Molecular features of exceptional response to neoadjuvant anti-androgen therapy in high-risk localized prostate cancer

High-risk localized prostate cancer (HRLPC) is associated with a substantial risk of recurrence and disease mortality. Recent clinical trials have shown that intensifying anti-androgen therapies administered before prostatectomy can induce pathologic complete responses or minimal residual disease, called exceptional response, although the molecular determinants of these clinical outcomes are largely unknown. Here, we perform whole-exome and transcriptome sequencing on pre-treatment multi-regional tumor biopsies from exceptional responders (ERs) and non-responders (NRs, pathologic T3 or lymph node-positive disease) to intensive neoadjuvant anti-androgen therapies. Clonal SPOP mutation and SPOPL copy-number loss are exclusively observed in ERs, while clonal TP53 mutation and PTEN copy-number loss are exclusively observed in NRs. Transcriptional programs involving androgen signaling and TGF-β signaling are enriched in ERs and NRs, respectively. These findings may guide prospective validation studies of these molecular features in large HRLPC clinical cohorts treated with neoadjuvant anti-androgens to improve patient stratification. [Display omitted] •SPOP mutation and SPOPL copy-number loss are exclusive to exceptional responders•Androgen signaling expression programs are enriched in exceptional responders•Non-responders harbor TP53 mutation, PTEN loss, and TGF-β transcriptional programs•Phylogenetic analysis reveals that key response mediators are truncal in nature Leveraging pretreatment multi-regional biopsies from patients with high-risk localized prostate cancer, Tewari et al. identify whole-exome and transcriptional features associated with exceptional response and non-response to neoadjuvant androgen pathway inhibition. These results may have major stratification and treatment implications for this large patient population.