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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)
- 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)
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Status: OngoingResearch Proposal
Project Title: Initial ADT or ADT plus novel androgen receptor signaling inhibitors for patients with metastatic castration-sensitive prostate cancer
Scientific Abstract:
Background: Randomized trials have shown that the combination of ADT with novel androgen receptor signaling inhibitors (ARSIs) for mestatic castration-sensitive prostate cancer (mCSPC) significantly improves overall survival. However, only a portion of patients in the control groups received subsequent novel ARSIs after progressing to mestatic castration-resistant prostate cancer (mCRPC). Therefore, it is critical to investigate whether patients with mCSPC can really benefit from intensification treatment of ADT with novel ARSIs.
Objective: To investigate whether the delayed administration of novel ARSIs could provide comparable survival benefits when compared with the initial intensification treatment approach
Study design: Post-hoc analysis of patients participating in randomized controlled trials.
Participants: Patients with mCSPC who were enrolled in LATITUDE and TITAN trials.
Main Outcome Measure: ARSIs failure-free survival (aFFS, defined as the time from randomization to the date of progression on first novel ARSIs) and overall survival (OS) will be determined.
Statistical Analysis: Baseline data will be described by descriptive statistics (median +/-SD), and comparison between groups will be performed by student t test or chi-square test. aFFS and OS will be estimated by Kaplan-Meier analysis, with hazard ratios calculated using a multivariate Cox proportional-hazard model.
Brief Project Background and Statement of Project Significance:
Treatment patterns for metastatic castration-sensitive prostate cancer (mCSPC) have evolved, with multiple randomized trials demonstrating improved survival through the combination of androgen deprivation therapy (ADT) with novel androgen receptor signaling inhibitors (ARSIs)[1]. Consequently, the combination of ADT with novel ARSIs is endorsed by clinical guidelines as first-line therapy for mCSPC[2].
However, only a portion of patients in the control groups received subsequent novel ARSIs after progressing to metastatic castration-resistant prostate cancer (mCRPC) in these trials. This raises the possibility that the OS benefit may be overestimated, as later receipt of novel ARSIs might confer a similar OS benefit[3-6]. Additionally, cost is a significant concern; the long-term use of novel ARSIs for mCSPC results in substantial increases in therapy expenditure, which may be unaffordable for patients in developing countries[7]. The potential for toxicities is also a consideration, as long-term administration of novel ARSIs may lead to increased severe adverse events[8]. Therefore, it is critical to compare the survival benefits of initial treatment with ADT for mCSPC, followed by subsequent novel ARSIs after progression to mCRPC, with the intensification treatment of ADT and novel ARSIs from the outset for mCSPC.
The Purpose of this study is to investigate whether the delayed administration of novel ARSIs could provide comparable survival benefits when compared with the initial intensification treatment approach (ADT combined with novel ARSIs) with a post-hoc analysis. The results are expected to clarify whether patients with mCSPC could really benefit from intensification treatment approach (ADT combined with novel ARSIs).
Specific Aims of the Project:
Aims:
To investigate whether the delayed administration of novel ARSIs could provide comparable survival benefits when compared with the initial intensification treatment approach (ADT combined with novel ARSIs) with a post-hoc analysis using individual patient data from LATITUDE and TITAN trials which including metastatic castration-sensitive prostate cancer.
Hypothesis:
Our hypothesis is that the delayed administration of novel ARSIs could provide comparable survival benefits when compared with the initial intensification treatment approach (ADT combined with novel ARSIs).
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 Confirm or validate previously conducted research on treatment effectiveness
Software Used: RStudio
Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study:
1. 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). (NCT01715285)
2. 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). (NCT02489318)
Inclusion criteria: all patients included in the trials. Exclusion criteria: Patients with missing data of progression of survival.
Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study:
Primary end points:
- ARSIs failure-free survival (aFFS), defined as the time from randomization to the date of progression on first novel ARSIs.
Secondary end points:
- Overall survival (OS), defined as the time from randomization to death.
- ARSIs treatment duration, defined as the time from initiation of the first novel ARSIs to discontinuation of the first novel ARSIs.
- adverse events.
Main Predictor/Independent Variable and how it will be categorized/defined for your study:
The timing of novel ARSIs, patients will be divided into two groups according to the timing of novel ARSIs.
Group #1: Patients received ADT plus placebo as first-line therapy, followed by ADT plus novel ARSIs after progression to mCRPC.
Group #2: Patients received intensification treatment with ADT combined with novel ARSIs as first-line therapy.
Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: Age (categorized), race, Eastern Cooperative Oncology Group (ECOG) performance status, baseline prostate-specific antigen (PSA) (categorized), Gleason score at diagnosis (categorized), prior taxane (no or yes), Tumor Stage, Nodal Stage, Metastases Stage, time from diagnosis to randomization. Baseline laboratory test results (PSA, Hb, LDH, ALP, and ALB). Survival data (PFS and OS). PSA response rate (PSA30, PSA50, and PSA90), AEs.
Statistical Analysis Plan: Participants who included in this study will be divided by the timing of novel ARSIs. Baseline data will be described by descriptive statistics (median +/-SD), and comparison between groups will be performed by student t test or chi-square test. Kaplan-Meier analysis and established multivariate Cox proportional-hazard model will be performed by survival and survminer package. AEs will be described by descriptive statistics (incidence rate).
Narrative Summary: Randomized trials have shown that the combination of ADT with novel androgen receptor signaling inhibitors (ARSIs) for mCSPC significantly improves overall survival. However, only a portion of patients in the control groups received subsequent novel ARSIs after progressing to mCRPC. In the control groups of both the LATITUDE and TITAN trials, a subset of patients crossed over to receive either abiraterone acetate or apalutamide, respectively. This study aims to investigate whether the delayed administration of novel ARSIs could provide comparable survival benefits when compared with the initial intensification treatment approach in the LATITUDE and TITAN trials.
Project Timeline: We anticipated start the project In May this year, finish the analysis before 1st Aug. 2025, and draft the manuscript for submission before 31st Dec. 2025.
Dissemination Plan: The findings of this project are expected to result in the development of a manuscript suitable for publication in a urologic (European Urology, Journal of Urology) or oncology (Annals of Oncology, JAMA oncology) journal. In addition, the results will be presented at appropriate urologic (AUA, EAU) or oncology conferences (ASCO, ESMO).
Bibliography:
[1] Chen K, O’Brien J, McVey A, Jenjitranant P, Kelly BD, Kasivisvanathan V, et al. Combination treatment in metastatic prostate cancer: is the bar too high or have we fallen short? Nat Rev Urol. 2023;20:116-23.
[2] Cornford P, Tilki D, van den Bergh RCN, Briers E, Eberli D, De Meerleer G, et al. EAU – EANM – ESTRO – ESUR – ISUP – SIOG Guidelines on Prostate Cancer 2024. European Association of Urology Guidelines 2024 Edition. Arnhem, The Netherlands: European Association of Urology Guidelines Office; 2024.
[3] de Bono J, Eisenberger M, Sartor O. Abiraterone in Metastatic Prostate Cancer. N Engl J Med. 2017;377:1694-5.
[4] Klotz L. Apalutamide for Metastatic, Hormone-Responsive Prostate Cancer. N Engl J Med. 2019;381:84-6.
[5] Tombal B, van Soest RJ. Prostate cancer: STAMPEDE, LATITUDE and Fernand Labrie’s legacy. Nat Rev Urol. 2017;14:588-90.
[6] Saad F. Continuing to improve outcomes of men with metastatic prostate cancer. Nat Rev Clin Oncol. 2019;16:597-8.
[7] Sathianathen NJ, Lawrentschuk N, Konety B, Azad AA, Corcoran NM, Bolton DM, et al. Cost Effectiveness of Systemic Treatment Intensification for Metastatic Hormone-sensitive Prostate Cancer: Is Triplet Therapy Cost Effective? Eur Urol Oncol. 2023.
[8] Cao B, Kim M, Reizine NM, Moreira DM. Adverse Events and Androgen Receptor Signaling Inhibitors in the Treatment of Prostate Cancer: A Systematic Review and Multivariate Network Meta-analysis. Eur Urol Oncol. 2023;6:237-50.