Xaluritamig (AMG509), a T-cell engager (TCE) targeting the six-transmembrane epithelial antigen of the prostate (STEAP1), has shown promising results in a first-in-human study for metastatic castration-resistant prostate cancer (mCRPC). The Phase 1 trial (NCT04221542), led by Kelly et al., evaluated Xaluritamig in heavily pre-treated mCRPC patients, demonstrating encouraging signs of efficacy and a manageable safety profile. This study marks a significant step forward in targeted immunotherapy for prostate cancer.
STEAP1-Targeted TCE: Clinical Data for Xaluritamig
The rationale behind targeting STEAP1 lies in its high expression on most prostate cancers and limited expression in normal tissues, making it a promising target for this malignancy. Xaluritamig is a humanized bi-specific antibody designed to bind both STEAP1 and CD3 on T cells, redirecting T cells to kill cancer cells. The molecule is engineered to minimize off-target toxicity by targeting cells with high STEAP1 expression.
Preclinical data showed complete tumor stasis at 0.01 mg/kg and tumor regression at higher doses in mouse models. Evaluation in cynomolgus monkeys indicated minimal off-tumor toxicity. Based on these data, a Phase 1 open-label dose-escalation study was initiated.
The study enrolled 97 patients with mCRPC who had progressed on androgen-receptor pathway inhibitors (ARPI) and 1-2 prior lines of taxane chemotherapy. STEAP1 expression was not required for enrollment. The median prostate-specific antigen (PSA) was 113, and 37% of patients had liver metastases, indicating a high-risk population.
Safety and Efficacy
A target dose of 1.5 mg weekly was achieved using a step-up dosing schedule after establishing 0.1 mg as the highest tolerable priming dose. Fifty-five percent of patients experienced grade ≥3 toxicities, and 19% discontinued therapy due to treatment-related adverse events. The most common toxicity was cytokine release syndrome (CRS), occurring in 72% of patients, though most events were low grade. Two patients experienced grade 3 CRS, one at a higher priming dose and the other before prophylactic dexamethasone was initiated.
Other treatment-related toxicities included fatigue (45% overall, 11% ≥ grade 3) and myalgias (34% overall, 12% ≥ grade 3). The etiology of these musculoskeletal adverse events is unclear, as STEAP1 is not highly expressed in muscle, and creatine kinase levels were not elevated.
Despite the toxicities, the study showed encouraging efficacy. In the PSA-evaluable cohort, PSA50 and PSA90 responses were observed in 49% and 28% of patients, respectively. Responses were numerically higher in the high-dose cohort, with 59% and 36% achieving PSA50 and PSA90 responses. In patients with measurable disease, 24% achieved a confirmed partial response. Radiographic responses were also more common in the high-dose cohort, with 41% achieving a confirmed response compared to 3% in the low-dose cohort. Responses occurred quickly, and preliminary data suggests a relatively long duration of response, with a median duration of RECIST response of 9.2 months.
Overcoming Challenges and Future Directions
A key limitation is the need for hospitalization due to the risk of CRS. Ongoing study cohorts are assessing the safety and tolerability of outpatient administration, either intravenously or subcutaneously, and in combination with standard-of-care therapies like abiraterone and enzalutamide. Strategies to minimize CRS, such as risk-adapted approaches and variations in dosing cadence, are being explored.
The optimal placement of Xaluritamig within the mCRPC treatment landscape also needs to be determined. As chemotherapy can negatively impact T cell function, earlier line settings may be more effective. The increasing use of 177Lu-PSMA-617 radioligand therapy (LuPSMA), which can induce lymphocytopenia, may also affect Xaluritamig's efficacy.
Alternative STEAP-1 Targeted Therapeutics
While bi-specifics show promise, antibody-drug conjugates (ADCs) and CAR-T cells are also being investigated as alternative strategies for targeting STEAP1. A prior attempt with the ADC vandortuzumab vedotin showed marginal efficacy and significant toxicity. However, T-cell redirection with a cellular payload may offer benefits compared to ADCs, including fewer off-target effects and the ability to target both active and dormant cells.
A recent study highlighted the potential of STEAP1-targeted CAR-T cell therapy, demonstrating anti-tumor efficacy and survival benefit in a mouse model without on-target off-tumor toxicities. A phase 1/2 clinical trial testing STEAP1 CAR-T cells in combination with enzalutamide is planned (NCT06236139).
Key to the success of STEAP1-targeted therapies is understanding and addressing potential resistance mechanisms, such as tumor antigen escape (loss of STEAP1). Personalized approaches may be needed to determine the best treatment option for individual patients.
Addressing Antigen Heterogeneity
Unlike trials of PSMA-targeted therapies, the Xaluritamig trial did not require STEAP1 expression assessment. While STEAP1 PET imaging is being explored, there is no standard way to ascertain global STEAP1 expression. Research into how STEAP1 expression correlates with response to Xaluritamig is needed to optimize patient selection. Combining Xaluritamig with therapies targeting other cell surface antigens may be necessary to overcome the heterogeneity of prostate cancer.
Better understanding of STEAP1 biology and regulation may also yield insights into combinations and treatment sequences that maximize outcomes with Xaluritamig. Epigenetic modulation and androgen receptor inhibition are potential strategies to increase STEAP1 expression and potentiate the effects of anti-STEAP1 therapies.
Approaches to increase T cell activation with TCEs, such as CD28 co-stimulation or interference with the programmed death pathway, are also being investigated in mCRPC trials (NCT03972657, NCT06085664, NCT06095089, and NCT05585034).
Conclusion
Xaluritamig represents a promising new therapeutic option for mCRPC patients. While a larger Phase 3 trial is needed, this study provides compelling evidence that STEAP1 can be safely targeted in prostate cancer and that T cell re-direction is a viable strategy. Further work to mitigate toxicity and improve patient selection will be crucial for the success of this therapy.
