Abstract Background: Androgen receptor pathway inhibitors (ARPIs) improve outcomes for patients with mCRPC. However, development of resistance to ARSIs is a significant clinical issue associated with aggressive variant prostate cancer (AVPC), and consequently there is an urgent need for novel, AR pathway-independent therapies. Expression of the metalloprotease methionine aminopeptidase 2 (METAP2) has been correlated with increased mCRPC aggressiveness: high expression was reported in dedifferentiated phenotypes, including NEPC/AVPC. METAP2 regulates protein translation, post-translational modifications and has a clinically validated role inhibiting angiogenesis. METAP2 also has tumor-specific functions coordinating plasticity, vascular mimicry, and hypoxia response. Evexomostat (SDX-7320) is a prodrug of a highly potent, novel METAP2 inhibitor which has completed a phase I safety study in late-stage cancer patients and is currently being clinically investigated in patients with metastatic breast cancer (NCT05570253, NCT05455619). It was hypothesized that SDX-7320 would demonstrate anti-tumor efficacy in non-clinical prostate cancer xenograft models of ARPI-resistant CRPC and AVPC. Methods: SDX-7320 was tested in NSG mice with LNCaP xenografts in intact, castrated, and CRPC models. SDX-7320 treatment was also evaluated in LuCaP35. CR patient-derived xenografts (PDX) in castrate mice as well as in combination with enzalutamide following development of resistance to daily enzalutamide treatment. SDX-7320 was further evaluated in the LTL545 and LUCAP49 (AR-negative, NE-positive) models of AVPC. Tumor growth was assessed and following dissection, subsequently analyzed for transcriptomic (RNAseq), protein (Western blot) or histological differences (H 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (2Suppl): Abstract nr B012.
Cornelius et al. (2026) studied this question.