Abstract Background: The prognosis for metastatic triple negative breast cancer (metTNBC) remains poor and novel therapeutic strategies are urgently needed. Insulin resistance 5.5% and/or BMI ≥30, and ≤2 prior treatment lines in the metastatic setting. In the safety run-in period, 15 patients received evexomostat 49 mg/m2 Q2 weeks + eribulin 1.4 mg/m2 on D1 the most frequent grade ≥3 AE was decreased neutrophil count. Accordingly, the safety stopping rule was not triggered and the trial advanced to the randomization phase. Exploratory analyses from baseline to week 12 demonstrated significant changes in LDL cholesterol, adiponectin, leptin, resistin, VEGF-D, and sFRP-5 (p=0.016, 0.009, 0.021, 0.016, 0.027, and 0.012 respectively; see Table). There was no increase in HOMA-IR (p0.9). Among 12 patients evaluable for response; ORR was 17% and clinical benefit rate was 67%. Conclusions: Evexomostat + eribulin safety was confirmed and the trial advanced to the randomization phase including a placebo-controlled arm with eribulin. Preliminary biomarker results indicate that insulin resistance was unchanged, and favorable changes were seen in other metabolic markers. Citation Format: S. Shen, V. Solomon, D. Williams, C. White, Y. Chen, M. Meem, I. Warren, P. Drullinsky, S. Schweber, R. Wang, M. Gorsky, A. Gucalp, J. Shen, R. Sanford, A. Widman, M. Robson, L. Norton, T. Traina, D. Graham, R. Mahtani, N. M. Iyengar. Aretha trial: Safety run-in results of eribulin + evexomostat in metastatic triple-negative breast cancer with metabolic dysfunction abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-02-23.
Shen et al. (Tue,) studied this question.