Abstract 973: Plasma androgen receptor (AR) copy number gain at progression in patients randomized in the STAMPEDE phase 3 abiraterone acetate, prednisolone (AAP) and enzalutamide (ENZ) trial: An ancillary biomarker study
Authors: Leone Gianmarco , Orlando Francesco , Thakali Suparna , Lall Sharanpreet , Wetterskog Daniel , Wingate Anna , Clarke Noel W. , James Nicholas D. , Demichelis Francesca , Attard Gerhardt 
Published: March 2024

Addition of ENZ or AAP to androgen deprivation therapy (ADT) as first-line treatment for advanced prostate cancer improves survival compared to ADT alone. Genomic alterations in AR associate with resistance to ENZ/AAP when started for castration-resistant prostate cancer (CRPC). We aimed to test whether early use of AAP/ENZ altered the incidence of AR alterations at progression. Between July 2014 and March 2016, 1976 patients with metastatic or high-risk locally advanced prostate cancer were randomized to ADT or ADT+ENZ+AAP in the STAMPEDE trial (NCT00268476). Consenting patients were given the option to donate blood for the ancillary biomarker study at trial-defined progression and prior to start of the next line of treatment. We focused on patients who progressed within 4 years from the end of recruitment (early progressors), as these patients represent the greatest unmet need. We obtained plasma DNA at emergence of CRPC from 115 early progressors (ADT n=63, ADT+ENZ+AAP n=52). We performed liquid biopsy-focused, custom, high-coverage targeted enrichment sequencing (PCF-SELECT, Orlando et al, NAR Cancer 2022). We used a bespoke computational pipeline, leveraging allelic imbalance and fragmentome analysis, to detect circulating tumor DNA (ctDNA) in plasma samples and copy number changes. Of 108 samples that passed quality control, 94 were positive for tumor (ADT n=52, ADT+AAP+ENZ n=42). The detection rate and ctDNA fractions were similar between the two treatment groups [ADT: 86.7% (52/60), mean ctDNA fraction 0.18; ADT+ENZ+AAP: 87.5% (42/48), mean ctDNA fraction 0.21; p=0.34]. The proportion of plasma with detectable ctDNA and AR gain was significantly higher with ADT+AAP+ENZ vs ADT alone (15/42, 35.7% vs 8/52, 15.4%, p=0.03). We then implemented the same approach on plasma collected from patients progressing on ENZ started for metastatic CRPC in a prospective Phase 3b trial (PRESIDE, NCT02288247): we confirmed a high prevalence of AR gain in plasma samples with detectable ctDNA (47.7%, 95% CI 38.8-54.9) in the CRPC setting. Significant copy number aberrations in relevant prostate cancer-related genes/pathways (deletions of TP53, RB1, PTEN or DNA repair genes, or gain of PI3K/AKT1) were identified in 9 out of 42 evaluable samples in the ADT group and 18 out of 38 evaluable samples in the ADT+ENZ+AAP group (21.4% vs 47.4%, p=0.014). Treatment with ADT+ENZ+AAP increases detection of plasma AR gain at emergences of CRPC in early progressors compared to ADT alone. Detection of plasma AR gain increases at progression on ADT+ENZ regardless of the treatment setting. The impact of early use of ENZ/AAP on the detection of copy number aberrations, especially homozygous deletions, in other prostate cancer-related genes in plasma requires further investigation.

Citation Format: Gianmarco Leone, Francesco Orlando, Suparna Thakali, Sharanpreet Lall, Daniel Wetterskog, Anna Wingate, Noel W. Clarke, Nicholas D. James, Francesca Demichelis, Gerhardt Attard. Plasma androgen receptor (AR) copy number gain at progression in patients randomized in the STAMPEDE phase 3 abiraterone acetate, prednisolone (AAP) and enzalutamide (ENZ) trial: An ancillary biomarker study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 973.