Darolutamide potentiates the antitumor efficacy of a PSMA-targeted thorium-227 conjugate (PSMA-TTC) by a dual mode-of-action in prostate cancer models.

Purpose: Androgen receptor (AR) inhibitors are well-established in the treatment of castration-resistant prostate cancer (CRPC) and have recently shown efficacy also in castration-sensitive prostate cancer (CSPC). Although most patients respond well to initial therapy, resistance eventually develops, and thus, more effective therapeutic approaches are needed. Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer and presents an attractive target for radionuclide therapy. Here, we evaluated the efficacy and explored the mode-of-action of the PSMA-targeted thorium-227 conjugate (PSMA-TTC) BAY 2315497, an antibody-based targeted alpha therapy, in combination with the AR inhibitor darolutamide. Experimental Design: The in vitro and in vivo antitumor efficacy and mode-of-action of the combination treatment were investigated in preclinical cell line- and patient-derived prostate cancer xenograft models with different levels of PSMA expression. Results: Darolutamide induced the expression of PSMA in androgen-sensitive VCaP and LNCaP cells in vitro, and the efficacy of darolutamide in combination with PSMA-TTC was synergistic in these cells. In vivo, the combination treatment showed synergistic antitumor efficacy in the low PSMA-expressing VCaP and in the high PSMA-expressing ST1273 prostate cancer models, and enhanced efficacy in the enzalutamide-resistant KUCaP-1 model. The treatments were well-tolerated. Mode-of-action studies revealed that darolutamide induced PSMA expression, resulting in higher tumor uptake of PSMA-TTC, and consequently, higher antitumor efficacy, and impaired PSMA-TTC-mediated induction of DNA damage repair genes, potentially contributing to increased DNA damage. Conclusions/Discussion: These results provide a strong rationale to investigate PSMA-TTC in combination with AR inhibitors in patients with prostate cancer.