Abstract B057: Pathway-Level Molecular Evolution and Composite Molecular Genomic Risk following Lu-177-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer

Abstract As PSMA-targeted radioligand therapy (RLT) becomes an established option in patients with metastatic castration-resistant prostate cancer (mCRPC), a major clinical challenge is understanding why resistance emerges, so clinicians can optimally sequence the growing range of post-RLT treatments, including antibody-drug conjugates, next-generation RLTs and T-cell-redirecting agents. To explore molecular drivers of resistance, we analyzed real-world clinico-genomic data from 305 men treated with Lu-177-PSMA-617. Each patient had Guardant Health (GH) liquid-biopsy profiling integrated within ConcertAI’s Prostate Translational360™ dataset, linking longitudinal electronic health records, claims, and molecular results. We examined associations between disease patterns, genomic profiles, and timing of molecular testing before therapy, and evaluated post-treatment ctDNA evolution in a serially tested subset. Baseline genomic profiles from samples drawn prior to Lu-177-PSMA-617 initiation, showed that AR amplification (24%), PTEN loss (6%), and HRR alterations (18%, defined as HRR genes consistently reported across GH assays) were the most frequent molecular events (Muniz et. al., J Clin Oncol, 2024). Patients with AR or PTEN alterations had shorter median progression-free survival (PFS, HR 1.85, 95% CI 1.39-2.45, p < 0.0001) and overall survival (OS, HR 2.06, 95% CI 1.49-2.85, p < 0.00001) compared with patients without alterations. When stratified by composite molecular risk, outcomes declined stepwise with increasing pathway alterations (median PFS 8.5, 6.5, and 4.8 months for patients with 0, 1 or >=2 pathway alterations [AR, PTEN, HRR, FGFR/EGFR/CTNNB1, respectively]). Timing of pre-treatment molecular testing relative to RLT initiation did not meaningfully change baseline TMB values or the proportion of patients with HRR alterations, suggesting molecular stability before therapy. Among 53 patients with serial ctDNA testing, post-treatment evolution revealed post-treatment molecular changes were detected despite temporary clinical benefit. Maximum variant allele fraction (mVAF) increased modestly after RLT, and new or expanded AR (21%), PTEN (24%), TP53 (41%), and FGFR/EGFR (11%) alterations emerged. These findings indicate convergent activation of AR, PTEN, HRR, and alternative signaling pathways as mechanisms of acquired resistance under RLT pressure. Together, these observations show that molecular complexity and pathway co-alterations at baseline and post-therapy are strongly associated with worse outcomes to PSMA-RLT. Incorporating serial ctDNA profiling and pathway based composite risk models could refine patient selection and guide development of combination strategies as RLT moves into earlier treatment settings. Citation Format: Ruth A. Pe Benito, Sahil KM. Mohammed, Brandon Nathasingh, Jiemin Liao, Yekaterina Khotskaya, Sowmya Jairam, Sheenu Chandwani. Pathway-Level Molecular Evolution and Composite Molecular Genomic Risk following Lu-177-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer [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 B057.