Abstract A009: Clinical value of ctDNA tumor fraction (TF) and evolving genomic landscape across lines of therapy (LOTs) in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC)

Abstract Background Baseline comprehensive genomic profiling (CGP) testing inadequately captures genomic changes that can inform pt management as tumors evolve in later LOTs. In addition, the value of ctDNA TF as a biomarker to inform tissue reflex following negative liquid CGP in mCRPC remains unclear. Here, we explore the clinical impact of repeat CGP testing at later LOTs in mCRPC by describing the genomic landscape of pts with mCRPC and evaluating the clinical value of ctDNA TF to inform tissue reflex across LOTs. Methods CGP results from 381 and 493 mCRPC pts with tissue and liquid specimens, respectively, collected within +/- 45 days of starting 1st line (1L), 2nd line (2L), and 3rd line (3L) therapy were queried for actionable alterations (alts) in the following genes: AR, NTRK, PTEN, RB1, SPOP, TP53, and HRR genes (ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, MLH1, MRE11A, NBN, PALB2, RAD45L, RAD51B, RAD51C, RAD51D). Tumor mutational burden (tissue (t)TMB ≥ 10 muts/Mb and blood (b)TMB ≥ 16 muts/Mb) was also evaluated across LOTs. This study used the US-based deidentified Flatiron Health (FH)-Foundation Medicine Prostate Clinico-Genomic Database comprising of patients who received care within the FH network from January 2011 to December 2024. Results Actionable alts were detected in 83% (206/248) of tissue specimens at 1L, 95% (78/82) at 2L, and 96% (49/51) at 3L; and in liquid, 74% (151/205) at 1L, 84% (157/186) at 2L, and 88% (90/102) at 3L. Among these, AR alts (short variants and amplifications) showed distinct patterns across LOTs: in tissue, 22% (1L), 55% (2L), and 63% (3L); in liquid, 25% (1L), 37% (2L), and 51% (3L).TMB also varied in prevalence, with tTMB ≥ 10 muts/Mb observed in 6% (1L), 9% (2L), and 1% (3L), and bTMB ≥ 16 muts/Mb was seen in 3% (1L), 3% (2L), and 3% (3L) of pts. Among pts with liquid tissue pairs, irrespective of when tissue specimen was collected, positive percent agreement for short variants and rearrangements between liquid and tissue CGP when TF ≥ 1% was 100% (6/6; 1L), 86% (6/7; 2L), and 100% (5/5; 3L). Conclusion These findings highlight the value of repeat CGP at later LOTs in mCRPC. In addition, we find that liquid CGP plays a central role for patient management across mCRPC’s LOT and ctDNA TF can be utilized to determine whether to reflex to tissue CGP if not concurrently ordered with liquid CGP. Citation Format: Candice Francheska B. Tambaoan, Russell Madison, Julia C.F. Quintanilha, Ryon Graf, Jeffrey S. Ross, Jerry Mitchell, Amaya Gascó, Richard S.P. Huang. Clinical value of ctDNA tumor fraction (TF) and evolving genomic landscape across lines of therapy (LOTs) in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A009.