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Effectiveness and durability of benefit of mTOR inhibitors in a real-world cohort of patients with metastatic prostate cancer and PI3K pathway alterations

Prostate Cancer and Prostatic Diseases volume 26, pages 188–193 (2023)Cite this article

Subjects

Abstract

Background

Alterations in the PTEN/PI3K/AKT/mTOR pathway are prevalent in prostate cancer. In this retrospective study, we evaluated the clinical effectiveness of mTOR inhibitors (mTORi) in patients with metastatic prostate cancer (mPCA) and tissue assessed phosphatidyl-3-inositol kinase (PI3K) pathway alterations.

Methods

This study used a nationwide (US-based) de-identified PCA clinico-genomic database, originating from approximately 280 US cancer clinics (~800 sites of care). We evaluated treatment data for patients with PCA from October 2014 to February 2020. In a cohort of 2301 PCA patients with 7208 evaluable treatment lines, we selected 17 mPCA patients (2 hormone-sensitive, 15 castrate-resistant) with tissue assessed PI3K pathway alterations by comprehensive genomic profiling who received mTORi treatment.

Results

Patients had a median age of 72 years (IQR 68.0, 76.0) and were heavily pretreated with a median 3 lines of therapy prior to mTORi use (range 0–6). The PI3K pathway alterations included PTENdel (10 patients, 58.8%), AKT1mut (4 patients, 23.5%), PTENmut (2 patients, 11.8%), and dual PTENmut and PIK3CAmut (1 patient, 5.9%). Most (15 patients, 88.2%) were treated with everolimus monotherapy. Among 10 patients with on treatment PSA available, 2 patients had a PSA decrease ≥10% at week 12 and 5 patients overall had a subsequent PSA decrease. For those on mTORi, the median time to next treatment was 3.62 months (range 0, 8.52).

Conclusions

In this small cohort of mPCA patients with tissue assessed PI3K pathway alterations, mTORi therapy was not effective with few PSA responses and short duration of therapy.

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Fig. 1: Cohort Selection.
Fig. 2: Response to mTOR Inhibitor Therapy.

Data availability

The data supporting the findings of this study originated from Flatiron Health, Inc. and Foundation Medicine, Inc. These de-identified data may be made available upon request, and are subject to a license agreement with Flatiron Health and Foundation Medicine; interested researchers should contact <cgdb-fmi@flatiron.com> and <dataaccess@flatiron.com> to determine licensing terms.

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Acknowledgements

We thank the patients whose data made this research possible, the clinical and laboratory staff at Foundation Medicine, and the team at Flatiron Health.

Funding

ETL and TWF received funding from the National Cancer Institute ETCTN and CTEP Program UM1 Supplement 1UM1-CA186688-04 for related preclinical work. Foundation Medicine pays the salaries of KW and RG.

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Authors and Affiliations

  1. University of Colorado Cancer Center, Aurora, CO, USA

    Corbin J. Eule, Thomas W. Flaig & Elaine T. Lam

  2. Foundation Medicine, Cambridge, MA, USA

    Katy Wong & Ryon Graf

Authors
  1. Corbin J. Eule
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  2. Thomas W. Flaig
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  4. Ryon Graf
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  5. Elaine T. Lam
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Contributions

CJE is responsible for methodology, formal analysis, writing—original draft, and project administration. TWF is responsible for conceptualization, writing—review & editing, and funding acquisition. KW is responsible for software, formal analysis, data curation, and writing—review & editing. RG is responsible for methodology, software, formal analysis, data curation, writing—review & editing, and visualization. ETL is responsible for conceptualization, methodology, writing—review & editing, supervision, and funding acquisition.

Corresponding author

Correspondence to Elaine T. Lam.

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Competing interests

CJE has no conflicts of interest to disclose. TWF has received research funding from Roche/Genentech. KW and RG are employees of Foundation Medicine, a wholly owned subsidiary of Roche, and have equity interest in Roche. ETL has received institutional research funding from Roche/Genentech.

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Eule, C.J., Flaig, T.W., Wong, K. et al. Effectiveness and durability of benefit of mTOR inhibitors in a real-world cohort of patients with metastatic prostate cancer and PI3K pathway alterations. Prostate Cancer Prostatic Dis 26, 188–193 (2023). https://doi.org/10.1038/s41391-022-00612-8

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