Abstract
Abstract Though often curable, high-risk localized prostate cancer has a significant chance of recurring either biochemically, locoregionally, or as distant metastatic disease. Efforts are ongoing to evaluate neoadjuvant strategies to reduce this risk of recurrence. Our recent clinical trial showed that intense androgen deprivation with enzalutamide, leuprolide, and abiraterone acetate with prednisone (ELAP) induced pathologic complete response or minimal residual disease (< 5mm) at prostatectomy in 30% of trial patients (exceptional responders). Though previous studies have identified the pathological and genomic heterogeneity of localized prostate cancer, the impact of this heterogeneity on treatment response is unknown. To address this, we performed multi-region whole-exome and whole transcriptome sequencing on tumor and normal prostate regions from 15 exceptional responders and 15 non-responders treated with intensive androgen deprivation prior to prostatectomy. Overall, we found heterogeneous somatic mutation patterns with strong evidence of intra-tumoral heterogeneity and no association between mutation frequency and response. However, when subsetting patients by treatment response, SPOP mutation and SPOPL copy number loss were only observed in exceptional responders, while TP53 mutations were only observed in the non-responders. We observed expression signature differences between exceptional responders and non-responders, with exceptional responders having an increase in Androgen Receptor related gene signatures. Though underpowered to identify statistically significant genomic correlates of response to neoadjuvant ADT, our findings may inform future studies to identify clinically relevant features of high-risk localized prostate cancers to stratify therapies to reduce the risk of disease recurrence. Citation Format: Alok Tewari, Alexander T. Cheung, Jake Conway, Jihye Park, Stephanie Wankowicz, Rosina T. Lis, Zhenwei Zhang, Saud AlDubayan, Rana R. McKay, Mary-Ellen Taplin, Eliezer M. Van Allen. Molecular features of complete response to neoadjuvant anti-androgen therapy in high risk localized prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1316.
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