T cells have long been recognized for their potent anti-neoplastic properties, leading to significant advancements in cancer treatment through immune checkpoint blockade. However, the efficacy of immune checkpoint inhibitors (ICIs) in treating advanced prostate cancer has been modest. Xaluritamig (AMG509), a bispecific T cell engager (TCE) targeting the six-transmembrane epithelial antigen of the prostate (STEAP1), represents a novel approach to overcoming the limitations of ICIs in prostate cancer.
STEAP1 is a prostate tumor antigen with limited expression in normal tissues, making it a promising target for therapy. Xaluritamig is designed to target cells with high expression of STEAP1, minimizing on-target, off-tumor toxicity. Preclinical studies have shown that Xaluritamig can induce tumor regression in mouse models and has minimal toxicity in cynomolgus monkeys.
A phase 1, open-label dose-escalation study of Xaluritamig in patients with mCRPC demonstrated a reasonable safety profile and encouraging signs of efficacy. The study enrolled 97 patients, with 55% experiencing grade ≥3 toxicities and 19% discontinuing therapy due to treatment-related adverse events. The most common toxicity was cytokine release syndrome (CRS), occurring in 72% of patients. Despite these challenges, the study observed significant PSA and radiographic responses, particularly in the high-dose cohort, indicating the potential of Xaluritamig as a treatment option for mCRPC.
Future directions for Xaluritamig include optimizing dosing schedules to minimize CRS and exploring its use in combination with standard-of-care therapies for prostate cancer. Additionally, research into the biology and regulation of STEAP1 may yield insights into combination therapies that could enhance the efficacy of Xaluritamig.
In conclusion, Xaluritamig represents a significant advancement in the treatment of mCRPC, offering new hope for patients with this challenging condition. Further studies are needed to confirm these findings and to explore the full potential of this novel therapeutic approach.
