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      string(210) "NCT02489318 - A Phase 3 Randomized, Placebo-controlled, Double-blind Study of Apalutamide Plus Androgen Deprivation Therapy (ADT) Versus ADT in Subjects With Metastatic Hormone-sensitive Prostate Cancer (mHSPC)"
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  ["project_title"]=>
  string(138) "First Radiographic Progression Phenotypes After Apalutamide in Metastatic Castration-Sensitive Prostate Cancer: A TITAN Secondary Analysis"
  ["project_narrative_summary"]=>
  string(789) "Although apalutamide has been shown to delay radiographic progression in patients with metastatic castration-sensitive prostate cancer, little is known about how the anatomical patterns of the first radiographic progression change after treatment. This study will perform a secondary analysis of the TITAN randomized clinical trial to describe and compare the first radiographic progression phenotypes, including bone-only, soft tissue-only, mixed progression, and death before radiographic progression. By evaluating the cumulative incidence of these competing progression phenotypes, this study aims to improve the understanding of disease evolution after treatment and provide clinically useful information for patient monitoring, imaging strategies, and future therapeutic development."
  ["project_learn_source"]=>
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  ["project_learn_source_exp"]=>
  string(44) "Previous approved YODA Project investigator."
  ["principal_investigator"]=>
  array(7) {
    ["first_name"]=>
    string(7) "Hiroaki"
    ["last_name"]=>
    string(7) "Iwamoto"
    ["degree"]=>
    string(7) "MD, PhD"
    ["primary_affiliation"]=>
    string(54) "Kanazawa University Graduate School of Medical Science"
    ["email"]=>
    string(22) "hiroaki017@yahoo.co.jp"
    ["state_or_province"]=>
    string(8) "Ishikawa"
    ["country"]=>
    string(5) "Japan"
  }
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    ["label"]=>
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  ["property_scientific_abstract"]=>
  string(1672) "Background:

Apalutamide plus androgen deprivation therapy (ADT) prolongs radiographic progression-free survival and overall survival in patients with metastatic castration-sensitive prostate cancer (mCSPC). However, whether apalutamide alters the anatomical patterns of first radiographic progression remains unknown.



Objective:

To determine whether apalutamide changes the cumulative incidence of competing phenotypes of first radiographic progression in patients enrolled in the TITAN trial.



Study Design:

This is a secondary analysis of the phase 3 TITAN randomized, double-blind, placebo-controlled trial. All randomized participants will be analyzed according to the intention-to-treat principle, with randomization defined as time zero.



Participants:

All randomized patients in the TITAN trial.



Primary and Secondary Outcome Measure(s):

The primary outcome is the cumulative incidence of mutually exclusive first radiographic progression phenotypes, including bone-only progression, soft tissue-only progression, mixed progression, and death before radiographic progression. Secondary outcomes include progression mode and overall survival after first radiographic progression.



Statistical Analysis:

Competing-risk methods will be used to estimate cumulative incidence functions for each phenotype. Treatment groups will be compared using Fine–Gray subdistribution hazard models and cause-specific hazard models where appropriate. Post-progression overall survival will be analyzed using Kaplan–Meier methods and Cox proportional hazards models."
  ["project_brief_bg"]=>
  string(3106) "Apalutamide plus androgen deprivation therapy (ADT) has become a standard treatment for metastatic castration-sensitive prostate cancer (mCSPC) based on the TITAN trial, which demonstrated significant improvements in radiographic progression-free survival (rPFS) and overall survival (OS) compared with ADT alone (1,2). While delaying radiographic progression is a major therapeutic goal, current evidence has focused primarily on the timing of progression rather than the anatomical phenotype of the first radiographic progression.



The site and mode of first radiographic progression may reflect distinct biological behavior, influence imaging surveillance strategies, and affect subsequent therapeutic decision-making. A recent secondary analysis of the TITAN trial described radiographic progression patterns among patients who experienced progression (3). However, because that study was limited to patients with radiographic progression, it could not evaluate the cumulative incidence of mutually exclusive first progression phenotypes in the entire randomized population or quantify the effect of initial treatment on these competing progression events.



The proposed study will address this important knowledge gap by analyzing all randomized participants in the TITAN trial according to the intention-to-treat principle. Using individual participant-level data and competing-risk methodology, we will estimate the cumulative incidence of mutually exclusive first radiographic progression phenotypes, including bone-only progression, soft tissue-only progression, mixed progression, and death before radiographic progression. This approach allows evaluation of the absolute occurrence of clinically relevant progression phenotypes while appropriately accounting for competing events.

Beyond anatomical progression sites, we also plan to evaluate progression according to radiographic mode, including progression of pre-existing lesions and development of new metastatic lesions. Integrating analyses of progression site and progression mode may provide a more comprehensive understanding of disease evolution during systemic therapy.



This study is expected to generate novel evidence regarding how apalutamide influences the natural history of metastatic disease beyond conventional time-to-event analyses. The findings may improve understanding of treatment-resistant disease evolution, inform imaging surveillance strategies, generate hypotheses regarding mechanisms of progression, and support the design of future clinical trials evaluating progression phenotypes as clinically meaningful endpoints. Because these objectives require detailed longitudinal radiographic assessments linked to participant-level clinical data, they can only be achieved using the individual participant-level data and supporting documentation from the TITAN trial.



References

1. Chi KN, et al. N Engl J Med. 2019;381:13-24.

2. Chi KN, et al. J Clin Oncol. 2021;39:2294-2303.

3. Fukuokaya W, et al. Eur Urol Oncol. 2025;8:263-269."
  ["project_specific_aims"]=>
  string(1530) "The primary objective of this study is to determine whether apalutamide alters the cumulative incidence of competing phenotypes of first radiographic progression in patients with metastatic castration-sensitive prostate cancer (mCSPC) enrolled in the TITAN trial. Unlike previous analyses restricted to patients who developed radiographic progression, this study will evaluate all randomized participants according to the intention-to-treat principle using competing-risk methodology.



The primary hypothesis is that apalutamide changes the cumulative incidence of mutually exclusive first radiographic progression phenotypes, including bone-only progression, soft tissue-only progression, mixed progression, and death before radiographic progression, compared with ADT alone.



The secondary objectives are:

1. To compare radiographic progression according to progression mode (progression of pre-existing lesions versus development of new metastatic lesions) between treatment groups.

2. To evaluate overall survival after first radiographic progression according to progression phenotype and treatment group.

3. To explore whether specific progression phenotypes are associated with distinct post-progression clinical outcomes.



This study aims to provide a comprehensive characterization of disease evolution after first-line systemic therapy and to improve understanding of the biological and clinical implications of radiographic progression phenotypes in mCSPC."
  ["project_study_design"]=>
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    ["label"]=>
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      ["label"]=>
      string(114) "New research question to examine treatment effectiveness on secondary endpoints and/or within subgroup populations"
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  ["project_research_methods"]=>
  string(2041) "This study will use individual participant-level data from the phase 3 TITAN trial (NCT02489318; protocol 56021927PCR3002), a randomized, double-blind, placebo-controlled trial comparing apalutamide plus androgen deprivation therapy (ADT) with placebo plus ADT in patients with metastatic castration-sensitive prostate cancer.



The primary study population will include all participants randomized in TITAN, analyzed according to the intention-to-treat principle. The original trial enrolled adult men with investigator-confirmed prostate adenocarcinoma, castration-sensitive metastatic disease documented by at least one bone lesion on technetium-99m bone scan, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with a single bone lesion required confirmation by computed tomography or magnetic resonance imaging. Limited prior ADT, docetaxel, radiotherapy, or surgery was permitted according to the original protocol.



No additional demographic or clinical exclusion criteria will be applied for the primary analysis. Participants will not be excluded because they did not experience radiographic progression, because death before radiographic progression is a competing outcome of interest. For analyses requiring classification of the first radiographic progression phenotype, participants with a documented radiographic progression event but insufficient radiographic or event-level information to determine the progression phenotype will be categorized as unclassifiable and excluded only from analyses requiring a specific phenotype classification. The number and characteristics of such participants will be reported.



Post-progression survival analyses will be restricted to participants who experienced a classifiable first radiographic progression event. No data from studies other than TITAN will be used or pooled with the YODA Project data. All participant-level analyses will be conducted within the secure YODA data-sharing platform using R or RStudio."
  ["project_main_outcome_measure"]=>
  string(1690) "Primary Outcome

The primary outcome is the first radiographic progression phenotype after randomization. Each participant will be classified according to the first documented radiographic progression event into one of the following mutually exclusive categories: (1) bone-only progression, (2) soft tissue-only progression, (3) mixed bone and soft tissue progression, or (4) death before documented radiographic progression. The primary endpoint will be the cumulative incidence of each phenotype from randomization, with competing events appropriately accounted for using competing-risk methodology.



Secondary Outcomes

Secondary outcomes include:

1. Radiographic progression mode, classified as progression of pre-existing lesions, development of new metastatic lesions, or both, based on radiographic assessment records.

2. Overall survival after first radiographic progression, defined as the time from the date of first radiographic progression to death from any cause.

3. Association between progression phenotype and post-progression survival, comparing survival outcomes according to the first radiographic progression phenotype and randomized treatment group.



Outcome definitions will follow the TITAN protocol, clinical study report, and radiographic assessment data whenever possible. If additional classification rules are required to define progression phenotypes or progression mode from participant-level radiographic records, these rules will be prespecified before analysis and reported transparently in the final publication. No changes to the primary or secondary outcome measures are currently anticipated."
  ["project_main_predictor_indep"]=>
  string(1156) "The primary independent variable is the randomized treatment assignment in the TITAN trial: apalutamide plus androgen deprivation therapy (ADT) versus placebo plus ADT. Treatment assignment will be analyzed according to the intention-to-treat principle, with participants retained in their originally randomized treatment groups regardless of treatment adherence or subsequent therapy.



The treatment group will be modeled as a binary categorical variable (apalutamide plus ADT vs placebo plus ADT) in all primary and secondary analyses. Randomization will serve as the basis for causal inference, and no reclassification of treatment exposure will be performed.



For sensitivity analyses, prespecified baseline characteristics, including disease volume, prior docetaxel use, geographic region, age, baseline prostate-specific antigen, Eastern Cooperative Oncology Group performance status, and metastatic sites, may be included as covariates to assess the robustness of the findings. These variables will not be considered primary independent variables but will be used only for exploratory adjusted analyses where appropriate."
  ["project_other_variables_interest"]=>
  string(1349) "Baseline demographic and clinical characteristics will be used to describe the study population, including age, race/ethnicity (if available), geographic region, Eastern Cooperative Oncology Group (ECOG) performance status, baseline prostate-specific antigen (PSA), Gleason score or Grade Group, disease volume (high vs low volume), metastatic sites (bone, lymph node, visceral), prior docetaxel use, prior local therapy, and time from initial diagnosis to randomization, as available in the TITAN dataset.



Radiographic assessment variables will be used to classify first radiographic progression phenotype and progression mode, including assessment dates, lesion locations, progression records, appearance of new metastatic lesions, and progression of pre-existing lesions. Overall survival status and date of death will also be used for outcome ascertainment.



These variables will primarily be used to characterize the study population and describe progression patterns. In sensitivity analyses, prespecified baseline characteristics, including disease volume, prior docetaxel use, geographic region, age, baseline PSA, ECOG performance status, and metastatic sites, may be included as adjustment variables to evaluate the robustness of the primary findings. No data-driven variable selection procedures will be used."
  ["project_stat_analysis_plan"]=>
  string(3230) "Baseline characteristics will be summarized by randomized treatment group using descriptive statistics. Continuous variables will be reported as means with standard deviations or medians with interquartile ranges, as appropriate, and categorical variables as frequencies and percentages. Because treatment allocation was randomized, baseline characteristics will be summarized descriptively without formal significance testing.



The primary analysis will follow the intention-to-treat principle. Time zero will be the date of randomization. Each participant will be classified according to the first observed event as bone-only radiographic progression, soft tissue-only radiographic progression, mixed progression, death before radiographic progression, or censoring. Cumulative incidence functions will be estimated for each mutually exclusive progression phenotype using competing-risk methodology (4) . Treatment groups will be compared using Fine–Gray subdistribution hazard models (4), with subdistribution hazard ratios (sHRs) and 95% confidence intervals (CIs) reported.



Cause-specific Cox proportional hazards models will be performed as complementary analyses to evaluate the instantaneous risk of each progression phenotype while treating alternative first events as competing events. The proportional hazards assumption will be assessed using standard diagnostic methods.



For secondary analyses, progression mode (progression of pre-existing lesions, development of new metastatic lesions, or both) will be compared descriptively between treatment groups. Overall survival after first radiographic progression will be estimated using the Kaplan–Meier method and compared using Cox proportional hazards models, with hazard ratios (HRs) and 95% CIs reported.



Primary analyses will be unadjusted because treatment assignment was randomized. Prespecified sensitivity analyses may additionally adjust for clinically relevant baseline characteristics, including disease volume, prior docetaxel use, geographic region, age, baseline prostate-specific antigen (PSA), Eastern Cooperative Oncology Group (ECOG) performance status, and metastatic sites, to evaluate the robustness of the findings. Prespecified subgroup analyses may be performed according to disease volume, prior docetaxel use, and baseline metastatic burden by including treatment-by-subgroup interaction terms.



Missing baseline data will be summarized. Missing outcome data will be handled according to the available trial data structure and the TITAN protocol whenever possible. Participants with insufficient information to classify the first radiographic progression phenotype will be excluded only from analyses requiring phenotype classification, and the number of such participants will be reported.



All statistical analyses will be performed using R (R Foundation for Statistical Computing, Vienna, Austria) within the secure YODA Project data-sharing platform. All statistical tests will be two-sided, and a P value <0.05 will be considered statistically significant.



References

4. Fine JP, Gray RJ. J Am Stat Assoc. 1999;94:496-509."
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  ["project_timeline"]=>
  string(449) "Anticipated project start date: December 2026 (following YODA approval and execution of the Data Use Agreement)

Data preparation and cohort definition: December 2026 – January 2027

Statistical analysis completed: March 2027

Manuscript drafted: April 2027

First manuscript submitted for publication: May 2027

Results reported back to the YODA Project: Upon publication or by November 2027, whichever occurs first."
  ["project_dissemination_plan"]=>
  string(1287) "The findings of this study will be disseminated through publication in a peer-reviewed international urology or oncology journal and presentation at major scientific meetings. The primary target audience includes urologists, medical oncologists, radiation oncologists, clinical trial investigators, and researchers involved in the management of metastatic prostate cancer.



The primary anticipated product is an original research manuscript describing the association between apalutamide treatment and competing phenotypes of first radiographic progression in the TITAN trial. Depending on the findings, additional methodological or exploratory analyses may be reported in separate publications.



Potential target journals include European Urology Focus, BJU International, and Prostate Cancer and Prostatic Diseases, depending on the scope and impact of the final results. Study findings may also be presented at international scientific meetings, including those organized by the American Urological Association (AUA), the European Association of Urology (EAU), and the American Society of Clinical Oncology (ASCO).



The results will also be reported to the YODA Project in accordance with the Data Use Agreement and YODA publication policies."
  ["project_bibliography"]=>
  string(789) "
1. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2019;381:13-24.
2. Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in Patients with Metastatic Castration-Sensitive Prostate Cancer: Final Overall Survival Analysis of the TITAN Study. J Clin Oncol. 2021;39:2294-2303.
3. Fukuokaya W, Yanagisawa T, Mori K, et al. Radiographic Progression Without Corresponding Prostate-specific Antigen Progression in Patients with Metastatic Castration-sensitive Prostate Cancer Receiving Apalutamide: Secondary Analysis of the TITAN Trial. Eur Urol Oncol. 2025;8:263-269.
4. Fine JP, Gray RJ. A Proportional Hazards Model for the Subdistribution of a Competing Risk. J Am Stat Assoc. 1999;94:496-509.
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