetate with prednisone versus placebo with prednisone. Compared to placebo, addition of abiraterone was associated with significant improvement in radiographic progression-free survival (HR: 0.53, 95% CI: 0.45–0.62) (17). At the updated analysis, overall survival was significantly longer in the abiraterone acetate group than in the placebo group (HR: 0·81, 95% CI: 0·70–0·93) (18). However, there was no subgroup analysis to determine treatment effect for patients who had prior local therapy. Herein we propose an exploratory analysis of COU-AA-302 study to determine if receipt of prior local therapy plays any effect modifying role on the treatment regimens in mCRPC patients and whether receipt of prior local therapy has an independent effect on survival.
SIGNIFICANCE:
Our findings will clarify whether the outcome and response to systemic therapy in mCRPC depends on the receipt of prior local therapy or the modality of prior local therapy. It will also provide additional information for future risk stratification of these patients and guide treatment modification depending on receipt of prior local therapy." ["project_specific_aims"]=> string(1315) "SPECIFIC AIMS:
Aim 1: Does receipt of prior local therapy has any association with oncologic outcome in patients with mCRPC
To investigate this, we will compare radiographic progression-free survival in patients treated with prior local therapy to prostate (radical prostatectomy or radiation therapy) as compared to patients with no local therapy to prostate. We also will compare overall survival in patients treated with prior local therapy to prostate (radical prostatectomy or radiation therapy) as compared to patients with no local therapy to prostate. Finally we will perform subgroup analysis to determine if the modality of the prior local therapy (prostatectomy vs. radiation therapy) has any association with radiographic progression-free survival or overall survival in these patients.
Aim 2: We aim to determine if the efficacy of androgen biosynthesis inhibitor therapy is dependent on receipt of prior local therapy
To investigate this aim, we will apply Cox regression models with interaction term between the treatment regimen (abiraterone vs. placebo) and receipt of prior local therapy to determine the heterogeneity of treatment effect (abiraterone vs. placebo) on radiographic progression-free survival and overall survival based on receipt of prior local therapy." ["project_study_design"]=> string(0) "" ["project_study_design_exp"]=> string(0) "" ["project_purposes"]=> array(1) { [0]=> array(2) { ["value"]=> string(56) "new_research_question_to_examine_treatment_effectiveness" ["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"]=> array(2) { ["value"]=> string(7) "rstudio" ["label"]=> string(7) "RStudio" } ["project_software_used_exp"]=> string(0) "" ["project_research_methods"]=> string(113) "Patients treated with Abiraterone + Prednisone versus Placebo + Prednisone in the COU-AA-302 trial (NCT00887198)." ["project_main_outcome_measure"]=> string(214) "'- The primary endpoint, radiographic progression-free survival (rPFS), will be defined as per the COU-AA-302 trial
- Overall survival (OS) will be defined as time since randomization to death from any cause" ["project_main_predictor_indep"]=> string(249) "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." ["project_other_variables_interest"]=> string(1299) "Baseline Factors:
- Treatment arm: Categorical
- Race: Categorical
- Age: Continuous and categorical
- Gleason Score at initial diagnosis: Ordinal
- Prior radical prostatectomy: yes/no (categorical)
- Prior radiation therapy: yes/no (categorical)
- Date of prior radical prostatectomy and prior radiation therapy
- Dose of prior radiation therapy
- Type of prior prostatectomy
- ECOG PS: Ordinal
- Date of randomization (date format)
- Prior systemic treatment (ADT) – (categorical)
- Tumor stage at diagnosis – categorical
- Nodal stage at diagnosis – categorical
- Metastatic stage at diagnosis – Categorical
- Time from initial diagnosis to randomization in years (continuous)
- Time from initiation of ADT or orchiectomy to randomization in years
- No of skeletal metastasis
Baseline and Post-Baseline Variables:
- PSA at time of study entry: continuous
- Post-baseline radiographic evaluation (bone scan/CT scan/MRI): categorical
- Time to radiographic progression or radiographic progression-free survival
- Time to clinical or PSA progression
- Deaths (yes/no)
- Time of death (date format) and cause of death" ["project_stat_analysis_plan"]=> string(1490) "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 multivariable cox proportional hazard regression models will be applied to estimate adjusted hazard ratios for receipt of local therapy for each of the endpoints. For overall survival and radiographic progression-free survival, 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 (abiraterone vs. placebo), receipt of prior ADT (yes/no), Gleason score at initial diagnosis, tumor stage at initial diagnosis, nodal stage at initial diagnosis, number of skeletal metastasis, PSA at the time of study entry, 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 on OS and rPFS based on receipt of prior local therapy after adjustment for the covariables listed above. Proportionality assumption will be visually checked by Schoenfeld’s residuals and will be tested using Grambsch-Therneau’s test." ["project_timeline"]=> string(275) "'- Project submission: July 2022
- Contract: September 2022
- Analysis: October 2022 to June 2023
- Abstract Submission (ASCO 2023 and ASTRO 2023): February 2023
- Paper Draft circulation: June to August 2023
- Paper Submission: August 2023" ["project_dissemination_plan"]=> string(250) "'- Abstract presentation in ASCO 2023 and ASTRO 2023
- Submission of manuscript first-quartile oncology journals: Journal of Clinical Oncology, European Urology, Annals of Oncology, International Journal of Radiation Oncology Biology, Physics." ["project_bibliography"]=> string(3611) "

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. 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.

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2022-5011

General Information

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

Conflict of Interest

Request Clinical Trials

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
What type of data are you looking for?: Individual Participant-Level Data, which includes Full CSR and all supporting documentation

Request Clinical Trials

Data Request Status

Status: Withdrawn/Closed

Research Proposal

Project Title: Effect of systemic therapy in Patients with Metastatic Castrate Resistant Prostate Cancer Previously Treated with or without Prior Local Therapy

Scientific Abstract: Background: Preclinical studies suggest that receipt of definitive local therapy at the time of diagnosis 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.
Objectives: We plan to perform a secondary analysis of COU-AA-302 trial to determine the heterogeneity of treatment effect on radiographic progression-free survival (rPFS) and overall survival (OS) in patients with metastatic castrate resistant prostate cancer (mCRPC) and compare the radiographic progression-free survival (rPFS) and overall survival (OS) in patients treated with prior local therapy compared to those who had no prior local therapy. Secondarily we would like to investigate if receipt of prior local therapy plays any effect modifying role on the treatment effect (abiraterone vs. placebo) on these endpoints.
Design and Participants: Secondary analysis with patients in the COU-AA-302 trial (NCT00887198).
Main outcome measures: The primary endpoint will be rPFS. The secondary endpoints will include overall survival (OS).
Main exposure variable: Receipt of prior local therapy (RP or RT) vs no local therapy.
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 ADT, Gleason score, tumor stage, metastatic stage, and nodal stage at initial diagnosis, presence of visceral metastasis, number of skeletal metastasis, PSA at the time of study entry, duration of ADT before start of protocol treatment and the time interval between initial diagnosis to time to randomization. An interaction term between the treatment arm and local therapy will be incorporated into the Cox models which will provide information on presence of any significant effect modification by local therapy on the effect of randomized treatment on these endpoints.

Brief Project Background and Statement of Project Significance: Definitive treatment for men with localized prostate cancer often comprises local therapy (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 local therapy after diagnosis affects response to this subsequent treatment is unclear. Preclinical studies have shown that use of 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 local therapy 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 local therapy (16).
In COU-AA-302, a phase III randomized controlled trial, 1088 patients with mCRPC were randomly assigned to receive abiraterone acetate with prednisone versus placebo with prednisone. Compared to placebo, addition of abiraterone was associated with significant improvement in radiographic progression-free survival (HR: 0.53, 95% CI: 0.45–0.62) (17). At the updated analysis, overall survival was significantly longer in the abiraterone acetate group than in the placebo group (HR: 0·81, 95% CI: 0·70–0·93) (18). However, there was no subgroup analysis to determine treatment effect for patients who had prior local therapy. Herein we propose an exploratory analysis of COU-AA-302 study to determine if receipt of prior local therapy plays any effect modifying role on the treatment regimens in mCRPC patients and whether receipt of prior local therapy has an independent effect on survival.
SIGNIFICANCE:
Our findings will clarify whether the outcome and response to systemic therapy in mCRPC depends on the receipt of prior local therapy or the modality of prior local therapy. It will also provide additional information for future risk stratification of these patients and guide treatment modification depending on receipt of prior local therapy.

Specific Aims of the Project: SPECIFIC AIMS:
Aim 1: Does receipt of prior local therapy has any association with oncologic outcome in patients with mCRPC
To investigate this, we will compare radiographic progression-free survival in patients treated with prior local therapy to prostate (radical prostatectomy or radiation therapy) as compared to patients with no local therapy to prostate. We also will compare overall survival in patients treated with prior local therapy to prostate (radical prostatectomy or radiation therapy) as compared to patients with no local therapy to prostate. Finally we will perform subgroup analysis to determine if the modality of the prior local therapy (prostatectomy vs. radiation therapy) has any association with radiographic progression-free survival or overall survival in these patients.
Aim 2: We aim to determine if the efficacy of androgen biosynthesis inhibitor therapy is dependent on receipt of prior local therapy
To investigate this aim, we will apply Cox regression models with interaction term between the treatment regimen (abiraterone vs. placebo) and receipt of prior local therapy to determine the heterogeneity of treatment effect (abiraterone vs. placebo) on radiographic progression-free survival and overall survival based on receipt of prior local therapy.

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: RStudio

Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: Patients treated with Abiraterone + Prednisone versus Placebo + Prednisone in the COU-AA-302 trial (NCT00887198).

Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: '- The primary endpoint, radiographic progression-free survival (rPFS), will be defined as per the COU-AA-302 trial
- Overall survival (OS) will be defined as time since randomization to death from any cause

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.

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: Continuous and categorical
- Gleason Score at initial diagnosis: Ordinal
- Prior radical prostatectomy: yes/no (categorical)
- Prior radiation therapy: yes/no (categorical)
- Date of prior radical prostatectomy and prior radiation therapy
- Dose of prior radiation therapy
- Type of prior prostatectomy
- ECOG PS: Ordinal
- Date of randomization (date format)
- Prior systemic treatment (ADT) – (categorical)
- Tumor stage at diagnosis – categorical
- Nodal stage at diagnosis – categorical
- Metastatic stage at diagnosis – Categorical
- Time from initial diagnosis to randomization in years (continuous)
- Time from initiation of ADT or orchiectomy to randomization in years
- No of skeletal metastasis
Baseline and Post-Baseline Variables:
- PSA at time of study entry: continuous
- Post-baseline radiographic evaluation (bone scan/CT scan/MRI): categorical
- Time to radiographic progression or radiographic progression-free survival
- Time to clinical or PSA progression
- Deaths (yes/no)
- Time of death (date format) and cause of death

Statistical Analysis Plan: 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 multivariable cox proportional hazard regression models will be applied to estimate adjusted hazard ratios for receipt of local therapy for each of the endpoints. For overall survival and radiographic progression-free survival, 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 (abiraterone vs. placebo), receipt of prior ADT (yes/no), Gleason score at initial diagnosis, tumor stage at initial diagnosis, nodal stage at initial diagnosis, number of skeletal metastasis, PSA at the time of study entry, 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 on OS and rPFS based on receipt of prior local therapy after adjustment for the covariables listed above. Proportionality assumption will be visually checked by Schoenfeld’s residuals and will be tested using Grambsch-Therneau’s test.

Narrative Summary: NARRATIVE SUMMARY:
Preclinical or animal studies have shown that primary local therapy directed to prostate triggers changes at cellular level 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 these patients treated with prior local therapy. This secondary analysis ofCOU-AA-302 will clarify this ambiguity and will provide robust evidence whether receipt of prior local therapy affect overall outcome including response to subsequent lines of therapy in men with metastatic castrate resistant prostate cancer.

Project Timeline: '- Project submission: July 2022
- Contract: September 2022
- Analysis: October 2022 to June 2023
- Abstract Submission (ASCO 2023 and ASTRO 2023): February 2023
- Paper Draft circulation: June to August 2023
- Paper Submission: August 2023

Dissemination Plan: '- Abstract presentation in ASCO 2023 and ASTRO 2023
- Submission of manuscript first-quartile oncology journals: Journal of Clinical Oncology, European Urology, Annals of Oncology, International Journal of Radiation Oncology Biology, Physics.

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