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Status: OngoingResearch Proposal
Project Title: The impact of metastatic sites on prognosis in Metastatic Prostate Cancer Receiving Androgen Receptor Pathway Inhibitors
Scientific Abstract:
Background
In metastatic castration-sensitive prostate cancer (mCSPC), new generation anti-androgen inhibitors improved overall survival. Currently, assessing disease volume is crucial for treatment choices. The CHAARTED criteria, evaluating disease volume via visceral metastases or >=4 bone lesions (one outside vertebral bodies/pelvis), are widely recognized. However, the impact of metastatic sites on survival remains unclear, particularly in patients receiving new generation anti-androgen inhibitors. This study aims to determine the effect of metastatic sites on survival in patients with mCSPC receiving ADT with or without apalutamide in the TITAN trial.
Objective
To conduct post-hoc analysis of prognosis based on the metastatic sites from randomized trials comparing ARPIs with placebo in patients with mCSPC.
Study design
Post-hoc analysis of data from placebo-controlled, double-blinded randomized clinical trials.
Participants
Patients with mCSPC who received either ARPIs (apalutamide) or placebo in the TITAN trials.
Primary and secondary measures
Primary: Overall survival
Secondary: progression free survival, objective response rate
Statistical analysis:
- Survival Analysis:
- Kaplan--Meier method for OS and PFS.
- Log-rank test to compare survival curves across metastatic site categories.
- Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for key covariates (age, ECOG PS, Gleason score, disease volume).
- Response Analysis:
- ORR will be compared using chi-square or Fisher's exact test.
Brief Project Background and Statement of Project Significance:
The addition of androgen receptor pathway inhibitors (ARPIs), such as apalutamide, has significantly improved overall survival in patients with metastatic castration-sensitive prostate cancer (mCSPC). Furthermore, the ARASENS trial demonstrated that triplet therapy with docetaxel, darolutamide, and androgen deprivation therapy further extends survival. Nevertheless, concerns remain regarding the higher incidence of adverse events and the associated treatment-related costs.
Currently, disease volume is a key determinant of treatment selection. The CHAARTED criteria, which define high-volume disease as the presence of visceral metastases or >=4 bone lesions (including at least one outside the vertebral bodies and pelvis), are widely applied. In line with this, the NCCN guidelines recommend triplet therapy for patients with high-volume mCSPC. However, the prognostic relevance of specific metastatic sites remains uncertain.
Of note, although lung metastases are categorized as visceral disease, several studies have reported more favorable outcomes compared with other metastatic sites. Existing criteria stratify patients solely by the presence of visceral versus bone metastases. A more detailed analysis of clinical trial data focusing on the prognostic implications of individual metastatic sites may allow for more refined stratification of patients according to disease biology.
Specific Aims of the Project: The aim of this project is to study the prognostic impact of specific metastatic sites in metastatic castration-sensitive prostate cancer (TITAN trial).
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: RStudio
Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: This study will include the intention-to-treat population from the TITAN trials. Participants who were not included in this population will be excluded from the analysis.
Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study:
Primary Outcome: Overall Survival (OS): Time from randomization to death from any cause.
Progression-Free Survival (PFS): Time from randomization to documented disease progression or death from any cause, whichever occurs first.
Secondary Outcome: Objective Response Rate (ORR): Proportion of patients achieving complete response (CR) or partial response (PR) according to RECIST version 1.1.
Main Predictor/Independent Variable and how it will be categorized/defined for your study:
The main independent variable will be the metastatic site at baseline.
Categorization/Definition:
Metastatic sites will be categorized into four groups based on radiographic assessment at study entry:
- Lung metastases
- Brain metastases
- Liver metastases
- Bone metastases
- Lymph node--only metastases
Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study:
ECOG Performance Status: 0--1 vs. >=2.
- Gleason Score / ISUP Grade Group: <=7 vs. >=8.
- Baseline PSA level: Dichotomized by the median value.
- Prior Local Therapy (radical prostatectomy and/or radiotherapy): Yes vs. No.
- Disease Volume: High vs. low, defined according to the CHAARTED criteria.
- Extent of Bone Metastases: Fewer than 4 lesions vs. >=4 lesions.
- Comorbidities: Presence vs. absence of significant comorbid conditions (e.g., cardiovascular disease, diabetes).
Statistical Analysis Plan:
The following statistical analysis will be implemented using R and JMP software .
- Descriptive Statistics: Baseline characteristics will be summarized using medians (IQR) for continuous variables and frequencies (%) for categorical variables.
- Survival Analysis:
- Kaplan--Meier method for OS and PFS.
- Log-rank test to compare survival curves across metastatic site categories.
- Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for key covariates (age, ECOG PS, Gleason score, disease volume).
- Response Analysis:
- ORR will be compared using chi-square or Fisher's exact test.
Narrative Summary: In metastatic castration-sensitive prostate cancer (mCSPC), assessing disease volume is crucial for treatment choices. The CHAARTED criteria, evaluating disease volume via visceral metastases or >=4 bone lesions (one outside vertebral bodies/pelvis), are widely recognized. However, the impact of metastatic sites on survival remains unclear, particularly in patients receiving apalutamide. Our study aims to determine the effect of metastatic sites on survival in patients with mCSPC receiving ADT with or without apalutamide in the TITAN trial.
Project Timeline:
The project will span approximately 12 months. During months 1-2, we will focus on data acquisition and processing of the data. During months 3-6, we will analyze the effect of apalutamide on overall survival differs according to metastatic sites in patients with mCSPC. Manuscript writing and preparation will occur during months 7-8. The final four months will be dedicated to responding to reviewer comments, refining analyses, and finalizing the manuscript.
Dissemination Plan:
We plan to share findings from this research through multiple channels. Our primary output will be a manuscript for submission to a peer-reviewed oncology journal. In addition to publication, we will present our findings at major oncology conferences, including the American Society of Clinical Oncology (ASCO) Annual Meeting and the European Association of Urology (EAU) Congress.
Bibliography: