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

Objective: Many preclinical hypotheses, including reciprocal feedback activation between AR-PI3K pathway in PTEN loss and ASI-induced "BRCAness" regardless of BRCA1/2 status, have struggled to translate into clinical benefit for metastatic prostate cancer patients. This gap in translatability, particularly in mCRPC, may stem from a limited understanding of prostate cancer evolution. A key challenge is how early-stage tumor genetics correlate with mCRPC. By examining clinical, genomic, and molecular changes over time, we aim to refine clinical trial design.

Methods: Using a comprehensive dataset from electronic health records (EHR) with genomic profiling, we observed a shift in the prognostic value of biomarkers from mHSPC to mCRPC. Additionally, genomic and transcriptomic analyses of primary tumors from the IPATential150 trial and mCRPC samples from the SU2C cohort examined the changing AR-PI3K signaling correlation.

Results: PI3K-AKT pathway alterations lost their prognostic significance in later stages. While 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 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.