Abstract 3311: Darolutamide potentiates the antitumor efficacy of a PSMA-targeted thorium-227 conjugate (PSMA-TTC) in a hormone-independent prostate cancer model

Abstract Androgen receptor (AR) inhibitors are standard of care for the treatment of advanced prostate cancer. Despite an initial response to treatment, patients eventually progress, and novel therapeutic approaches are required. Prostate-specific membrane antigen (PSMA; FOLH1) is an integral membrane glycoprotein that is highly expressed in prostate cancer but has limited expression in normal tissues. PSMA-TTC (227Th-pelgifatamab corixetan; BAY 2315497) consists of the alpha emitter thorium-227 complexed to a 3,2-HOPO chelator conjugated to a PSMA targeting antibody. PSMA-TTC delivers potent radiation to PSMA expressing cells. Here we evaluated the efficacy of PSMA-TTC in combination with darolutamide, a novel AR inhibitor in a hormone insensitive prostate cancer model and investigated the mode of action of the combination treatment. In vitro, darolutamide induced the expression of PSMA in the androgen-independent cell lines C4-2 and 22Rv1 more than 3-fold and 2-fold, respectively. Expression of the apoptosis marker CDKN1A was significantly induced in the PSMA-TTC alone and in the combination group compared to vehicle. Expression of the DNA repair genes BRCA1, XRCC2 and XRCC3 were significantly reduced in PSMA-TTC alone and in the combination group compared to vehicle. In vivo, a single i.v. injection of PSMA-TTC at 300 kBq/kg resulted in a tumor/control (T/C) ratio of 0.44 on day 19 in the 22Rv1 hormone-insensitive prostate cancer model while a twice daily oral treatment with 100 mg/kg darolutamide showed a T/C ratio of 0.82. The combination of darolutamide and PSMA-TTC resulted in a higher efficacy with a T/C ratio of 0.27. Tumor area on day 19 after treatment was significantly reduced in the PSMA-TTC alone group and more so in the combination group, compared to vehicle. As expected, darolutamide alone was not efficacious in this hormone insensitive model. Nine out of 10 mice showed disease control (CR, PR or SD) in the combination group whereas no animals showed disease control in either of the monotherapy groups. This difference was significant by Fisher’s exact test analysis. Treatments were well tolerated with no significant changes in body weight in any of the treatment groups. Using the tumor dissociation kit Miltenyi individual tumor cells were isolated from darolutamide treated and untreated 22Rv1 xenograft tumors. FACS analysis showed a 50fold increase in PSMA expression in the darolutamide treated 22Rv1 tumors compared to vehicle treated animals. These data indicate that darolutamide induces PSMA expression in the hormone independent 22Rv1 model, which may have contributed to the stronger efficacy observed when combined with PSMA-TTC. Altogether these results support the further evaluation of darolutamide combination with PSMA radionuclides. Citation Format: Christoph Schatz, Urs Hagemann, Sabine Zitzmann-Kolbe, Bernard Haendler, Hartwig Hennekes, Stefanie Hammer, Arne Scholz. Darolutamide potentiates the antitumor efficacy of a PSMA-targeted thorium-227 conjugate (PSMA-TTC) in a hormone-independent prostate cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3311.