Clinical Context Shapes the Relationship between Genomic Alterations and Response to AR Inhibitors and Chemotherapy in Metastatic Prostate Cancer.

PURPOSE: Many preclinical hypotheses, including reciprocal feedback activation between the androgen receptor (AR)-PI3K pathway in PTEN loss and AR signaling inhibitor-induced "BRCAness" regardless of BRCA1/2 status, have struggled to translate into clinical benefit for patients with metastatic prostate cancer. This gap in translatability, particularly in metastatic castration-resistant prostate cancer (mCRPC), may stem from a limited understanding of prostate cancer evolution. A key challenge is the correlation between early-stage tumor genetics and mCRPC. By examining clinical, genomic, and molecular changes over time, we aimed to refine clinical trial design. EXPERIMENTAL DESIGN: Using a comprehensive dataset from electronic health records with genomic profiling, a shift in the prognostic value of biomarkers from metastatic hormone-sensitive prostate cancer (mHSPC) to mCRPC was observed. Additionally, genomic and transcriptomic analyses of primary tumors from the IPATential150 trial and mCRPC samples from the Stand Up To Cancer cohort examined the changing AR-PI3K signaling correlation. RESULTS: PI3K-AKT pathway alterations lost their prognostic significance in later stages. Although AR and PI3K-AKT signaling were inversely correlated in primary tumors, this relationship was disrupted in mCRPC, independent of PIK3CA/AKT1/PTEN status. We identified broad transcriptional rewiring associated with AR signaling, increasing tumor heterogeneity. Improving the understanding of early-stage disease, we identified a high-risk mHSPC subset enriched for AR alterations. Additionally, in a subset of patients, AR ligand-binding domain mutations preceded amplification, potentially leading to preferential amplification of the mutant AR form. CONCLUSIONS: Our findings underscore the dynamic nature of prostate tumor biology and emphasize the need for translational research to validate preclinical hypotheses in clinically relevant settings, ultimately improving trial design and therapeutic strategies.