TPS285 Background: Prostate cancer is the second most common cancer in men and the fifth leading cause of cancer-related deaths in men. Despite treatment advances, 5-year survival estimates for patients with advanced disease remain low, ranging from 26%–37%. Hence, there is an urgent unmet need to develop novel therapies that delay disease progression, improve or maintain quality of life, and prolong survival in patients with metastatic castration-resistant prostate cancer (mCRPC). GSK5458514 is a bispecific immunoglobulin G-like T-cell engager designed to bind to prostate-specific membrane antigen (PSMA), a clinically validated tumor-associated antigen, on one arm and CD3 of the T-cell receptor complex on the other arm. Co-binding of GSK5458514 to CD3 and PSMA brings T cells and tumor cells in proximity, which is designed to trigger subsequent T-cell activation, cytokine secretion, and T-cell–mediated killing of PSMA-positive tumor cells. Methods: This first-in-human, open-label, multicenter, phase 1/2 trial (NCT06990880) opened on June 12, 2025, and aims to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of GSK5458514 alone or in combination with other anticancer agents in adult patients who have histologically confirmed adenocarcinoma of the prostate classified as mCRPC, novel antiandrogen receptor therapy failure, and treatment failure with 1–2 taxane-based chemotherapy regimens. During the dose escalation phase, participants will be administered GSK5458514 using a step-up dosing regimen (step-up treatment period) to mitigate the risk of cytokine release syndrome, followed by a fixed-dose treatment period once the intended target dose is achieved. In part 1, the objectives are to determine the safety and tolerability of GSK5458514 and to inform the dose-expansion phase. Ascending dosing cohorts will explore different doses and dosing regimens to determine the maximum tolerated dose. The primary endpoints for part 1 are safety during the dose-limiting toxicity period (first 28 days), frequency of adverse events, and any subsequent dose modifications (duration of trial and follow-up). Secondary endpoints include objective response rate in patients with measurable disease and duration of response, pharmacokinetics, 50% decrease in prostate-specific antigen (PSA50) response, and immunogenicity (antidrug antibodies against GSK5458514). Expected enrollment for part 1 is ≈45 patients. Open sites are located in the United States, Japan, and Canada. Additional sites are planned to open in 2026 in Spain and France. Clinical trial information: NCT06990880 .
Garmezy et al. (Sun,) studied this question.