pelgifatamab corixetan (BAY 2315497)

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.

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. 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/ These results provide a strong rationale to investigate PSMA-TTC in combination with AR inhibitors in patients with prostate cancer.

Changes in markers of DNA damage response following treatment will be presented. In summary, combination of PSMA-TTC with olaparib shows synergistic preclinical anti-tumor activity and support further clinical investigation of this combination treatment in prostate cancer patients.

In vivo, PSMA-TTC showed strong antitumor efficacy with T/C values of 0.01-0.31 after a single injection at 300-500 kBq/kg in subcutaneous cell line and PDX models including models resistant to standard-of-care drugs such as enzalutamide. Specific tumor uptake and efficacy were demonstrated using various PSMA-TTC doses and dosing schedules. Induction of DNA double-strand breaks was identified as a key mode-of-action for PSMA-TTC both in vitro and in vivo The strong preclinical antitumor activity of PSMA-TTC supports its clinical evaluation, and a phase I trial is ongoing in mCRPC patients (NCT03724747).