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Comprehensive genomic profiling of treatment resistant metastatic castrate sensitive prostate cancer reveals high frequency of potential therapeutic targets

Published:February 21, 2022DOI:https://doi.org/10.1016/j.clgc.2022.02.004

      Clinical Practice Points

      • Comprehensive genomic profiling (CGP) remains under-utilized in the setting of metastatic castrate sensitive prostate cancer (mCSPC).
      • Given the potential clinical benefit there is a clear unmet need in this stage of disease, but no targetable approach in mCSPC currently exist.
      • The presence of a pathogenic and/or likely pathogenic de novo variant was found in more than half of patients and provides biological basis for evaluating intensification strategies of systemic therapy.
      • While clinical features such as volume of disease do not reliably predict outcomes, our data suggest the presence of specific variants including AR and DDR might provide additional important prognostic information.
      • This data supports the potential role of CGP in biomarker development and future clinical trials design for patients with mCSPC.

      Abstract

      INTRODUCTION

      While comprehensive genomic profiling (CGP) data is becoming increasingly important in the management of prostate cancer, it remains under-utilized in the setting of metastatic castrate sensitive prostate cancer (mCSPC). We aimed to explore the feasibility and potential utility of CGP in mCSPC.

      PATIENTS AND METHODS

      Patients with mCSPC were prospectively recruited at the Princess Margaret Cancer Centre to the OCTANE trial (NCT02906943). The objective was to assess the feasibility of profiling archival standard diagnostic tumor tissue using next generation sequencing with a custom hybridization capture DNA-based or a targeted DNA/RNA amplicon-based panel. Clinical data were extracted from electronic health records.

      RESULTS

      Among 39 mCSPC patients enrolled, 21 (54%) had sufficient archival tissue for CGP. Most had high volume (71%) or de novo (71%) mCSPC, with the majority being androgen deprivation therapy (ADT) naïve. In total, 62% of patients had a pathogenic and/or a likely pathogenic variant, many of which involved DNA damage repair (DDR, 19%), cell cycle (24%), and Androgen Receptor (AR, 10%) pathways. After median follow-up of 32.1 months, 18 of 21 patients progressed, with median time to mCRPC of 14.3 months (95% CI 10.2-21.0). Patients with AR and DDR variants seemed to have shorter median time to mCRPC; 10.2 (95% CI 9.50-NR) and 10.3 months (95% CI 6.6-14.3) respectively.

      CONCLUSION

      In this cohort of highly treatment resistant mCSPC, most of which were ADT-naïve, CGP using archival tumor tissue was feasible for over half of patients, and 62% of patients profiled had a pathogenic and/or a likely pathogenic variant. The presence of de novo variants provides biological basis for evaluating intensification strategies of systemic therapy. This highlights the potential role of routine CGP in biomarker development and clinical trial design in the setting of mCSPC.

      Keywords

      Abbreviations:

      AACR (American Association for Cancer Research), ADT (androgen deprivation therapy), AR (androgen receptor), ARAT (androgen receptor axis targeted agents), ASCO (American Society of Clinical Oncology), CGP (comprehensive genomic profiling), DDR (DNA damage repair), ECOG (Eastern Cooperative Oncology Group), ESMO (European Society for Medical Oncology), mCRPC (metastatic castrate resistant prostate cancer), mCSPC (metastatic castrate sensitive prostate cancer), NGS (Next-generation sequencing), OCTANE (Ontario-wide Cancer TArgeted Nucleic acid Evaluation trial), OS (overall survival), PM (Princess Margaret Cancer Center), PSA (prostate-specific antigen), VUS (variant of unknown significance)
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