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Randomized phase II trial of neoadjuvant everolimus in patients with high-risk localized prostate cancer

  • PHASE II STUDIES
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Summary

Background Despite definitive local therapy, patients with high-risk prostate cancer have a significant risk for local and distant failure. To date, no systemic therapy given prior to surgery has been shown to improve outcomes. The phosphatidilinositol 3-kinase/AKT/mTOR pathway is commonly dysregulated in men with prostate cancer. We sought to determine the clinical efficacy and safety of the mTOR/TORC1 inhibitor everolimus in men with high-risk prostate cancer undergoing radical prostatectomy. Methods This is a randomized phase II study of everolimus at two different doses (5 and 10 mg daily) given orally for 8 weeks before radical prostatectomy in men with high-risk prostate cancer. The primary endpoint was the pathologic response (histologic P0, margin status, extraprostatic extension) and surgical outcomes. Secondary endpoints included changes in serum PSA level and treatment effects on levels of expression of mTOR, p4EBP1, pS6 and pAKT. Results Seventeen patients were enrolled: nine at 10 mg dose and eight at 5 mg dose. No pathologic complete responses were observed and the majority of patients (88%) had an increase in their PSA values leading to this study being terminated early due to lack of clinical efficacy. Treatment-related adverse events were similar to those previously reported with the use of everolimus in other solid tumors and no additional surgical complications were observed. A significant decrease in the expression of p4EBP1 was noted in prostatectomy samples following treatment. Conclusions Neoadjuvant everolimus given at 5 mg or 10 mg daily for 8 weeks prior to radical prostatectomy did not impact pathologic responses and surgical outcomes of patients with high-risk prostate cancer. Trial registration NCT00526591.

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Acknowledgements

This research was supported by the research infrastructure at the Cleveland Clinic and Case Comprehensive Cancer Center.

Funding

This trial was supported by a research grant provided by Novartis and paid to the institution.

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Authors and Affiliations

  1. University of California San Francisco, San Francisco, CA, USA

    Vadim S. Koshkin

  2. Instituto Valenciano Oncologia, Valencia, Spain

    Maria C. Mir

  3. Tulane University, New Orleans, LA, USA

    Pedro Barata

  4. Department of Solid Tumor Oncology and Urology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA

    Anita Gul, Ruby Gupta, Andrew J. Stephenson, Jihad Kaouk, Ryan Berglund, Eric A. Klein & Jorge A. Garcia

  5. University of Alabama at Birmingham, Birmingham, AL, USA

    Cristina Magi-Galluzzi

  6. University of Virginia, Charlottesville, VA, USA

    Robert Dreicer

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  1. Vadim S. Koshkin
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Correspondence to Jorge A. Garcia.

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All authors declare that they have no specific conflicts of interest related to this manuscript. Jorge A. Garcia received Research Funding - paid to institution: Novartis and GSK.

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All procedures performed in this study involving human participants were approved by the Cleveland Clinic Institutional Review Board. All procedures were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Koshkin, V.S., Mir, M.C., Barata, P. et al. Randomized phase II trial of neoadjuvant everolimus in patients with high-risk localized prostate cancer. Invest New Drugs 37, 559–566 (2019). https://doi.org/10.1007/s10637-019-00778-4

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