1839P Circulating tumor DNA (ctDNA) low pass whole genome sequencing (lpWGS) studies identify genomic alterations associating with taxane outcomes in prospective phase III taxane trials for metastatic castration resistant prostate cancer (mCRPC) sufferers

Taxanes are a standard of care for mCRPC and no clinically qualified biomarker has as yet been identified for these. lpWGS of ctDNA identifies copy-number alterations (CNAs) common in advanced PC and may identify mCRPC subtypes most responsive to taxane therapy. ctDNA lpWGS identified genomic aberrations associating with treatment outcomes for participants of three prospective Phase III taxane trials (CARD, FIRSTANA and PROSELICA). Genomic alterations in ctDNA were assessed for correlations with overall survival (OS), radiologic progression-free survival (rPFS), and PSA or radiological response rate (RR) using univariable and multivariable mixed-effect regression models to study CNAs significantly associated with differential outcomes of prognostic and predictive significance. Genome-wide analysis identified several genomic alterations that were significantly associated with worse OS in these taxane-treated individuals including chromosome 2p, 9p and 13 deletions. Several CNAs remained independently significant (Chr2p HR 2.89, p<0.01; Chr9p HR 2.9, p<0.01, Chr12q HR 2.06, p<0.01) following multivariable analyses incorporating PSA, LDH, haemoglobin, the presence of visceral metastases and tumour fraction estimate. Conversely, several loci including 20q and X gain, and 15q loss associated with worse rPFS and OS on the CARD control arm (abiraterone post enzalutamide or vice versa) but exhibited no difference in rPFS and OS on the cabazitaxel-treated arm. To confirm these results, we explored the association of CNAs with response rate in the FIRSTANA and PROSELICA study cohorts and found that several loci were associated with higher taxane-response rates in biomarker-positive individuals. These ctDNA lpWGS studies in mCRPC patients have identified genomic alterations in ctDNA of prognostic and predictive significance in men suffering from mCRPC receiving taxane treatment. Prospective validation will facilitate treatment selection and identify potential clinical biomarkers associated with outcome.