Persistence Pays Off - Validating STEAP1 as a Target for Prostate Cancer Therapeutic Delivery

Six Transmembrane Epithelial Antigen of the Prostate (STEAP1) is a member of a family of metalloreductases that have ability to form heterodimers or heterotrimers with other STEAP family proteins.¹  The function of STEAP1 is quite broad.  It has known functional roles in cell proliferation, invasion, and epithelial to mesenchymal transition (EMT).^2-4  STEAP1 is an antigen highly expressed in most prostate cancers, with limited normal tissue expression.²  STEAP1 is especially highly expressed in metastatic castration-resistant prostate cancer in both metastatic lesions to the bone and also in lymph nodes.⁵  For this reason, it has been considered a highly promising therapeutic target for novel drug delivery systems for men who harbor metastatic castration-resistant prostate cancer.

Early attempts to target STEAP1 were fraught with challenges.  The antibody drug conjugate, vandortuzumab vedotin (DSTP3086S), targets STEAP1 and brings a monomethyl auristatin E payload to the tumor.  However, the initial clinical trial had limited efficacy and rather significant toxicity, likely due to off target effects.  These dose limiting toxicities included transaminitis, hyperglycemia, and hypophosphatemia.  Although the trial eligibility required significant STEAP1 expression, demonstrated by immunohistochemistry, only 14.3% of patients had a PSA decline of 50% or greater and only 1 of 46 total patients had a confirmed radiographic response.⁶ 

Time and time again we find that old targets that have been dismissed as a viable therapeutic development strategy due to lack of past success, re-emerge as novel and better targeting constructs are developed.  Hence, for an antibody drug conjugate, many factors beyond the antigen expression are at play, including factors like the antibody binding epitope, antibody internalization, payload linker, drug antibody ratio, and the mechanism of action of the payload, itself.  As a result, newer antibody drug conjugates and STEAP1 targeting by other methodologies may offer improved outcomes in the future.

Considering this context, the use of a T-cell engaging bispecific antibody has strong potential to accomplish this goal.  Xaluritamig (AMG509) is a humanized bispecific antibody with two STEAP1 binding domains, a CD3e binding fragment variable domain, and a Fc domain to prevent effector function.⁷  Recently, results from the 97-patient phase 1 clinical trial were published.  The enrolled patients were heavily pretreated with a median of 4 prior lines of therapy, a median PSA of 113 ng/mL, and 37% harboring liver metastases.  Interestingly, STEAP1 expression was not mandated.  PSA declines of 50% or greater were seen in 49% of the population, and 24% of patients with measurable disease had a confirmed partial response.  Cytokine release syndrome occurred in 72% of patients, but fortunately, most events were low grade, although 27% received tocilizumab.  Fatigue and myalgias were the other common toxicities.⁸

Chimeric Antigen Receptor T-cells (CAR-T) therapy is another means of targeting STEAP1.  A recently published CAR-T cell with a 4-1BB costimulatory domain with a defined CD4:CD8 composition directed against STEAP1 had significant antitumor effects in a pre-clinical STEAP1 murine model, without significant toxicity.⁹  This agent is now going into a phase 1/2 clinical trial, in combination with enzalutamide, for the treatment of men with metastatic castration-resistant prostate cancer (see details listed below).

Below, I highlight a few such STEAP1 targeting trials, that are actively accruing patients.

Highlighted trials with agents targeting STEAP1 for prostate cancer patients

• STEAP1 CAR-T with enzalutamide (NCT06236139)
• Prime-boost immunotherapeutic trial in men with biochemical recurrence targeting 4 antigens, including STEAP1 (NCT05617040)
• AMG-509 (NCT04221542)

References:

1. Oosterheert W and Gros P. Cryo-electron microscopy structure and potential enzymatic function of human six-transmembrane epithelial antigen of the prostate 1 (STEAP1). J Biol Chem 2020; 295:9502-12.
2. Gomes IM, et al. Knockdown of STEAP1 inhibits cell growth and induces apoptosis in LNCaP prostate cancer cells counteracting the effect of androgens. Med Oncol 2018; 35:1-10.
3. Hubert RS, et al. STEAP: a prostate-specific cell-surface antigen highly expressed in human prostate tumors. Proc Natl Acad Sci USA 1999; 96:14523-8.
4. Huo SF, et al. STEAP1 facilitates metastasis and epithelial-mesenchymal transition of lung adenocarcinoma via the JAK2/STAT3 signaling pathway. Biosci Rep 2020; 40:BSR20193169.
5. Nolan-Stevaux O. AMG 509: A novel, humanized, half-Life extended, bispecific STEAP1 × CD3 T cell recruiting XmAb® 2+1 antibody. Cancer Res 2020; 80:DDT02-03-DDT02-03.
6. Danila DC, et al. Phase I Study of DSTP3086S, an Antibody-Drug Conjugate Targeting Six-Transmembrane Epithelial Antigen of Prostate 1, in Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol 2019; 37:3518-27.
7. Nolan-Stevaux O, et al. AMG 509 (Xaluritamig), an Anti-STEAP1 XmAb 2+1 T-cell Redirecting Immune Therapy with Avidity-Dependent Activity against Prostate Cancer. Cancer Discov 2024; 14:90-103.
8. Kelly WK, et al. Xaluritamig, a STEAP1 × CD3 XmAb 2+1 Immune Therapy for Metastatic Castration-Resistant Prostate Cancer: Results from Dose Exploration in a First-in-Human Study. Cancer Discov 2024; 14:76-89.
9. Bhatia V, et al. Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy. Nat Commun 2023; 14:2041.