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


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: identifier: NCT02833883.

Publication types

  • Multicenter Study
  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzamides*
  • DNA / therapeutic use
  • Humans
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Nitriles / therapeutic use
  • Phenylthiohydantoin*
  • Phosphatidylinositol 3-Kinases
  • Prostate-Specific Antigen / therapeutic use
  • Prostatic Neoplasms, Castration-Resistant* / pathology
  • Pyrazines*
  • Triazoles*


  • enzalutamide
  • 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino(2,3-b)pyrazin-2(1H)-one
  • Prostate-Specific Antigen
  • Mechanistic Target of Rapamycin Complex 1
  • Phosphatidylinositol 3-Kinases
  • Nitriles
  • DNA
  • Triazoles
  • Phenylthiohydantoin
  • Pyrazines
  • Benzamides

Associated data