Standard of care management for synchronous metastatic castration-sensitive prostate cancer (mCSPC) includes androgen deprivation therapy with a second-generation antiandrogen therapy and/or docetaxel. Recently, randomized data have demonstrated that prostate-directed therapy (PDT) is associated with an improvement in overall survival (OS) among patients with low-volume metastatic disease. Tumor genomics represents an additional dimension to define the clinical trajectory of patients with mCSPC.
To evaluate a high-risk (HiRi) genomic signature to predict the benefit from PDT.
We performed a single-institution retrospective review of men with synchronous low-volume mCSPC who underwent DNA panel sequencing of their tumor. Patients were classified according to the presence of HiRi mutation including pathogenic mutations in TP53, ATM, BRCA1, BRCA2, or Rb1.
The primary endpoint was to determine the effect of PDT on OS in patients with and without a HiRi mutation. A survival analysis was performed with the Kaplan-Meier method compared with log-rank test and multivariable Cox regression. The interaction between HiRi mutation and PDT was evaluated.
A total of 101 patients with synchronous low-volume CSPC were included with a median follow-up of 44 mo. Approximately half of patients were found to have a HiRi pathogenic mutation (49%). Patients with HiRi mutations demonstrated median OS of 73 versus 66.8 mo (p = 0.3) for no PDT versus PDT. Conversely, patients without a HiRi mutation demonstrated a significant improvement in OS of 60 versus 105.3 mo (p < 0.001) for no PDT versus PDT. The p value for interaction for OS between PDT and HiRi mutation was statistically significant (p < 0.001). Limitations include the retrospective nature of the study.
Here, we have identified a HiRi genomic biomarker that appears predictive for the lack of benefit from PDT in men with synchronous low-volume mCSPC. Further work validating these results is warranted.
In this report, we evaluated a high-risk genomic biomarker to predict the benefit from prostate-directed therapy for men with synchronous low-volume metastatic castration-sensitive prostate cancer. We found that men without a high-risk mutation appear to experience a greater clinical benefit from prostate-directed therapy than those with a high-risk mutation.
European urology oncology. 2023 Aug 08 [Epub ahead of print]
Philip Sutera, Amol C Shetty, Yang Song, Theresa Hodges, Tung Hoang, Zaker Rana, Kenneth Pienta, Felix Feng, Daniel Y Song, Theodore DeWeese, Silke Gillessen, Christopher Sweeney, Nicholas James, Gerhardt Attard, Matthew Deek, Phuoc T Tran
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA., Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biochemistry and Molecular Biology, Johns Hopkins University, School of Public Health, Baltimore, MD, USA., Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA., Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA., Departments of Medicine, Urology and Radiation Oncology, UCSF, San Francisco, CA, USA., Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA., Istituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland., South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, Australia., The Royal Marsden Hospital NHS Foundation Trust and The Institute of Cancer Research, London, UK., Division of Molecular Pathology, The Institute of Cancer Research, London, UK., Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA., Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address: .