Transcriptomic heterogeneity of metastatic disease timing within metastatic castration-sensitive prostate cancer.

person Philip Sutera Johns Hopkins University, Baltimore, MD info_outline Philip Sutera, Amol Shetty, Alexander K. Hakansson, Kim Van der Eecken, Yang Song, Yang Liu, Valerie Fonteyne, Sofie Verbeke, Daniel Y. Song, Ashley Ross, Felix Y Feng, Silke Gillessen, Gerhardt Attard, Nicholas D. James, Tamara L. Lotan, Elai Davicioni, Christopher Sweeney, Phuoc T. Tran, Matthew Pierre Deek, Piet Ost

Authors person Philip Sutera Johns Hopkins University, Baltimore, MD info_outline Philip Sutera, Amol Shetty, Alexander K. Hakansson, Kim Van der Eecken, Yang Song, Yang Liu, Valerie Fonteyne, Sofie Verbeke, Daniel Y. Song, Ashley Ross, Felix Y Feng, Silke Gillessen, Gerhardt Attard, Nicholas D. James, Tamara L. Lotan, Elai Davicioni, Christopher Sweeney, Phuoc T. Tran, Matthew Pierre Deek, Piet Ost Organizations Johns Hopkins University, Baltimore, MD, University of Maryland, Baltimore, MD, Veracyte, Inc., Vancouver, BC, Canada, Ghent University Hospital, Ghent, Belgium, Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, Northwestern University Feinberg School of Medicine, Chicago, IL, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland, Institute of Cancer Research, University College, London, United Kingdom, Institute of Cancer Research, London, United Kingdom, Johns Hopkins University School of Medicine, Baltimore, MD, Veracyte, Inc., San Francisco, CA, South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, Australia, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, Ghent University, Ghent, Belgium Abstract Disclosures Research Funding No funding received None. Background: Metastatic castration-sensitive prostate cancer (mCSPC) is commonly partitioned into high- and low-volume subgroups which have demonstrated differential biology, prognosis, and response to therapy. Timing of metastasis has similarly demonstrated differences in clinical outcomes, however less is known about any potential underlying biologic differences between these disease states. Herein we aim to compare transcriptomic differences between synchronous and metachronous mCSPC and identify any differential responses to therapy. Methods: We performed an international multi-institutional retrospective review of men with mCSPC who completed RNA expression profiling evaluation of their primary tumor. Patients were stratified according to disease timing (synchronous vs metachronous). The primary endpoint was to identify differences in transcriptomic profiles between disease time. Median genomic scores between groups were compared with Mann-Whitney U test. Secondary analyses included determining clinical and transcriptomic variables associated with overall survival (OS) from time of metastasis. Survival analysis was performed with the Kaplan-Meier Method and Multivariable Cox regression. Results: 252 patients were included with a median follow-up of 39.6 months. Patients with synchronous disease experienced worse 5-yr OS (39% vs 79%, p<0.01) and demonstrated lower median Androgen Receptor Activity (AR-A) (11.78 vs 12.64, p<0.01) and Hallmark Androgen Response (HAR) (3.15 vs 3.32; p<0.01). Multivariable cox-regression identified only high-volume disease (HR=4.97, 95%CI 2.71-9.10; p<0.01) and HAR score (HR=0.51, 95%CI 0.28-0.88; p=0.02 significantly associated with OS. Finally, patients with synchronous (HR=0.47, 95%CI 0.30-0.72; <0.01) but not metachronous (HR=1.37, 95%CI 0.50-3.92; p=0.56) disease were found to have better OS with Androgen Receptor (AR) + non-AR combination therapy as compared to monotherapy (p value for interaction = 0.05). Conclusions: We have demonstrated a potential biologic difference between metastatic timing of mCSPC. Specifically, for patients with low volume disease, those with metachronous low volume disease have a more hormone dependent transcriptional profile and exhibit a better prognosis than synchronous low volume disease. Gene expression profiles between synchronous and metachronous disease values represent median (IQR). Synchronous Metachronous p- value HAR Entire cohort High-Volume Low-Volume AR-A Entire cohort High-Volume Low-Volume 3.15 (2.68-3.49) 3.16 (2.75-3.47) 3.10 (2.52-3.54) 11.78 (10.08-13.20) 11.99 (10.19-13.08) 11.30 (9.21-13.90) 3.32 (3.05-3.59) 3.26 (2.87-3.71) 3.32 (3.05-3.59) 12.64 (11.24-13.69) 12.06 (10.39-14.41) 12.65 (11.58-13.63) <0.01 0.35 0.02</p <0.01 0.59 0.07