Abstract 3841: Prognostic significance of PI3K-AKT pathway alterations identified by ctDNA sequencing in metastatic castration-resistant prostate cancer

Abstract Background: Aberrations in the PI3K-AKT pathway are key drivers of castration-resistant prostate cancer (CRPC), promoting therapeutic resistance and poor outcomes. As these alterations become increasingly relevant for targeted therapy, defining their prevalence and prognostic value through noninvasive genomic profiling is essential. We therefore assessed PI3K-AKT pathway alterations in metastatic CRPC using high-depth circulating tumor DNA (ctDNA) sequencing. Methods: A total of 127 patients with mCRPC underwent high-depth ctDNA sequencing using the AlphaLiquid®100 assay, covering PI3K-AKT pathway genes and homologous recombination repair genes. Paired PBMCs were available for 87 patients, while 40 underwent plasma-only profiling with our machine learning-based model applied to remove CHIP-related variants. For orthogonal comparison, PTEN immunohistochemistry (IHC) was performed using a mouse monoclonal antibody (clone 6H2.1, M3627, Dako). ctDNA metrics were evaluated with baseline clinical data and overall survival (OS), and outcomes were compared between PI3K-AKT-altered and wild-type disease. Results: Among 127 patients (median age, 66 years), high-grade tumors were common (Gleason ≥8 in 71.7%), with advanced clinical T3-T4 disease in 78.7%, nodal involvement in 59.8%, and synchronous metastasis in 58.3%. The median PSA at diagnosis was 53.7 ng/mL, and 33.1% had undergone prior surgery. Somatic ctDNA alterations were detected in 91.3% (median 3; range 0-47), with substantial heterogeneity in variant types and tumor fractions (median 0.98%; range 0.05-79.6%). PTEN pathogenic mutations were found in 9.4% and activating PIK3CA and AKT1 alterations in 7.9% and 0.8%. PTEN loss by IHC was present in 46.9% (30/64), with the overall 54.7% concordance with PTEN pathogenic mutations in cfDNA. Baseline clinical features were similar between PI3K-AKT-altered and wild-type tumors, except for higher T3-T4 disease (p<0.001). PTEN IHC loss was not associated with overall survival (OS) in the full cohort (HR 1.47, 95% CI 0.36-6.06) or in synchronous metastasis (HR 2.41, 95% CI 0.37-15.55). In contrast, PTEN pathogenic mutations detected via ctDNA were associated with inferior OS in the overall cohort (HR 3.19, 95% CI 0.90-11.37; p=0.073) and showed significant impact in synchronous metastasis (HR 4.91, 95% CI 1.29-18.67; p=0.019). A similar trend was seen for PIK3CA and/or AKT1 mutations (HR 3.25, 95% CI 0.95-11.16; p=0.061). Conclusion: PTEN pathogenic mutations identified through ctDNA sequencing were strongly associated with worse overall survival in mCRPC and outperformed PTEN IHC in prognostic value. These results underscore the utility of ctDNA profiling for detecting PI3K-AKT pathway alterations and its potential to inform targeted treatment strategies in mCRPC. Citation Format: DongSoo Kyung, Yongjun Cha, Chang Wook Jeong, Seung-hwan Jeong, Chel Lee, Won Yeong Ko, Jee-Soo Lee, Moon-Woo Seong, Cheol Kwak, Tae-You Kim. Prognostic significance of PI3K-AKT pathway alterations identified by ctDNA sequencing in metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3841.