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Transcriptomic and Clinical Heterogeneity of Metastatic Disease Timing Within Metastatic Castration-Sensitive Prostate Cancer - Beyond the Abstract

Among men with metastatic castration-sensitive prostate cancer (mCSPC), efforts have aimed to identify those at highest risk of disease progression and benefit from early treatment intensification. Timing of metastatic disease has previously demonstrated valuable prognostic information with synchronous metastatic disease associated with worse outcomes. Although synchronous disease is associated with worse outcomes, the mechanisms underlying respective responsiveness to standard of care therapies are poorly understood. Tumor transcriptomics may provide critical information to better understand this more aggressive phenotype and allow for greater therapeutic precision. Therefore, we aimed to evaluate for differences in transcriptomic profiles relative to timing of metastatic disease and associate it with clinical outcomes and response to therapy.

We performed an international multi-institutional retrospective review of men enrolled in the CHAARTED, STOMP, and ORIOLE clinical trials with mCSPC who underwent RNA expression profiling evaluation of their primary tumor via either RNA sequencing (RNAseq) or microarray. Gene expression signatures for Androgen Receptor Activity (AR-A) and Hallmark Androgen response (HAR) were calculated for all patients. Patients were stratified according to timing (Synchronous: presence of metastatic disease at first diagnosis of prostate cancer, Metachronous: metastatic recurrence following definitive prostate treatment) and volume of disease (high vs low) per CHAARTED criteria. Initial management was classified as either monotherapy (ADT alone for synchronous; ADT alone or Metastasis Directed Therapy alone for metachronous) or Androgen Receptor (AR) + non-AR combination therapy (ADT+Docetaxel or ADT+ prostate/metastasis directed radiotherapy). Our primary endpoint of interest was to identify differences in transcriptomic profiles between timing of disease. Secondary analyses included determining clinical and transcriptomic variables associated with overall survival (OS) from time of diagnosis of metastasis. Subset analyses evaluated response to therapy and clinical and transcriptomic differences accounting for both timing and volume of disease.

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 expression for AR-A (11.78 vs 12.64, p<0.01) and 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) as significantly associated with OS. 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). When evaluating for timing and volume of disease, among patients with high-volume disease, there were no significant differences between timing of disease in 3-yr OS (46% vs 54%, p=0.67). Conversely, among patients with low-volume disease, metachronous metastasis was associated with significantly better 3-yr OS (94% vs 76%, p<0.01). Comparing transcriptomic differences demonstrated synchronous disease has a lower HAR in low- (p=0.03) but not high- (p=0.35) volume disease.

Here we report on the biologic and clinical differences between two distinct groups of mCSPC based on timing of metastasis. Specifically, we have identified synchronous mCPSC is associated with a lower androgen response transcriptomic profile. Further we have demonstrated that while synchronous metastatic disease experiences a more aggressive clinical course on univariable analysis, consistent with prior reports, when accounting for disease volume and androgen response biology, timing of metastatic disease alone no longer appears to be as strong of a prognostic indicator. Further, we have demonstrated patients with synchronous (but not metachronous) disease may experience improved outcomes with AR + non-AR combination therapy, likely a result of their lower androgen response profile.

Written by: P. A. Sutera,1 A. C. Shetty,2 A. Hakansson,3 K. Van der Eecken,4 Y. Song,2 Y. Liu,3 J. Chang,5 V. Fonteyne,6 A. A. Mendes,7 N. Lumen,6 L. Delrue,8 S. Verbeke,4 K. De Man,9 Z. Rana,5 T. Hodges,2 A. Hamid,10 N. Roberts,11 D. Y. Song,12 K. Pienta,13 A. E. Ross,14 F. Feng,15 S. Joniau,16 D. Spratt,17 S. Gillessen,18 G. Attard,19 N. D. James,20 T. Lotan,7 E. Davicioni,3 C. Sweeney,21 P. T. Tran,22 M. P. Deek,23 P. Ost24

  1. Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, USA.
  2. Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, USA; Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, USA.
  3. Veracyte, San Diego, USA.
  4. Department of Pathology, Ghent University Hospital, Ghent, Belgium.
  5. Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, USA.
  6. Department of Radiation Oncology, Ghent University Hospital, Ghent, Belgium.
  7. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, USA.
  8. Department of Radiology, Ghent University Hospital, Ghent, Belgium.
  9. Department of Nuclear Medicine, Ghent University Hospital, Ghent, Belgium.
  10. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA.
  11. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, USA.
  12. Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, USA; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA; James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, USA.
  13. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA; James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, USA.
  14. Department of Urology, Northwestern University, Chicago, USA.
  15. Department of Medicine, UCSF, San Francisco, USA; Department of Urology, UCSF, San Francisco, USA; Department of Radiation Oncology, UCSF, San Francisco, USA.
  16. Department of Urology, Catholic University Leuven, Leuven, Belgium.
  17. Department of Radiation Oncology, University Hospitals, Cleveland, USA.
  18. Istituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland.
  19. Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
  20. The Royal Marsden Hospital NHS Foundation Trust, London, UK; The Institute of Cancer Research, London, UK.
  21. South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, Australia.
  22. Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, USA; Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, USA.
  23. Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, USA. 
  24. Department of Radiation Oncology, Iridium Network, Antwerp, Belgium; Department of Human Structure and Repair, Ghent University, Ghent, Belgium. 

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