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Associated Trial(s):- 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)
- NCT01946204 - A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Study of ARN-509 in Men With Non-Metastatic (M0) Castration-Resistant Prostate Cancer
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Status: OngoingResearch Proposal
Project Title: Radiographic Progression Without PSA Rise in Apalutamide-Treated Advanced Prostate Cancer: An IPD Analysis of TITAN and SPARTAN
Scientific Abstract:
Background: PSA kinetics are widely used to monitor treatment response and progression in advanced prostate cancer. However, radiographic progression can occur without PSA rise during androgen receptor signaling inhibitor treatment, potentially delaying recognition of treatment resistance. Although this phenomenon has been reported with enzalutamide, its significance during apalutamide treatment remains unclear.
Objective: To evaluate the incidence, clinical characteristics, and prognostic significance of radiographic progression with and without PSA rise in patients treated with apalutamide.
Study Design: Post hoc pooled analysis of individual patient data from the phase 3 TITAN and SPARTAN trials.
Participants: Patients with metastatic castration-sensitive prostate cancer in TITAN and nonmetastatic castration-resistant prostate cancer in SPARTAN who received apalutamide-based therapy.
Primary and Secondary Outcome Measures: The primary outcome is the proportion of patients developing radiographic progression without PSA rise. Secondary outcomes include timing of PSA progression, radiographic progression-free survival, overall survival, associated baseline clinical factors, and PSA kinetics before progression.
Statistical Analysis: Patients will be classified according to PSA rise at radiographic progression using PCWG2/3 criteria. Kaplan--Meier and Cox proportional hazards models will evaluate survival outcomes, while logistic regression analyses will identify factors associated with radiographic progression without PSA rise.
Brief Project Background and Statement of Project Significance:
Prostate-specific antigen (PSA) is the most widely used biomarker for monitoring treatment response and disease progression in advanced prostate cancer. In clinical practice, rising PSA levels often trigger additional imaging studies or treatment modification. However, accumulating evidence suggests that radiographic progression may occur despite stable or low PSA levels during treatment with androgen receptor signaling inhibitors (ARSIs). This discordance between PSA kinetics and radiographic disease status may lead to delayed recognition of treatment resistance and suboptimal clinical decision-making.
A post hoc analysis of the ARCHES and PROSPER trials demonstrated that a subset of patients treated with enzalutamide experienced radiographic progression without PSA rise and that these patients had distinct clinical characteristics and outcomes. These findings highlighted an important limitation of PSA-based monitoring strategies during ARSI treatment and suggested that reliance on PSA alone may underestimate disease progression in certain patients. However, whether similar progression patterns occur during treatment with apalutamide remains insufficiently understood.
Apalutamide is a next-generation ARSI that significantly improves survival outcomes in both metastatic castration-sensitive prostate cancer (mCSPC) and nonmetastatic castration-resistant prostate cancer (nmCRPC), as demonstrated in the TITAN and SPARTAN phase 3 trials. Despite its widespread clinical use, the relationship between PSA kinetics and radiographic progression during apalutamide treatment has not been comprehensively evaluated using individual patient-level data. Understanding this relationship is clinically important because PSA monitoring remains central to routine surveillance strategies in patients receiving apalutamide.
The proposed study will perform a post hoc pooled analysis of individual patient data from the TITAN and SPARTAN trials to characterize radiographic progression occurring with and without PSA rise during apalutamide treatment. Specifically, we will evaluate the frequency, timing, clinical features, PSA kinetics, and prognostic implications of discordant progression patterns. We will also investigate baseline clinical factors associated with radiographic progression without PSA rise.
This study has the potential to materially enhance scientific and clinical understanding of disease monitoring during ARSI therapy. The findings may help refine surveillance strategies, improve interpretation of PSA kinetics, and inform optimal timing of imaging assessments in patients treated with apalutamide. Furthermore, identifying patients at risk for radiographic progression without PSA rise may contribute to more individualized management approaches and improve outcomes in advanced prostate cancer.
Specific Aims of the Project:
The primary aim of this study is to evaluate the frequency and clinical significance of radiographic progression occurring without prostate-specific antigen (PSA) rise in patients with advanced prostate cancer treated with apalutamide. Using individual patient data from the phase 3 TITAN and SPARTAN trials, we will characterize progression patterns during apalutamide treatment and assess the relationship between PSA kinetics and radiographic disease progression.
The first objective is to determine the proportion of patients who develop radiographic progression without PSA rise according to PCWG2/3 criteria. We hypothesize that a clinically meaningful subset of patients treated with apalutamide will experience radiographic progression despite stable or low PSA levels.
The second objective is to compare clinical outcomes between patients with radiographic progression with PSA rise and those without PSA rise. We hypothesize that discordant progression patterns are associated with distinct prognostic outcomes and clinical characteristics.
The third objective is to identify baseline clinical factors and PSA kinetic patterns associated with radiographic progression without PSA rise. We hypothesize that specific patient or disease characteristics may predict discordance between PSA kinetics and radiographic progression.
This study aims to improve understanding of disease monitoring during androgen receptor signaling inhibitor therapy and may help optimize imaging surveillance strategies and clinical decision-making in advanced prostate cancer.
Study Design: Individual trial analysis
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: R, RStudio
Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study:
Data Source:
This study will use individual patient data from the phase 3 TITAN and SPARTAN trials made available through the YODA Project. No external datasets will be used.
Inclusion Criteria:
Patients will be eligible if they were enrolled in TITAN or SPARTAN, were randomized to an apalutamide-containing treatment arm, had advanced prostate cancer as defined in each parent trial, and had available baseline PSA data and follow-up radiographic assessment data.
For TITAN, eligible patients will include men with metastatic castration-sensitive prostate cancer treated with apalutamide plus androgen deprivation therapy.
For SPARTAN, eligible patients will include men with nonmetastatic castration-resistant prostate cancer treated with apalutamide plus ongoing androgen deprivation therapy.
Exclusion Criteria:
Patients will be excluded if they were not assigned to apalutamide, had no post-baseline radiographic assessment, had missing baseline or follow-up PSA data required to classify PSA progression, or had insufficient data to determine radiographic progression status.
All analyses will be conducted within the YODA Project secure research environment using patient-level data from TITAN and SPARTAN. Data from the two trials may be pooled for selected analyses when clinically appropriate, with trial-specific subgroup analyses also performed.
Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study:
Primary Outcome Measure:
The primary outcome measure will be the proportion of patients who develop radiographic progression without PSA rise during apalutamide treatment. Radiographic progression will be defined according to the criteria used in the TITAN and SPARTAN trials, including PCWG2/3 criteria for bone progression and RECIST criteria for soft tissue progression where applicable. PSA rise will be defined according to PCWG2/3 criteria. Patients will be categorized into two groups at the time of radiographic progression: (1) radiographic progression with PSA rise and (2) radiographic progression without PSA rise.
Secondary Outcome Measures:
Secondary outcome measures will include:
Timing of PSA progression relative to radiographic progression, including the interval between radiographic progression and subsequent PSA rise.
Radiographic progression-free survival and overall survival according to PSA rise status at radiographic progression.
PSA kinetics before radiographic progression, including PSA nadir and percentage PSA change from baseline or nadir.
Baseline clinical characteristics associated with radiographic progression without PSA rise, including age, disease burden, Gleason score, baseline PSA, and metastatic status.
Frequency of progression without any PSA increase from baseline or nadir.
Patients will be categorized according to PSA rise status at the time of radiographic progression using predefined PCWG2/3 criteria. Analyses will be performed separately for TITAN and SPARTAN, with pooled analyses conducted where clinically appropriate.
Any modifications to outcome definitions or categorizations identified during the analysis phase will be clearly described and justified in the final publication.
Main Predictor/Independent Variable and how it will be categorized/defined for your study:
The primary independent variable in this study will be PSA rise status at the time of radiographic progression during apalutamide treatment. Patients will be categorized into two groups: (1) radiographic progression with PSA rise and (2) radiographic progression without PSA rise.
PSA rise will be defined according to PCWG2/3 criteria using serial PSA measurements collected during the TITAN and SPARTAN trials. Radiographic progression will be defined according to trial-specific radiographic assessment criteria, including PCWG2/3 criteria for bone lesions and RECIST criteria for measurable soft tissue disease where applicable.
Additional independent variables to be evaluated include baseline demographic and clinical characteristics, such as age, ECOG performance status, Gleason score, baseline PSA level, metastatic disease burden, presence of visceral metastases, prior therapies, and disease setting (metastatic castration-sensitive prostate cancer in TITAN versus nonmetastatic castration-resistant prostate cancer in SPARTAN).
PSA kinetic variables, including PSA nadir, percentage PSA decline from baseline, PSA doubling time, and any PSA increase from baseline or nadir before radiographic progression, will also be analyzed as exploratory independent variables associated with discordant progression patterns and survival outcomes.
For pooled analyses, trial cohort (TITAN versus SPARTAN) will be included as a covariate or stratification factor where appropriate.
Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study:
Additional variables of interest will include demographic, clinical, treatment-related, laboratory, and disease-related factors collected in the TITAN and SPARTAN trials. These variables will be used to characterize the study population and for multivariable analyses evaluating factors associated with radiographic progression without PSA rise and survival outcomes.
Demographic and baseline clinical variables will include age, race/ethnicity, ECOG performance status, Gleason score, disease setting (metastatic castration-sensitive prostate cancer in TITAN or nonmetastatic castration-resistant prostate cancer in SPARTAN), time from diagnosis to trial enrollment, and prior local therapy.
Disease-related variables will include baseline PSA level, metastatic burden, presence of visceral metastases, lymph node involvement, number and location of bone metastases, and measurable soft tissue disease based on RECIST criteria where applicable.
Treatment-related variables will include treatment arm, duration of apalutamide exposure, ongoing androgen deprivation therapy, prior systemic therapies, and treatment discontinuation status.
PSA kinetic variables will include PSA nadir, maximum PSA decline from baseline, PSA doubling time, time to PSA progression, and any PSA increase from baseline or nadir before radiographic progression.
Outcome-related variables will include radiographic progression-free survival, overall survival, time from radiographic progression to PSA progression, and subsequent therapy after progression.
Continuous variables will generally be analyzed as continuous measures and categorized where clinically appropriate using predefined cutoffs or quartiles. Missing data will be handled according to the extent and pattern of missingness in each variable.
Statistical Analysis Plan:
Descriptive statistics will be used to summarize baseline demographic and clinical characteristics of the study population. Continuous variables will be reported as means with standard deviations or medians with interquartile ranges, as appropriate, and categorical variables will be summarized using frequencies and percentages.
Patients will be categorized according to PSA rise status at the time of radiographic progression during apalutamide treatment: (1) radiographic progression with PSA rise and (2) radiographic progression without PSA rise. PSA rise will be defined using PCWG2/3 criteria. Additional exploratory analyses will evaluate progression without any PSA increase from baseline or PSA nadir.
Comparisons between groups will be performed using Student's t-test or Mann--Whitney U test for continuous variables and chi-square or Fisher's exact test for categorical variables, as appropriate.
Time-to-event outcomes, including radiographic progression-free survival and overall survival, will be analyzed using the Kaplan--Meier method and compared using log-rank tests. Cox proportional hazards regression models will be used to estimate hazard ratios and 95% confidence intervals. Multivariable Cox regression analyses will adjust for clinically relevant covariates, including age, ECOG performance status, Gleason score, baseline PSA level, metastatic burden, visceral metastases, and trial cohort (TITAN versus SPARTAN).
Logistic regression analyses will be performed to identify baseline clinical and PSA kinetic factors associated with radiographic progression without PSA rise. Variables with clinical relevance or significance in univariable analyses will be included in multivariable models.
PSA kinetic analyses will include evaluation of PSA nadir, percentage PSA decline from baseline, PSA doubling time, and timing of PSA progression relative to radiographic progression. Correlations between PSA kinetics and survival outcomes will also be explored.
Analyses will initially be conducted separately for TITAN and SPARTAN because of differences in disease states and eligibility criteria. Pooled analyses using combined individual patient-level data will subsequently be performed where clinically appropriate, with trial cohort included as a stratification factor or covariate.
Sensitivity analyses will be conducted using alternative PSA progression definitions, including any PSA increase from baseline or nadir. Missing data will be assessed for extent and pattern of missingness. Complete-case analyses will be primarily performed, with additional sensitivity analyses considered if missing data are substantial.
All statistical tests will be two-sided, and p values <0.05 will be considered statistically significant. Statistical analyses will be conducted within the YODA Project secure research environment using standard statistical software packages available within the platform.
Narrative Summary: This study will investigate radiographic progression without a rise in PSA levels in patients with advanced prostate cancer treated with apalutamide. PSA is widely used to monitor treatment response and disease progression; however, some patients experience worsening disease on imaging scans despite stable or low PSA levels. Using individual patient data from the TITAN and SPARTAN clinical trials, we will evaluate how frequently this progression pattern occurs, identify associated clinical characteristics, and assess patient outcomes. We also aim to better understand the clinical significance of progression without PSA rise. The findings may help physicians recognize disease progression missed by PSA monitoring alone and contribute to improved surveillance strategies and treatment decisions in advanced prostate cancer.
Project Timeline:
The anticipated project start date is June 2026, following approval of the data request and access to the YODA Project research environment. Initial data review, cohort definition, and data preprocessing are expected to be completed within the first 2 months.
Descriptive and primary statistical analyses are anticipated to be completed by October 2026. Secondary, subgroup, and sensitivity analyses are expected to be finalized by December 2026.
Preparation of the first manuscript draft is planned for January--February 2027, with initial submission to a peer-reviewed journal anticipated by March 2027. Revisions and additional analyses requested during peer review will be completed as needed.
Study findings and publication status will be reported back to the YODA Project following manuscript submission and publication. All planned analyses are expected to be completed within the initial 12-month data access period. If additional time is required for peer review--related analyses or manuscript revisions, an extension request may be submitted in accordance with YODA Project policies.
Dissemination Plan:
The primary anticipated product of this project is a peer-reviewed original research manuscript describing the incidence, clinical characteristics, and prognostic implications of radiographic progression with and without PSA rise during apalutamide treatment in advanced prostate cancer. Additional conference abstracts and presentations at international oncology and urology meetings may also be developed based on the study findings.
The target audience includes medical oncologists, urologists, radiation oncologists, clinical researchers, and healthcare professionals involved in the management of advanced prostate cancer. The findings may be particularly relevant to clinicians using androgen receptor signaling inhibitors and monitoring disease progression using PSA kinetics.
Potential journals for manuscript submission include European Urology Oncology, and Prostate Cancer and Prostatic Diseases. Results may also be presented at major scientific meetings such as the American Society of Clinical Oncology Annual Meeting, the European Association of Urology Congress, and the American Urological Association Annual Meeting.
The study is expected to contribute to improved understanding of disease monitoring during androgen receptor signaling inhibitor therapy and may help inform future clinical surveillance strategies in advanced prostate cancer.
Bibliography:
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- Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in Patients with Metastatic Castration-Sensitive Prostate Cancer: Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study. J Clin Oncol. 2021;39:2294-2303.
- Smith MR, Saad F, Chowdhury S, et al. Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. N Engl J Med. 2018;378:1408-1418.
- Smith MR, Saad F, Chowdhury S, et al. Apalutamide and Overall Survival in Prostate Cancer. Eur Urol. 2021;79:150-158.
- Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol. 2019;37:2974-2986.
- Hussain M, Fizazi K, Saad F, et al. Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2018;378:2465-2474.
- Armstrong AJ, de Bono J, Sternberg CN, et al. Radiographic Progression with Nonrising PSA in Metastatic Castration-Resistant Prostate Cancer: Post Hoc Analysis of the PREVAIL Trial. J Clin Oncol. 2017;35:433-440.
- Mehra N, et al. Radiographic progression without prostate-specific antigen progression in patients treated with enzalutamide: Post hoc analyses of the ARCHES and PROSPER studies. Eur Urol Open Sci. 2024.
- Scher HI, Morris MJ, Stadler WM, et al. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3 (PCWG3). J Clin Oncol. 2016;34:1402-1418.
- 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. J Clin Oncol. 2008;26:1148-1159.