General Information
Conflict of Interest
Request Clinical Trials
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)
- NCT01715285 - A Randomized, Double-blind, Comparative Study of Abiraterone Acetate Plus Low-Dose Prednisone Plus Androgen Deprivation Therapy (ADT) Versus ADT Alone in Newly Diagnosed Subjects With High-Risk, Metastatic Hormone-naive Prostate Cancer (mHNPC)
Request Clinical Trials
Data Request Status
Status: OngoingResearch Proposal
Project Title: Continuation of androgen receptor pathway inhibitors beyond radiographic progression in metastatic hormone-sensitive prostate cancer
Scientific Abstract:
Background: Clinical trials of androgen receptor pathway inhibitors in metastatic hormone-sensitive prostate cancer allow treatment continuation beyond radiographic progression. However, evidence to support this clinical decision remains limited.
Objective: To estimate the effect of continuing ARPI therapy beyond radiographic progression versus discontinuing at progression.
Study Design: Individual participant data meta-analysis using target trial emulation within each eligible randomized trial.
Participants: Patients with metastatic hormone-sensitive prostate cancer enrolled in trials of ARPI + androgen deprivation therapy with protocol-defined radiographic assessments and permission to continue study drug after radiographic progression.
Primary and Secondary Outcome Measure(s): Primary outcome is overall survival from randomization. Secondary outcomes are time to initiation of cytotoxic chemotherapy and progression on first subsequent therapy or death (PFS2), when available.
Statistical Analysis: Within the target trial emulation framework, we will evaluate two strategies (continue ARPI beyond radiographic progression vs discontinue at progression) using the clone-censor-weight approach. We will estimate stabilized inverse-probability of censoring weights from models of adherence to the assigned strategy and fit a weighted pooled logistic (discrete-time hazard) model to obtain standardized risks, risk differences, and risk ratios.
Brief Project Background and Statement of Project Significance:
ARPIs administered with androgen deprivation therapy are standard of care for metastatic hormone-sensitive prostate cancer and improve survival [1--4]. Radiographic progression can occur despite initial benefit and may precede symptomatic progression. The Prostate Cancer Clinical Trials Working Group 3 emphasizes that the first evidence of radiographic progression does not necessarily mandate treatment discontinuation when patients still derive clinical benefit [5]. Some clinical trials allow treatment beyond progression, but evidence supporting this decision remains limited. However, the net benefit or harm of continuing ARPI therapy beyond radiographic progression remains uncertain, and practice varies.
Using individual participant data from clinical trials, this project will provide comparative effectiveness evidence on two clinically relevant strategies: continuing versus discontinuing ARPI therapy at radiographic progression. Findings will inform clinical decision-making, trial interpretation, and future guidelines for post-progression management in mHSPC.
Specific Aims of the Project:
Aim 1: Estimate the effect of continuing ARPI therapy beyond radiographic progression versus discontinuing at progression on overall survival.
Aim 2: Compare strategies for time to initiation of cytotoxic chemotherapy and PFS2 (progression on first subsequent therapy or death), when available.
Study Design: Meta-analysis (analysis of multiple trials together)
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: We will include patients with mHSPC enrolled in clinical trials who received ARPI plus androgen deprivation therapy. We will exclude patients who did not receive ARPI.
Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study:
Primary outcome: Overall survival (OS), defined as time from time zero to death from any cause.
Secondary outcomes: (1) Time to initiation of cytotoxic chemotherapy (time from time zero to first chemotherapy start date). (2) Progression on first subsequent therapy or death (PFS2), defined per trial protocol when available and harmonized across trials. If a trial lacks a PFS2 definition or requisite variables, that trial will contribute only to outcomes it can support.
Time zero will be defined as the date of randomization for randomized clinical trials. For nonrandomized clinical trials, time zero may be defined as treatment initiation.
Main Predictor/Independent Variable and how it will be categorized/defined for your study: The post-progression treatment strategy (continuation vs discontinuation of ARPI therapy beyond radiographic progression).
Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: Variables include baseline demographics (age and Eastern Cooperative Oncology Group performance status), disease characteristics (Gleason score, number of bone metastases, pain scale, presence of visceral metastases), and laboratory values (PSA, hemoglobin, lactate dehydrogenase). The final set of variables may be modified if some included clinical trials do not have specific variables available.
Statistical Analysis Plan:
We will emulate a target trial within each eligible trial. Time zero will be the date of randomization (or treatment initiation if required by a specific dataset). Each eligible patient will be cloned into two copies, one assigned to Strategy A (continue ARPI beyond radiographic progression) and one to Strategy B (discontinue at progression). A clone will be censored when it deviates from its assigned strategy. We will use stabilized inverse probability of censoring weights estimated from pooled logistic regression models that include baseline and time-varying covariates predictive of deviation from strategy.
We will estimate strategy-specific survival curves using weighted pooled logistic regression models and derive standardized risks, risk differences, and risk ratios. Uncertainty will be quantified via nonparametric bootstrapping within each trial. Trial-specific effect estimates will be pooled using a Bayesian random-effects meta-analysis model, given the limited number of included trials. If Bayesian estimation is not computationally feasible, we will use a frequentist random-effects model. Missing covariate data will be handled using multiple imputation within trials when feasible. If a covariate is systematically missing within a trial, we will use multilevel multiple imputation.
Narrative Summary: Patients with metastatic hormone-sensitive prostate cancer (mHSPC) often receive androgen receptor pathway inhibitors (ARPIs) plus androgen deprivation therapy. Imaging sometimes shows tumor growth before symptoms worsen. Although some clinical trials permit treatment beyond radiographic progression, evidence to support this clinical decision remains limited. We will use individual participant data from eligible clinical trials to compare two strategies: continuing ARPI therapy after radiographic progression versus stopping it at progression. We will estimate effects on overall survival and on time to chemotherapy or next-line progression. Results will inform clinicians, patients, and guideline developers about post‑progression ARPI management.
Project Timeline:
Anticipated milestones:
- Project start: 2026-02-15
- Data access and harmonization complete: 2026-04-15
- Primary analyses complete: 2026-09-01
- Manuscript draft complete: 2026-11-01 -
First submission for publication: 2026-12-15
Dissemination Plan: We will submit a primary manuscript to a high‑impact oncology or urology journal (e.g., European Urology, Journal of Clinical Oncology, or The Lancet Oncology) and present findings at major conferences (e.g., ASCO, ESMO, JUA, or AUA).
Bibliography:
[1] Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. New England Journal of Medicine 2017;377:352--60. https://doi.org/10.1056/NEJMoa1704174.
[2] Armstrong AJ, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, Villers A, Azad A, et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. Journal of Clinical Oncology 2019;37:2974--86. https://doi.org/10.1200/jco.19.00799.
[3] Chi KN, Agarwal N, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, et al. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. New England Journal of Medicine 2019;381:13--24. https://doi.org/10.1056/nejmoa1903307.
[4] Smith MR, Hussain M, Saad F, Fizazi K, Sternberg CN, Crawford ED, et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. New England Journal of Medicine 2022;386:1132--42. https://doi.org/10.1056/nejmoa2119115.
[5] Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. Journal of Clinical Oncology 2016;34:1402--18. https://doi.org/10.1200/jco.2015.64.2702.