Abstract 5614: Genomic aberrations in circulating tumor DNA (ctDNA) and clinical outcomes from [177Lu]Lu-PSMA-617 in metastatic castration-resistant prostate cancer (mCRPC)
Authors: Fettke Heidi , Kostos Louise , Buteau James , Steen Jason A. , Medhurst Elizabeth , Haskali Mo B. , Murphy Declan , Docanto Maria , Bukczynska Patricia , Ng Nicole , Sandhu Shahneen , Foroughi Siavash , Furic Luc , Nguyen-Dumont Tu , Hofman Michael S. , Azad Arun A. 
Published: April 2023

Abstract
[177Lu]Lu-PSMA-617 (LuPSMA) radionuclide therapy improves overall survival in mCRPC, and was recently approved by the FDA. Nevertheless, owing to the heterogeneous nature of mCRPC, responses to LuPSMA therapy can be variable, and resistance is inevitable. As a result, biomarkers linked to clinical outcome with LuPSMA are urgently required. Using plasma ctDNA, we present the first comprehensive genomic analysis of a prospective cohort of mCRPC patients treated with LuPSMA. Targeted sequencing of 78 genes was performed on baseline plasma and matched buffy coat samples from patients who received LuPSMA on a prospective registry (NCT04769817). Reportable alterations included pathogenic single-nucleotide and copy number variants. Association between alterations and clinical outcomes were assessed using log rank, cox proportional, and chi-squared analyses. Clinical data collected included PSA decline by ≥50% or ≥90% (PSA50-response rate, PSA50-RR; and PSA90-RR), and PSA progression free survival (PSA-PFS). In total, 100 patients (median age 74 years, range 52-90) received a median of 4 cycles of LuPSMA. 83 patients had detectable ctDNA (median fraction 17%, range 0-94%) with PSA50-RR 50%, PSA90-RR 22%, and a median PSA-PFS of 7.2 months. Patients with an AR or PTEN aberration had significantly shorter PSA-PFS (HR 0.50 and 0.59, respectively; Table), as did patients with any PI3K pathway aberration (HR 0.56). Additionally, patients with a high ctDNA burden had significantly worse PSA-PFS (HR 0.42, Table). There were no significant differences in PSA-RR based on deleterious genomic changes. Our data reveal that aberrations in the AR and PI3K pathways, along with pre-treatment ctDNA fraction, whilst not linked to PSA-RR, are prognostic for durability of response to LuPSMA. If validated in larger cohorts, these data will help to optimise the use of LuPSMA by improving patient selection and enhancing prognostication.
Analysis of clinical endpoints based on deleterious genomic changes in ctDNA n PSA-PFS (months, wild type (wt) vs variant) PSA-PFS HR (95% CI, wt vs variant) PSA50-RR (wt vs variant) PSA90-RR (wt vs variant) Exonic AR variants 47 8.1 vs 6.0 p=0.005 0.50 (0.30-0.83) p=0.006 58% vs 40% p=0.09 23% vs 21% p=0.8 Any AR variant (intronic and upstream enhancer regions included) 49 8.1 vs 6.0 p=0.007 0.53 (0.31-0.83) p=0.008 60% vs 41% p=0.09 24% vs 20% p=0.7 RB1 variant 19 7.9 vs 5.5 p=0.2 0.67 (0.39-1.2) p=0.2 51% vs 42% p=0.5 23% vs 21% p=0.9 PTEN variant 25 7.8 vs 6.3 p=0.04 0.59 (0.36-1.00) p=0.045 50% vs 48% p=0.9 22% vs 24% p=0.8 TP53 variant 43 8.1 vs 6.7 p=0.1 0.67 (0.42-1.1) p=0.1 52% vs 47% p=0.6 20% vs 26% p=0.5 BRCA2 variant 10 7.7 vs 5.1 p=0.2 0.63 (0.29-1.30) p=0.2 51% vs 40% p=0.7 20% vs 40% p=0.1 PIK3CA variant 8 7.7 vs 4.1 p=0.08 0.48 (0.20-1.1) p=0.09 52% vs 13% p=0.06 23% vs 13% p=0.5 PI3K pathway variant 35 7.8 vs 5.5 p= 0.02 0.56 (0.34-0.91) p=0.02 55% vs 40% p=0.2 22% vs 23% p=0.9 ctDNA fraction ≥20% 43 9.0 vs 5.1 p=0.0002 0.42 (0.26-0.67) p&lt;0.001 55% vs 42% p=0.2 21% vs 23% p=0.8
Citation Format: Heidi Fettke, Louise Kostos, James Buteau, Jason A. Steen, Elizabeth Medhurst, Mo B. Haskali, Declan Murphy, Maria Docanto, Patricia Bukczynska, Nicole Ng, Shahneen Sandhu, Siavash Foroughi, Luc Furic, Tu Nguyen-Dumont, Michael S. Hofman, Arun A. Azad. Genomic aberrations in circulating tumor DNA (ctDNA) and clinical outcomes from [177Lu]Lu-PSMA-617 in metastatic castration-resistant prostate cancer (mCRPC). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5614.