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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: Investigating the Canonical Polycomb Repressive Complex 1 (cPRC1) as an Intrinsic Mechanism of Resistance to Apalutamide in Advanced Prostate Cancer
Scientific Abstract:
Background:
We have performed a proliferation based genome-wide CRISPRi screen in LNCaP prostate cancer cells in vitro, in the presence and absence of ASI, to identify genes mediating resistance to ASI treatment. This screen identified the polycomb repressive complex 1 (PRC1) as a major mediator of ASI resistance. We have further shown that knockout of this complex sensitizes to ASI treatment in vitro and in vivo, and that PRC1 modulates global transcriptional patterns to promote a less AR-dependent cell state.
Objective:
Our objective is to determine if cPRC1 promotes ASI resistance in patients, and to test cPRC1 expression as a candidate predictive biomarker of ASI response.
Study Design:
We will analyze the TITAN and SPARTAN trials of mCRPC and nmCRPC, respectively, by stratifying patients who received apalutamide treatment by high versus low expression of cPRC1 subunits including PHC3, RING1, RNF2, PCGF2, and BMI1. Patients receiving ADT only will be used as a control arm for comparison.
Participants:
All patients enrolled in the TITAN and SPARTAN trials.
Primary and Secondary Outcome Measures:
- Primary outcome: Overall survival
- Secondary outcome: Time to progression
Statistical Analysis:
Treatment failure rate and survival probability in the respective biomarker classifications will be modeled using the Kaplan-Meier method and Cox proportional hazards regression. Multivariable Cox modeling will be used to adjust for known prognostic variables (e.g. PSA, LDH, Hb, ECOG PS, age, sites of metastasis at time of biopsy).
Brief Project Background and Statement of Project Significance: Second-generation androgen signaling inhibitors (ASIs) such as apalutamide bind directly to the androgen receptor (AR) to antagonize androgen signaling, and robustly increase patient survival in advanced prostate cancer. However, not all patients respond to treatment, and resistance inevitably develops with prolonged exposure through mechanisms which are poorly understood. We have identified a candidate mechanism of resistance to ASIs, namely, the activity of the cPRC1 complex, and comprehensively validated this finding in vitro. Our goal with this proposal is to determine whether cPRC1 promotes resistance to ASI therapy in patients. Successful completion of this project would nominate cPRC1 as a candidate predictive biomarker for response to ASI, and also as a candidate therapeutic target in advanced prostate cancer. Both achievements have potential to significantly impact treatment of patients with advanced prostate cancer.
Specific Aims of the Project:
Our overall hypothesis is that cPRC1 expression levels will predict response to ASI treatment in advanced prostate cancer. We will test this hypothesis in 2 specific aims:
1) Investigate ability of cPRC1 expression levels to predict response to apalutamide in mHSPC.
- To accomplish this aim, we will analyze data from the TITAN trial of apalutamide in mHSPC
2) Investigate ability of cPRC1 expression levels to predict response to apalutamide in nmCRPC.
- To accomplish this aim, we will analyze data from the SPARTAN trial of apalutamide in nmCRPC
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
Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study:
Inclusion criteria: apalutamide treatment
Exclusion criteria: none
Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study:
Primary outcome measures: overall survival, progression free survival. These outcome measures will be defined as mean (+/- 95% CI) survival and progression free survival.
Secondary outcome measures: none
Main Predictor/Independent Variable and how it will be categorized/defined for your study: Main independent variable: cPRC1 subunit expression levels (including PHC3, RING1, RNF2, PCGF2, BMI1, and several others). Relative expression levels will be calculated and grouped (top 50% versus bottom 50% expression levels). We may need to analyze based on a composite variable, such as the average expression level of all subunits.
Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: We perform risk-adjustment using variables known to be prognostic, assessed at the time of trial enrollment: PSA, LDH, Hb, ECOG, PS, age, sites of metastasis.
Statistical Analysis Plan: Treatment failure rate and survival probability in the respective biomarker classifications will be modeled using the Kaplan-Meier method and Cox proportional hazards regression. Multivariable Cox modeling will be used to adjust for known prognostic variables (e.g. PSA, LDH, Hb, ECOG PS, age, sites of metastasis at time of biopsy).
Narrative Summary: In our laboratory we have found that the cPRC1 complex promotes resistance to apalutamide in prostate cancer cells. We would now like to investigate whether or not cPRC1 influences the response to apalutamide in human prostate cancer. To do this, we propose to use data from the TITAN and SPARTAN trials of apalutamide in metastatic hormone sensitive and non-metastatic castration resistant prostate cancer, respectively. We will stratify patients by cPRC1 expression levels and then compare outcomes when treated with apalutamide or not, to see if cPRC1 expression influences the response to apalutamide in patients.
Project Timeline:
Anticipated project start: Sept 2024
Analysis completion date: Aug 2025
Manuscript drafted: Oct 2025
Results reported to YODA Project: Jan 2026
Dissemination Plan: Our target audience for this work is basic and translational prostate cancer researchers. We anticipate disseminating findings from this study through a published manuscript in a basic/translational sciences journal (e.g. Cancer Discovery, Clinical Cancer Research) and through presentations at national/international conferences such as ASCO, ASCO GU, PCF Annual Research Conference, and others.
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