Plasma Androgen Receptor Copy Number Status at Emergence of Metastatic Castration-Resistant Prostate Cancer: A Pooled Multicohort Analysis.

Abstract

Increases in androgen receptor (<i>AR</i>) copy number (CN) can be detected in plasma DNA when patients develop metastatic castration-resistant prostate cancer. We aim to evaluate the association between <i>AR</i> CN as a continuous variable and clinical outcome. PCR2023 was an international, multi-institution, open-label, phase II study of abiraterone acetate plus prednisolone (AAP) or abiraterone acetate plus dexamethasone that included plasma <i>AR</i> assessment as a predefined exploratory secondary end point. Plasma <i>AR</i> CN data (ClinicalTrials.gov identifier: NCT01867710) from this study (n = 133) were pooled with data from the following three other cohorts: cohort A, which was treated with either AAP or enzalutamide (n = 73); the PREMIERE trial (ClinicalTrials.gov identifier: NCT02288936) of biomarkers for enzalutamide (n = 94); and a phase II trial from British Columbia (ClinicalTrials.gov identifier: NCT02125357) that randomly assigned men to either AAP or enzalutamide (n = 201). The primary outcome measures for the biomarker analysis were overall survival and progression-free survival. Using multivariable fractional polynomials analysis using Cox regression models, a nonlinear relationship between plasma <i>AR</i> CN and outcome was identified for overall survival, where initially for small incremental gains in CN there was a large added hazard ratio that plateaued at higher CN. The CN cut point associated with the highest local hazard ratio was 1.92. A similar nonlinear association was observed with progression-free survival. In an exploratory analysis of PCR2023, the time from start of long-term androgen-deprivation therapy to start of AAP or abiraterone acetate plus dexamethasone was significantly shorter in patients with plasma <i>AR</i> CN of 1.92 or greater than patients with plasma <i>AR</i> CN of less than 1.92 (43 <i>v</i> 130 weeks, respectively; <i>P</i> = .005). This was confirmed in cohort A (<i>P</i> = .003), the PREMIERE cohort (<i>P</i> = .03), and the British Colombia cohort (<i>P</i> = .003). Patients with metastatic castration-resistant prostate cancer can be dichotomized by a plasma <i>AR</i> CN cut point of 1.92. Plasma <i>AR</i> CN value of 1.92 or greater identifies aggressive disease that is poorly responsive to AR targeting and is associated with a prior short response to primary androgen-deprivation therapy.