Abstract 5047: PSMA-targeted actinium-225 conjugate (225Ac-pelgifatamab) potentiates the antitumor efficacy of darolutamide in androgen-dependent and -independent prostate cancer models

Abstract Patients with advanced prostate cancer have few treatment options. While androgen receptor (AR) inhibitors are the standard of care for the systemic treatment, patients often develop resistance despite an initial response. Thus, novel therapeutic approaches are required. Prostate-specific membrane antigen (PSMA; FOLH1) is highly expressed in prostate cancer with limited expression in normal tissues. Therefore, PSMA presents an attractive target for radionuclide therapy and PSMA-targeted therapies have already shown efficacy in the clinical setting. Here, we evaluated the efficacy of 225Ac-pelgifatamab, a PSMA-targeted actinium-225 conjugate, in combination with the AR inhibitor darolutamide in androgen-dependent and -independent prostate cancer models. AR inhibitors are known to upregulate PSMA expression, therefore providing a rationale for combining 225Ac-pelgifatamab with darolutamide and potentially resulting in an enhanced treatment effect. In vitro, darolutamide induced the expression of PSMA in androgen-dependent VCaP and androgen-independent 22Rv1 cells by more than 10-fold and 2-fold, respectively. The efficacy of darolutamide in combination with 225Ac-pelgifatamab was synergistic in these cells with combination indexes of 0.12 and 0.47, respectively. In the androgen-dependent, patient-derived ST1273 model, a single i.v. injection of 225Ac-pelgifatamab at 75 kBq/kg resulted in a treatment/control (T/C) ratio of 0.22 on day 30, while twice daily (BID) oral (p.o.) treatment with 100 mg/kg darolutamide showed a T/C ratio of 0.29. However, the combination of darolutamide and 225Ac-pelgifatamab resulted in enhanced antitumor efficacy with a T/C ratio of 0.008. Furthermore, 5/10 mice remained tumor-free 86 days after the 225Ac-pelgifatamab injection. In the androgen-independent cell line-derived 22Rv1 model, darolutamide (100 mg/kg, p.o., BID) monotherapy was not efficacious with a T/C of 0.84 on day 16 but a single i.v. dose of 225Ac-pelgifatamab at 150 kBq/kg resulted in a T/C ratio of 0.69. Remarkably, the combination of darolutamide and 225Ac-pelgifatamab resulted in further enhanced efficacy with a T/C ratio of 0.34. Flow cytometric analysis of isolated 22Rv1 tumors showed a 50-fold increase in PSMA expression upon darolutamide treatment compared with vehicle. Taken together, these results suggest that upregulation of PSMA expression contributes to the higher efficacy observed when darolutamide is combined with 225Ac-pelgifatamab. In conclusion, our results provide a proof of concept for investigating the combination of 225Ac-pelgifatamab with darolutamide in the clinical setting. Citation Format: Christoph A. Schatz, Bernard Haendler, Sabine Zitzmann-Kolbe, Aasmund Larsen, Hartwig Hennekes, Carsten H. Nielsen, Maria Z. Alfsen, Alan Cuthbertson, Stefanie Hammer, Arne Scholz, Urs B. Hagemann. PSMA-targeted actinium-225 conjugate (225Ac-pelgifatamab) potentiates the antitumor efficacy of darolutamide in androgen-dependent and -independent prostate cancer models. [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 5047.