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Clinical Trial
. 2024 Jan;130(1):53-62.
doi: 10.1038/s41416-023-02487-5. Epub 2023 Nov 18.

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)

Jimmy L Zhao  1   2 , Emmanuel S Antonarakis  3   4 , Heather H Cheng  5 , Daniel J George  6 , Rahul Aggarwal  7 , Elyn Riedel  1 , Takayuki Sumiyoshi  8 , Joseph D Schonhoft  9 , Amanda Anderson  9 , Ninghui Mao  1 , Samuel Haywood  1 , Brooke Decker  1 , Tracy Curley  1 , Wassim Abida  1 , Felix Y Feng  7 , Karen Knudsen  10 , Brett Carver  1 , Mario E Lacouture  1 , Alexander W Wyatt  8 , Dana Rathkopf  11
Affiliations
Clinical Trial

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)

Jimmy L Zhao et al. Br J Cancer. 2024 Jan.

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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Conflict of interest statement

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.

Figures

Fig. 1
Fig. 1. Percent PSA change from baseline by 12 weeks, by dose and mutation status.
a Waterfall plot of PSA response at 12 weeks by CC-115 dose, PTEN mutation status, TSC1, TSC2 or PIK3CA mutation status and the presence of Grade 3 rash. b Summary table of PSA50 and PSA90 response by CC-115 dose and mutation status.
Fig. 2
Fig. 2. Median radiographic progression-free survival (rPFS), overall and by mutation status.
Kaplan–Meier curves of rPFS in all patients (a), separated by PTEN mutation status (b) and by PI3K pathway mutation status (including PTEN, PIK3CA, TSC1 and TSC2) (c). d Summary table of median rPFS by mutation status.
Fig. 3
Fig. 3. Swimmer’s plot—time on treatment by dose and mutation status.
Swimmer’s plot was annotated with doses, PI3K pathway mutation status and Grade 3 rash. Annotation of potential mechanisms of resistance in two patients (Patients A and B) of early progression (<3 months after the beginning of treatment) who had both screening and end-of-treatment ctDNA analysis.
Fig. 4
Fig. 4. ctDNA analysis at screening and disease progression.
a ctDNA analysis from 24 patients at screening. b ctDNA analysis from 16 patients with matched screening and end-of-treatment samples.
See this image and copyright information in PMC

References

    1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49. doi: 10.3322/caac.21660. - DOI - PubMed
    1. American Cancer Society. Cancer Statistics Center. 2022. http://cancerstatisticscenter.cancer.org.
    1. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424–33. doi: 10.1056/NEJMoa1405095. - DOI - PMC - PubMed
    1. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995–2005. doi: 10.1056/NEJMoa1014618. - DOI - PMC - PubMed
    1. Watson PA, Arora VK, Sawyers CL. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat Rev Cancer. 2015;15:701–11. doi: 10.1038/nrc4016. - DOI - PMC - PubMed

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