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Clinical Studies

Phase 1b study of enzalutamide plus CC-115, a dual mTORC1/2 and DNA-PK inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC)

British Journal of Cancer volume 130, pages 53–62 (2024)Cite this article

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Abstract

Background

CC-115, a dual mTORC1/2 and DNA-PK inhibitor, has promising antitumour activity when combined with androgen receptor (AR) inhibition in pre-clinical models.

Methods

Phase 1b multicentre trial evaluating enzalutamide with escalating doses of CC-115 in AR inhibitor-naive mCRPC patients (n = 41). Primary endpoints were safety and RP2D. Secondary endpoints included PSA response, time-to-PSA progression, and radiographic progression.

Results

Common adverse effects included rash (31.7% Grades 1–2 (Gr); 31.7% Gr 3), pruritis (43.9% Gr 1–2), diarrhoea (37% Gr 1–2), and hypertension (17% Gr 1–2; 9.8% Gr 3). CC-115 RP2D was 5 mg twice a day. In 40 evaluable patients, 80% achieved ≥50% reduction in PSA (PSA50), and 58% achieved ≥90% reduction in PSA (PSA90) by 12 weeks. Median time-to-PSA progression was 14.7 months and median rPFS was 22.1 months. Stratification by PI3K alterations demonstrated a non-statistically significant trend towards improved PSA50 response (PSA50 of 94% vs. 67%, p = 0.08). Exploratory pre-clinical analysis suggested CC-115 inhibited mTOR pathway strongly, but may be insufficient to inhibit DNA-PK at RP2D.

Conclusions

The combination of enzalutamide and CC-115 was well tolerated. A non-statistically significant trend towards improved PSA response was observed in patients harbouring PI3K pathway alterations, suggesting potential predictive biomarkers of response to a PI3K/AKT/mTOR pathway inhibitor.

Clinical trial registration

ClinicalTrials.gov identifier: NCT02833883.

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Fig. 1: Percent PSA change from baseline by 12 weeks, by dose and mutation status.
Fig. 2: Median radiographic progression-free survival (rPFS), overall and by mutation status.
Fig. 3: Swimmer’s plot—time on treatment by dose and mutation status.
Fig. 4: ctDNA analysis at screening and disease progression.

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Data availability

All relevant data generated or analysed during this study are included in this published article and its Supplementary Information files.

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Acknowledgements

We thank all the patients, their families, and the study site investigators and staff who participated in the study.

Funding

The study was supported and funded by Celgene/BMS and Gateway for Cancer Research. The trial was managed by Prostate Cancer Clinical Trials Consortium (PCCTC). JLZ was supported by a K12 Paul Calabresi Career Development Award for Clinical Oncology and a Prostate Cancer Foundation Young Investigator Award.

Author information

Author notes

  1. Jimmy L. Zhao

    Present address: University of Minnesota Masonic Cancer Center, Minneapolis, MN, 55455, USA

  2. Emmanuel S. Antonarakis

    Present address: R&D in Oncology, AstraZeneca, New York, NY, 10016, USA

Authors and Affiliations

  1. Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

    Jimmy L. Zhao, Elyn Riedel, Ninghui Mao, Samuel Haywood, Brooke Decker, Tracy Curley, Wassim Abida, Brett Carver, Mario E. Lacouture & Dana Rathkopf

  2. The Sidney Kimmel Cancer Comprehensive Cancer Center at Johns Hopkins, 401 N. Broadway, Baltimore, MD, 21231, USA

    Emmanuel S. Antonarakis

  3. University of Washington and Fred Hutch Cancer Research Center, 1144 Eastlake Avenue, Seattle, WA, 98109, USA

    Heather H. Cheng

  4. Duke Cancer Institute, 20 Duke Medicine Circle, Durham, NC, 27710, USA

    Daniel J. George

  5. University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, 1825 4th Street, San Francisco, CA, 94158, USA

    Rahul Aggarwal & Felix Y. Feng

  6. Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada

    Takayuki Sumiyoshi & Alexander W. Wyatt

  7. Epic Sciences, 9381 Judicial Drive Suite 200, San Diego, CA, 92121, USA

    Joseph D. Schonhoft & Amanda Anderson

  8. Sidney Kimmel Cancer Center, Thomas Jefferson University, 914 Chestnut Street, Philadelphia, PA, 19107, USA

    Karen Knudsen

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Contributions

JLZ and ESA designed the study, acquired the data, interpreted the results, and drafted and revised the manuscript. HHC, DJG, RA, WA, FYF, KK, MEL and AWW designed the study, acquired the data, interpreted the results, and revised the manuscript. ER designed statistical methods, interpreted the results and drafted and revised the manuscript. TS designed the ctDNA analysis, acquired the data, interpreted the results and revised the manuscript. JDS and AA designed the CTC analysis, acquired the data, interpreted the results and revised the manuscript. NM, SH and BC designed the pre-clinical experiment, acquired the data, interpreted the results and revised the manuscript. BD and TC acquired the data, interpreted the results, and revised the manuscript. DR corresponding author, supervised the study, designed the study, acquired the data, interpreted the results, and drafted and revised the manuscript.

Corresponding author

Correspondence to Dana Rathkopf.

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Competing interests

JLZ is currently a full-time employee at AstraZeneca, which is not involved in the funding and conduct of the trial. The authors declare no competing interests.

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IRB committee approval was obtained from all participating sites and written consent was obtained by all participating patients. The study was performed in accordance with the Declaration of Helsinki.

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Zhao, J.L., Antonarakis, E.S., Cheng, H.H. et al. Phase 1b study of enzalutamide plus CC-115, a dual mTORC1/2 and DNA-PK inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC). Br J Cancer 130, 53–62 (2024). https://doi.org/10.1038/s41416-023-02487-5

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