Abstract 1656: Evexomostat: A novel therapeutic in development for the treatment of prostate cancer

Abstract Background: Prostate cancer (PCa) is the second-most diagnosed malignancy among men and is a leading cause of cancer death worldwide (WHO, 2020). Elevated expression of the enzyme methionine aminopeptidase type 2 (MetAP2) in prostate cancer was recently shown to be associated with higher grade tumors and with worse clinical outcomes (Xie, 2021). Evexomostat/SDX-7320 is a polymer-drug conjugate of a novel fumagillin-derived MetAP2 inhibitor attached to a polymer backbone via a cleavable linker. This design alters biodistribution (limits CNS penetration) and improves pharmacokinetics relative to small molecule fumagillin-derived MetAP2 inhibitors. Evexomostat completed a phase I safety study in late-stage cancer patients and is in two phase 2 breast cancer studies (NCT05455619, NCT05570253). Methods: To evaluate the efficacy of evexomostat in a model of prostate cancer, NSG mice were injected subcutaneously with 2×106 LNCaP cells. When tumors reached ≈200 mm3, mice were randomized into 4 groups. A cohort of intact mice (Group 1; n=4/group) received treatment with SDX-7320 (12 mg/kg, s.c. Q4D) or vehicle (5% mannitol/water). Group 2 were castrated and randomized to SDX-7320 (6 mg/kg, 12 mg/kg) or Vehicle (5% mannitol) upon recovery (n=4/group). Group 3 (n=13/group) and Group 4 (n=14/group) were castrated and randomized to Vehicle or SDX-7320 at recurrence of tumor growth with Group 4 additionally receiving enzalutamide (10 mg/kg, p.o., QD). Tumor growth and body weight were assessed twice/week. Upon necropsy, tumors were dissected, weighed and snap frozen for RNAseq analysis or formalin fixed along with major organs for histological processing (H&E staining, and tumor CD31, CD34 IHC analysis). Results: Evexomostat elicited a significant reduction in tumor growth in the absence of significant changes in body weight. Survival in evexomostat-treated mice was doubled relative to vehicle-treated mice (12.5 vs 23.5 days). In castrated mice (Group 2), evexomostat (6 and 12 mg/kg) attenuated tumor growth with no change in body weight, and in CRPC mice (Group 3), evexomostat also significantly inhibited tumor growth. Treatment of CRPC mice (Group 4) with enzalutamide alone elicited a mixed response, with 6/14 mice showing sustained response to enzalutamide (responders). At endpoint, tumors from enzalutamide non-responders averaged 0.54g (± 0.09g) and enzalutamide responders 0.27g (± 0.07g), p&lt0.05, while tumors from SDX-7320 plus enzalutamide-treated mice weighed 0.19g (± 0.07g), p&lt0.005 compared to enzalutamide non-responders. Conclusions: MetAP2 inhibition has potential as a new approach for the treatment of prostate cancer. The clinical-stage MetAP2 inhibitor evexomostat/SDX-7320 significantly inhibited the growth of LNCaP tumors in intact, castrated and CRPC mice. Clinical evaluation of evexomostat in castration-sensitive as well as castration-resistant prostate cancer patients is warranted. Citation Format: Peter Cornelius, Benjamin Mayes, Bradley J. Carver, James Shanahan, Jennifer Gunter, Colleen Nelson. Evexomostat: A novel therapeutic in development for the treatment of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1656.