1809P Dynamics of Plasma Tumour DNA and Copy Number Alterations in Advanced Metastatic Castration-Resistant Prostate Cancer (mcrpc) Patients Treated with Cabazitaxel: A Prospective Biomarker Trial

Liquid biopsies enable non-invasive detection of circulating biomarkers for disease monitoring and treatment resistance interrogation. We aimed to study circulating tumour DNA (ctDNA) to identify biomarkers of response from cabazitaxel in mCRPC patients (pts). mCRPC pts (N=104) candidate for cabazitaxel treatment were enrolled in a prospective biomarker multi-centre trial (NCT03381326). Plasma was collected at baseline (BL), prior to cycle 3/4 (C3) and at progression (PD) and analyzed using a bespoke prostate cancer capture panel (PCF_SELECT, Orlando et al, NAR Cancer 2022 ). ctDNA fraction was calculated using allelic imbalance-based quantitation of the most abundant hemi-deletions. Primary outcome measures were overall survival (OS) and progression-free survival (PFS). Medians and [IQR] or 95% CI are reported. 97 pts were evaluable. ctDNA fraction was significantly lower at C3 (0.05 [0.04-0.38]) versus (vs) BL (0.40 [0.25-0.51]) and PD (0.41 [0.27-0.59] p=0.003). ctDNA dynamics strongly associated with outcome: pts with any increase in ctDNA fraction at C3 vs BL (N=20/65) had the worst outcome (PFS 2.6 months (mo), 95% CI 2.2-3.1; OS 7.5 mo, 95% CI 5.2-9.9) whilst pts who had a decrease at C3 (N=27/65) had a similar PFS (6.7 mo, 95% CI (5.1-8.2) but worse OS (15.7 mo, 95% CI 11.4-21.4) compared to undetectable ctDNA at both BL and C3 (N=18/65; PFS 8.2 mo, 95% CI 4.9-11.2; OS 29.9 mo, 95% CI 22.5-39.6). Median ctDNA fraction was significantly higher (0.50 [0.38-0.64]) in early progressors (at or before C3) vs late (after 4 cycles; 0.32 [0.17-0.55] p=0.03). In samples with detectable ctDNA, there was overall a consistent prevalence of gene copy number alterations at BL and PD; however, a significantly higher prevalence of gains of PIK3CB (chr3q22; 55 vs 29%, p=0.01) and AKT1 (chr14q32; 31 vs 14%, p=0.048) was observed in PD samples compared to BL. ctDNA dynamics associated with cabazitaxel outcomes and identified pts progressing early. An enrichment in PIK3CB and AKT1 gains was observed upon cabazitaxel progression.