Plasma androgen receptor copy number status at emergence of metastatic castration-resistant prostate cancer: a pooled multi-cohort analysis
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Importance Increases in androgen receptor (AR) copy number (CN) can be detected in plasma DNA when patients develop metastatic castration-resistant prostate cancer (mCRPC). We aim to evaluate the association between AR CN as a continuous variable and clinical outcome.
Patients and Methods PCR2023 was an international, multi-institution, open-label, phase 2 study of abiraterone acetate plus prednisolone or dexamethasone (AAP/D) that included plasma AR assessment as a pre-defined exploratory secondary end-point. Plasma AR CN from this study (N=133) was pooled with data from three other cohorts: cohort A treated with either AAP or enzalutamide (N=73); the PREMIERE trial of biomarkers for enzalutamide (N=94); and a phase II trial, British Columbia Cohort; randomising men between AAP or enzalutamide (N=201). The primary outcome measures for the biomarker analysis were overall survival (OS) and progression free survival (PFS).
Results Using multivariable fractional polynomials analysis Cox regression models, a non-linear relationship between plasma AR CN and outcome was identified for OS, where initially for small incremental gains in CN there was a large added Hazard Ratio (HR) that plateaus at higher CN. The CN cut-point associated with the highest local HR was 1.92. A similar non-linear association was observed with PFS. In an exploratory analysis of PCR2023, the time from start of long-term androgen deprivation therapy to start of AAP/D was significantly shorter in patients with plasma AR CN >1.92 at mCRPC (43 versus 130 weeks; p=0.005). This was confirmed in Cohort A (p=0.003); PREMIERE (p=0.03) and British Colombia (p=0.003) cohorts.
Conclusions Dichotomising mCRPC patients by plasma AR CN 1.92 identifies aggressive disease poorly responsive to AR targeting and associates with a prior short response to primary ADT.
Patients and Methods PCR2023 was an international, multi-institution, open-label, phase 2 study of abiraterone acetate plus prednisolone or dexamethasone (AAP/D) that included plasma AR assessment as a pre-defined exploratory secondary end-point. Plasma AR CN from this study (N=133) was pooled with data from three other cohorts: cohort A treated with either AAP or enzalutamide (N=73); the PREMIERE trial of biomarkers for enzalutamide (N=94); and a phase II trial, British Columbia Cohort; randomising men between AAP or enzalutamide (N=201). The primary outcome measures for the biomarker analysis were overall survival (OS) and progression free survival (PFS).
Results Using multivariable fractional polynomials analysis Cox regression models, a non-linear relationship between plasma AR CN and outcome was identified for OS, where initially for small incremental gains in CN there was a large added Hazard Ratio (HR) that plateaus at higher CN. The CN cut-point associated with the highest local HR was 1.92. A similar non-linear association was observed with PFS. In an exploratory analysis of PCR2023, the time from start of long-term androgen deprivation therapy to start of AAP/D was significantly shorter in patients with plasma AR CN >1.92 at mCRPC (43 versus 130 weeks; p=0.005). This was confirmed in Cohort A (p=0.003); PREMIERE (p=0.03) and British Colombia (p=0.003) cohorts.
Conclusions Dichotomising mCRPC patients by plasma AR CN 1.92 identifies aggressive disease poorly responsive to AR targeting and associates with a prior short response to primary ADT.
Date Issued
2019-09-24
Date Acceptance
2019-08-06
Citation
JCO Precision Oncology, 2019, 3
ISSN
2473-4284
Publisher
American Society of Clinical Oncology
Journal / Book Title
JCO Precision Oncology
Volume
3
Copyright Statement
© 2019 American Society of Clinical Oncology. All rights reserved.
Subjects
Science & Technology
Life Sciences & Biomedicine
Oncology
CIRCULATING TUMOR DNA
ABIRATERONE ACETATE
ENZALUTAMIDE
SURVIVAL
MEN
CHEMOTHERAPY
MODEL
Publication Status
Published
Date Publish Online
2019-09-24