Since we talked about AMG 509 (Xaluritamig) in a past article and we have kept an eye on its development, I wanted to share the latest data about this novel drug (October 2024).

Xaluritamig, is a STEAP1-targeted T-cell engager, with huge potential for treating metastatic castration-resistant prostate cancer (mCRPC). This therapy leverages the high expression of STEAP1 in prostate cancer cells to direct T-cell-mediated killing, representing a novel approach in the treatment landscape.

Xaluritamig binds both STEAP1 on cancer cells and CD3 on T-cells, facilitating targeted immune killing of prostate cancer cells. STEAP1 is highly expressed in prostate cancer but minimally expressed in normal tissues, enhancing its precision.

Safety Profile From Phase 1/2

• Cytokine Release Syndrome (CRS): Occurring in 75% of patients, CRS was generally mild and managed with steroids or tocilizumab, particularly after the first dose.
• Musculoskeletal Inflammatory Events: Seen in 76% of patients, these were managed by holding doses and using steroids or tocilizumab. Every-other-week dosing reduced incidence.
• First-dose administration requires 24-hour hospital monitoring.

Efficacy:

• PSA Responses: Between 36-60% of patients achieved a ≥50% PSA reduction (PSA 50), while 20-30% saw ≥90% reductions (PSA 90).
• RECIST Responses: Objective responses ranged from 14-28%, with 20% of patients with liver metastases showing a response.
• Survival Outcomes: The median radiographic progression-free survival (rPFS) was 7.7 months, extending to 8.3 months at doses of 0.75 mg or higher. Median overall survival (OS) reached 17.7 months, comparable to results from the VISION trial (PSMA lutetium, OS: 15.3 months).

The Phase 3 trial will randomize 675 patients to Xaluritamig versus cabazitaxel or an AR switch. This trial aims to establish its superiority as a second-line treatment for patients progressing after AR-targeted therapies and chemotherapy.

Interestingly, patient selection based on STEAP1 expression was not required in the current trial, despite STEAP1 being expressed in 80% of advanced prostate cancers. This broadens its applicability across the mCRPC population.

Source.