Abstract A020: Utilization of liquid biopsy in metastatic castrate resistant prostate cancer (mCRPC): patient characteristics, treatment selection, and mutational status

Abstract Background: Targeted therapies for metastatic castrate resistant prostate cancer (mCRPC) increasingly rely on genomic profiling, including liquid biopsy of circulating tumor DNA (ctDNA), to enable precision treatment. Integrating multi-patient ctDNA-derived molecular insights with deeply abstracted real-world clinical data offers the opportunity to improve biomarker identification, patient selection, and reverse translation. Methods: Data were obtained from the ConcertAI Translational360™ dataset. Specifically, mCRPC patients with overlapping liquid biopsy ctDNA testing results from Guardant Health were identified. Patient characteristics, timing of ctDNA testing, prior treatments, and the prevalence of specific mutations were described. Using all mCRPC patients in the cohort, treatment-agnostic univariate Cox proportional hazards models were trained on the 3 most frequent mutations and on maximum allele frequency. Results: Among 1,167 mCRPC patients from primarily community oncology practices (78.3%) with at least one ctDNA test, median age at mCRPC diagnosis was 68 (IQR: 60, 80) years; 72% of patients were white, 17% were Black, and 2% were Asian. The first ctDNA test occurred a median 2.2 years (IQR: 0.9, 5.0) after patients became castrate-resistant. For 200 patients with longitudinal testing, a median of 1.2 years (IQR: 0.6, 1.9) elapsed between the first and last ctDNA test. Treatment patterns shifted after ctDNA testing. Specifically, PARP inhibitor therapy increased from 5% of patients before ctDNA testing to 20% after ctDNA testing. Longitudinal changes in mutations were associated with treatment. Among patients who initiated PARP inhibitor therapy between their first and last ctDNA tests (n=22; median 5 prior lines of therapy (IQR: 3.2, 7.8)), the increase in mutation count was greater than in other patients: median increase of 8.5 unique mutations (IQR 5.0, 15.5) vs. 3 (IQR 0, 7.2), Wilcoxon rank-sum p<0.001. Forty-one distinct ctDNA genomic alterations were detected in 1% or more of mCRPC patients including single nucleotide variants (SNV), indel, splice, and copy number variants (CNV). The three most frequent genomic alterations — AR amplification (29%), EGFR amplification (11%), and AR p.L702H (11%) — were each associated with worse rwOS in univariate Cox proportional hazards models (p< 0.001; C-index: AR amplification = 0.61; EGFR amplification = 0.54; AR p.L702H = 0.53). By comparison, maximum allele frequency (MAF), a measure of total ctDNA burden, had greater discrimination for rwOS than the individual mutations (C-index = 0.64; hazard ratio per 1 SD increase = 1.41; 95% CI: 1.32-1.50). Conclusions: In this real world cohort of mCRPC patients with at least one ctDNA test, a shift toward targeted therapies occurred after the first ctDNA test and acquired mutations were apparent at the time of the subsequent ctDNA test. Both individual mutations and MAF were associated with rwOS, highlighting the opportunity to utilize real world datasets for translational research and investigation of novel biomarkers. Citation Format: Matthew S. Hall, Kathryn L. Penney, Jiemin Liao, Sean Gordon, Brooke Overstreet, Michael Rossi, Jennifer R. Rider. Utilization of liquid biopsy in metastatic castrate resistant prostate cancer (mCRPC): patient characteristics, treatment selection, and mutational status [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr A020.