STEAP1 Offers Potential Multifunctional Target in Prostate Cancer

Rahul Aggarwal, MD

The six transmembrane epithelial antigen of the prostate 1 (STEAP1) has gained traction as a potential therapeutic target in recent years in multiple cancer types due to its overexpression in certain malignant tissues and low levels of expression in normal tissues. Because STEAP1 is often overexpressed in prostate cancer, a disease that still largely lacks safe and effective treatment options, investigators are using it as the basis for developing novel therapies.¹

“STEAP1 is overexpressed in a lot of prostate cancer tissues compared with normal tissues in the body; it has a good therapeutic index to be able to safely target,” Rahul Aggarwal, MD, a medical oncologist in the Division of Hematology/Oncology, coleader of the Genitourinary Medical Oncology program, and the associate director for clinical sciences at the University of California, San Francisco, said in an interview with OncologyLive. “[This is one of] a number of exciting cell surface targets. This is an area [in] general in prostate cancer drug development where you’re seeing a lot of excitement, enthusiasm, clinical trials, and
clinical development.”

STEAP1 is a cell surface protein that is thought to be an ion channel or transporter protein at the cell-to-cell junctions, potentially playing a part
in cell-to-cell communication. Study results have shown that the protein, when overexpressed, can inhibit apoptosis, leading to enhanced cell proliferation and invasion. At the same time, inducing higher than normal levels of STEAP1 can cause epithelial to mesenchymal transition, subsequently leading to heightened tumor progression and disease aggressiveness.¹

Outside of prostate cancer, STEAP1 also isoverexpressed in other solid tumors, including those of the bladder and colon, as well as Ewing
sarcoma. Although the exact role of STEAP1 in cancer development is not fully understood, there is mounting evidence that overexpression of
STEAP1 could be a biomarker of worsened prognosis in prostate cancer.²

STEAP1 is expressed on the surface of approximately 89% of metastatic castration-resistant prostate cancer (mCRPC) lesions, as well as 84% of mCRPC bone metastases, and it displays low or absent expression in normal tissues.³ Although patients with mCRPC have gained multiple new treatment options in recent years, the long-term benefit of these agents is inconsistent and often accompanied by significant toxicities, underscoring the need for targeted treatments. Investigators have developed or are planning to evaluate drugs of different agent classes that target STEAP1 for the treatment of patients with mCRPC.

“First-generation [STEAP1-directed] antibody drug conjugates [ADCs] have shown some promising results,” Aggarwal noted. “There’s
also enthusiasm to use some of the newer modalities of therapy, including bispecific antibodies, to see if they may show even more promising results than [what has already been seen].”

DSTP3086S Shows Activity

An example of a STEAP1 ADC that has been examined in mCRPC is
DSTP3086S. The agent consists of a humanized immunoglobulin 1 anti-STEAP1 monoclonal antibody, MSTP2109A, that is linked to the potent antimitotic agent monomethyl auristatin E (MMAE). After the agent binds to STEAP1 on cancer cells, MMAE is released into the cell, inhibiting cell division and ultimately leading to cell death.⁴

Following encouraging preclinical findings, investigators evaluated DSTP3086S in mCRPC in a phase 1 trial (NCT01283373). The multicenter study enrolled a total of 84 patients: 77 who received treatment once every 3 weeks and 7 patients on a weekly dosing schedule. Patients treated once every 3 weeks experienced dose delays, reductions, and/or discontinuation of DSTP3086S due to adverse effects (AEs) at rates of 38%, 16%, and 22%, respectively. In the weekly dosing cohort, 1 patient had a dose reduction, 3 had a dose delay, and 1 discontinued treatment because of AEs.⁴

Preliminary efficacy was measured by prostate specific antigen (PSA) changes illustrated by waterfall plots, disease progression, and radiographic response. Findings from the study demonstrated that 14% (95% CI, 7%-24%) of patients overall met the criteria of a confirmed
PSA reduction of at least 50%. Among patients who received more than 2 doses of DSTP3086S, (n = 62), PSA responses were observed in 14%
(95% CI, 0%-58%) of patients treated with the 2.25-mg/kg dose (n = 7), 13% (95% CI, 4%-27%) of patients treated with the 2.4-mg/kg dose
(n = 39), and 31% (95% CI, 11%-59%) of patients treated with the 2.8-mg/kg dose (n = 16).⁴

Among 46 patients with RECIST-evaluable disease at baseline, 2 achieved a partial response (PR) and 24 experienced stable disease as their best radiographic response. Fourteen patients were able to continue treatment with DSTP3086S for at least 6 months, including both patients with PRs. However, both patients eventually had to discontinue DSTP3086S due to disease progression.⁴

Study authors concluded that DSTP3086S displayed evidence of antitumor activity with an acceptable safety profile. They noted that further optimization of the agent would be needed for further clinical study. However, they said that their findings could help to inform the development of future STEAP1-directed novel ADCs, chimeric antigen receptor T-cell therapies, and bispecific antibodies.⁴

T-Cell Engager Binds to STEAP1

Investigators have been particularly interested in developing immunotherapy approaches based on T cells to target STEAP1 in mCRPC. One such agent is the novel bispecific antibody AMG 509, which has shown high avidity binding to STEAP1 in preclinical study. Once bound to STEAP1, the agent links T cells with cancer cells and mediates the lysis of the cancer cells.

“[AMG 509] is a T-cell engager that is a 2-headed antibody, with one head that binds to STEAP1 on the cancer cell surface and the other
that binds to T cells,” Aggarwal explained. “It tries to bring those tumor cells into close proximity with the T cells and elicit an antitumor
immune response. It also has additional technology to extend the half-life of the agent. [The structure of AMG 509] may permit weekly or
maybe even biweekly dosing schedules.”

Investigators are evaluating the safety and preliminary efficacy of AMG 509 in patients with mCRPC in an ongoing phase 1 trial (NCT04221542). The study opened in January 2020 and is recruiting patients whose
progressive disease is refractory to antiandrogen
therapy.³

The trial is divided into 4 parts. In part 1, patients will receive intravenous (IV) AMG 509 monotherapy during dose exploration and again
during dose expansion after the determination of the maximum-tolerated dose (MTD) and the recommended phase 2 dose (RP2D). Patients in
parts 2 and 3 will be treated with subcutaneous AMG 509 and IV AMG 509 in earlier lines of treatment, respectively. AMG 509 will be given in combination with abiraterone acetate (Zytiga) in part 4A and with enzalutamide (Xtandi) in part 4B.³

As of June 2022, the study had enrolled 65 of 110 patients for treatment in part 1 and enrollment for parts 2 and 4 had commenced. Part 3 will begin enrollment after the determination of the MTD and the RP2D. Investigators may also choose to add more parts as data emerge. The
coprimary end points are dose-limiting toxicities and safety. Secondary end points include pharmacokinetics, duration of response, progression-
free survival, and overall survival (OS).³

Potential Role for STEAP1 in Prostate Cancer

In addition to being used as a treatment target in the development of novel therapeutics, STEAP1 also has shown potential in prostate cancer as a component in diagnostic imaging techniques. Specifically, investigators developed ⁸⁹Zr-DFO-MSTP2109A, which consists of the same IgG1 STEAP1-directed monoclonal antibody, MSTP2109, as DSTP3086S but is radiolabeled with the positron emitter ⁸⁹Zr.
Investigators hypothesized that⁸⁹Zr-DFOMSTP2109A could be used to detect mCRPC lesions because of MSTP2109A’s ability to
bind to STEAP1.⁵

⁸⁹Zr-DFO-MSTP2109A was subsequently evaluated in a prospective phase 1/2 imaging study (NCT01774071) that enrolled patients with
mCRPC. This trial ran parallel to the phase 1 trial of DSTP3086S. The imaging study enrolled 19 patients, 15 of whom were later enrolled in
the therapeutic study of DSTP3086S.⁵

Findings from the study showed that the mean radiosynthesis yield was 81% (range, 64%-92%) and the product radiochemical purity by radio–
thin-layer chromatography was 99.8% (range, 98.7%-100%). Additionally, the median immunoreactivity fraction was 96% (range, 91%-99%).⁵

⁸⁹Zr-DFO-MSTP2109A displayed exceptional uptake in both patients with bone (n = 18) and soft tissue lesions (n = 9), reaching a median maximized standardized uptake value (SUVmax) of 20.6 (range, 4.4-59.3) and 16.8 (range, 9.0-24.0), respectively. Most lesions (n = 16/17)
that were biopsied were positive on imaging with ⁸⁹Zr-DFO-MSTP2109A, and all sites were histologically positive. Investigators estimated by Bayesian analysis that 86% (95% CI, 75%-100%) of histologically positive lesions were true-positive based on imaging. No correlation was observed between SUVmax tumor uptake and STEAP1
immunohistochemistry or change in PSA level.⁵

In terms of safety, 4 patients had AEs. Two patients experienced grade 1 chills that were thought to be related to infusion, and 1 patient each had back pain and vomiting, which were not attributed to ⁸⁹Zr-DFO-MSTP2109A. Two patients had serious AEs.⁵

Study authors concluded that ⁸⁹Zr-DFOMSTP2109A was well tolerated and displayed good localization in mCRPC sites in both
bone and soft tissue. They wrote that the reagent warranted further investigation as a companion diagnostic for STEAP1-targeted therapy in mCRPC^.5

BC261 Emerges in Ewing Sarcoma

Outside of prostate cancer, investigators have begun development of STEAP1 T cell–engaging bispecific antibodies for the treatment of patients with Ewing sarcoma. There remains an unmet need for effective treatment options with fewer toxicities than intensive chemotherapy; Ewing sarcoma is the second most common bone tumor in pediatric and young adult patients, and the OS rate among patients with metastatic or relapsed disease ranges from 20% to 30%. To date, other antigen-targeted immunotherapies have fallen short of producing an effective T-cell receptor-mediated response, but T cell–engaging bispecific antibodies have not been thoroughly evaluated in this disease setting.⁶

In response to this unmet need, investigators used a rehumanized STEAP1 IgG to create the novel T cell–engaging bispecific antibody BC261. BC261 possesses a design similar to that of AMG
509. It carries the anti-CD3 humanized antibody OKT3 single-chain variable fragments as the agent’s second specificity, making it bispecific
for both STEAP1 and CD3.⁶

In preclinical study, BC261 maintained high purity through prolonged heat stress and consistently displayed the greatest mean fluorescence
intensity among the 4 novel STEAP1 bispecific antibodies being examined, all of which were built using the same platform but used differing variable heavy chain and variable light chain components. BC261 was found to expand to the highest number of Ewing sarcoma cell lines and to bind to prostate cancer and canine osteosarcoma
cell lines.⁶

Moreover, findings from an in vivo antitumor study showed the agent achieved complete tumor regression, even in established tumors sized
approximately 2000 mm3.

“STEAP1 is an appealing target for T-cell immunotherapy, and the STEAP1 T-cell bispecific antibody BC261 offers a novel solution to engage T cells to traffic into immunologically ‘cold’ STEAP1-positive malignancies. BC261 induced robust antitumor responses without long-term toxicities for stand-alone bispecific antibodies or bispecific antibody–armed T cells, warranting clinical development for human solid tumors with major unmet need,” the study authors concluded.⁶