Abstract 3726: Preclinical activity of PSMA-TTC (BAY 2315497) in combination with androgen receptor antagonists in prostate cancer models

Targeted alpha therapy (TAT) agents are able to deliver high linear energy transfer alpha-radiation selectively to tumors. The PSMA targeted thorium-227 conjugate PSMA-TTC (BAY 2315497) is a TAT approach for mCRPC consisting of a human anti-PSMA antibody covalently linked to the chelator moiety (3,2 HOPO) radiolabeled with the alpha emitter thorium-227. PSMA-TTC has shown strong anti-tumor activity in PSMA-positive prostate cancer models (Hammer et al. AACR 2017/2018). Androgen receptor (AR) antagonists like enzalutamide have been effective in improving overall survival in CRPC patients, however, not all patients respond to these therapies and those responding develop resistance and progression of disease. Herein we evaluate in prostate cancer models combination treatments of PSMA-TTC with enzalutamide and the novel AR antagonist darolutamide, which has recently completed a clinical phase 3 trial. AR antagonists induced PSMA levels in LNCaP and C4-2 prostate cancer cells in vitro resulting in increased sensitivity to growth inhibition by PSMA-TTC. In vivo , the combination of PSMA-TTC with enzalutamide was tested in the hormone- and enzalutamide-sensitive patient-derived prostate cancer model ST1273 (South Texas Accelerated Research Therapeutics, San Antonio, Texas). A single i.v. injection of PSMA-TTC at 250 kBq/kg (0.14 mg/kg) resulted in stable disease in 50% and partial response in 38% of the animals 40 days after dosing. Daily treatment with enzalutamide (30 mg/kg po for 28d) resulted in stable disease in 86% and partial response in 14% of the animals. Combining PSMA-TTC and enzalutamide at the mentioned concentrations achieved tumor reduction in all animals, with partial response in 67% and complete response in 33% of the animals 40 days after start of treatment. No significant adverse effects on body weight were detected compared to vehicle treated animals in any of the groups. Additionally, the combination of PSMA-TTC with darolutamide was tested in the enzalutamide resistant patient-derived prostate cancer model KUCaP-1 (provided by Prof. O. Ogawa, University of Kyoto, Japan). PSMA-TTC monotherapy at 150 kBq/kg (0.43 mg/kg) injected twice at an interim of two weeks resulted in 79% tumor growth inhibition and darolutamide treatment (200 mg daily) achieved 60% tumor growth inhibition compared to vehicle treated animals. The combination of PSMA-TTC with darolutamide increased tumor growth inhibition compared to vehicle to 85% and, importantly, 77% of the animals showed stable disease or partial response until 57 days after start of treatment. In summary, combining PSMA-TTC with AR antagonists shows promising preclinical data in patient-derived prostate cancer models with increased response rates even in an enzalutamide-resistant model. Clinical investigation of this targeted alpha pharmaceutical investigational agent alone and in combination is warranted. Citation Format: Stefanie Hammer, Urs B. Hagemann, Sabine Zitzmann-Kolbe, Aasmund Larsen, Chrstine Ellingsen, Oliver von Ahsen, Jenny Karlsson, Roger M. Bjerke, Olav B. Ryan, Pascale Lejeune, Hartwig Hennekes, Alan Cuthbertson, Dominik Mumberg. Preclinical activity of PSMA-TTC (BAY 2315497) in combination with androgen receptor antagonists in prostate cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3726.