Bispecific T-cell Engagers in Metastatic Castration-Resistant Prostate Cancer

Prostate cancer is the most common cancer in men and the second leading cause of cancer-related deaths after lung cancer (1). Metastatic castration-resistant prostate cancer (mCRPC) is a lethal form of prostate cancer with a dismal prognosis. The median overall survival of patients with mCRPC after prior treatment with androgen receptor pathway inhibitors (ARPI) is approximately two years (2). Recently, novel agents or regimens have been added to the therapeutic armamentarium of patients with mCRPC. Poly-ADP ribose polymerase (PARP) inhibitors monotherapy (i.e., olaparib and rucaparib) or in combination with ARPI can be offered to patients harboring BRCA gene mutations (i.e., olaparib with abiraterone, niraparib with abiraterone) or homologous recombination repair (HRR) alterations (i.e., talazoparib with enzalutamide; ref. 3). Lutetium-177-PSMA-617, a radioligand theranostic drug, is now approved for patients with mCRPC with high prostate-specific membrane antigen (PSMA) expression after prior progression on ARPI and docetaxel and has recently shown efficacy in the pre-docetaxel mCRPC setting (1). Patients with bone metastases and minimal symptoms can undergo treatment with radium-223, whereas those with microsatellite instability-high or mismatch-repair deficiency on genomic tumor testing can receive pembrolizumab (PD1-inhibitor). Other treatment options used include ARPI switch, taxane chemotherapy (i.e., docetaxel and cabazitaxel), and sipuleucel-T. However, most of these agents or regimens confer only modest survival benefits. In addition, many of these treatment options are increasingly being utilized in the earlier castration-sensitive setting, further limiting the treatment options in the mCRPC setting (1). Thus, there remains an unmet need to urgently develop new therapeutic agents with novel mechanisms of action to improve survival outcomes.

The immunosuppressive microenvironment of prostate cancer has always presented challenges to immune targeting therapies; immune-checkpoint inhibitors monotherapy or in combination with drugs with different mechanisms of action have shown no to modest efficacy in patients with metastatic prostate cancer so far (4). Bispecific T-cell engagers (BiTE), which are currently undergoing investigation, could potentially circumvent the challenges encountered by immune-checkpoint inhibitors by simultaneously binding to CD3 receptors on T cells and to a specific cell-surface antigen expressed on cancer cells. This interaction leads to T-cell activation and proliferation, releasing inflammatory cytokines, including perforin and granzyme, that lead to tumor cell apoptosis (5).

Although BiTEs have been approved for hematologic malignancies, their development in solid cancers has been more challenging. Blinatumomab was the first BiTE to provide clinical proof of concept for BiTE antitumor activity and to gain Food and Drug Administration (FDA) approval in relapsed or refractory B-cell precursor acute lymphoblastic leukemia. By binding the CD19 receptor on malignant B cells, this antibody significantly improved overall survival in these patients while sparing adverse events encountered with standard-of-care chemotherapy (5). More recently, tarlatamab showed encouraging disease response results and safety profile in a phase I study in heavily pretreated patients with small cell lung cancer. Tarlatamab binds delta-like ligand 3 (DLL3) overly expressed on lung cancer cells and CD3 receptor, resulting in T cell–mediated tumor cell lysis (6).

Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is a cell-surface antigen highly expressed on prostate cancer cells, particularly in patients with mCRPC, with low to no expression in noncancerous prostate and other normal tissues (7). Xaluritamig (AMG 509) is a novel humanized bispecific antibody distinguished by its avidity since it was designed to bind STEAP1 on cancer cells with 2 fragment antigen-binding domains (Fab) and CD3 receptor through a binding single chain fragment variable domain (scFv). Thus, xaluritamig allows T-cell activation and killing of STEAP1-expressing tumor cells by preferentially targeting cells with high STEAP1 expression (Fig. 1; ref. 7).

The study led by Nolan-Stevaux and colleagues showed encouraging preclinical results with xaluritamig in prostate cancer (7). In mice models, xaluritamig resulted in significant antitumor activity, leading to tumor stabilization and even tumor shrinkage at higher doses. Administration of xaluritamig in cynomolgus monkeys, who have a similar structure to human STEAP1, resulted in minor hematologic changes and immune cell tissue infiltration, and provided evidence that xaluritamig was associated with no to minimal T cell–mediated killing of off-target cells which have low STEAP1 expression (7).

Kelly, Danila, and colleagues conducted the first clinical phase I study assessing the safety and preliminary efficacy of xaluritamig in 97 patients with mCRPC who had disease progression on prior 1 to 2 taxanes and ARPI (8). The median number of prior lines of therapy was four, with 37% of the patients with visceral metastases (n = 51) having liver metastases, which represents a very high-risk population of patients. In this dose-exploration study, patients received xaluritamig as an intravenous (i.v.) infusion every week (QW) or every 2 weeks (Q2W) within a 28-day cycle. Based on safety results from these cohorts, the investigators found that 0.1 mg was the maximum tolerated priming dose, whereas the maximum tolerated dose or recommended phase II dose was 1.5 mg acquired through a 3-step i.v. dose increase QW at days 8, 15, and 22. Out of 97 treated patients, 87 had an evaluable PSA at baseline, with 43 (49%) experiencing a PSA decline of ≥50% (PSA 50) and 24 (28%) patients experiencing a PSA decline of ≥90% (PSA 90), confirmed by a second test value ≥3 weeks later. Furthermore, in 67 patients with RECIST-evaluable disease at baseline, 16 (24%) experienced a confirmed partial response (PR). The median duration of these responses was 9.2 months (range, 1.9–17.7 months). Remarkably, these promising PSA responses and the objective responses were seen in all cohorts, which included patients who were recruited in earlier cohorts receiving lower doses of xaluritamig in this dose-exploration study. Cytokine release syndrome (CRS), graded by Lee criteria, was the most common side effect occurring in 72% of patients. CRS occurred primarily during cycle 1, with 27% of patients receiving tocilizumab (anti-IL6 antibody). However, only 2% of patients experienced grade 3 CRS, no patients experienced grade 4–5 CRS, and only 3% of patients discontinued xaluritamig due to CRS (8). Systemic premedication with dexamethasone prior to cycle 1, step dose increase, prompt treatment of CRS with dexamethasone, and tocilizumab appear to attenuate the severity of CRS. Thus, physician education and access to these agents seem to mitigate this common BiTEs-related adverse event, which has been reported with previous BiTEs (5, 6). This phase I study showed an encouraging safety profile and efficacy of xaluritamig in patients with heavily pretreated mCRPC.

Previous studies have assessed the safety and efficacy of BiTEs in prostate cancer but were limited by toxicities and/or modest efficacy. Previous BiTEs were designed to bind PSMA on prostate cancer cells. JNJ-63898081 was administered to 39 patients with mCRPC and prior progression on docetaxel or ARPI. Two patients had a PSA50 response (5.1%), and no objective response was seen. CRS was encountered in 66.7% of patients, with no patients experiencing grade ≥3 CRS (9). Another PSMA-targeting BiTE with an extended half-life, AMG 160, was assessed in 32 patients with mCRPC and prior progression on 1 to 2 taxanes and ARPI. PSA50 responses were reported in only 3 of 22 (13.6%) evaluable patients, whereas 1 partial objective response was seen among 18 patients (5.6%) with measurable disease. CRS was reported in 84.4% of patients, with 31.3% having grade 3 CRS (10).

In summary, xaluritamig has a tolerable and manageable safety and a very encouraging efficacy profile, especially compared with prior studies assessing BiTEs in the mCRPC setting. Future directions will include establishing the safety and efficacy in larger cohorts and possibly combining xaluritamig with other agents with different mechanisms of action. Xaluritamig is currently being investigated in the phase I study in combination with ARPI (abiraterone or enzalutamide) or as monotherapy in patients with mCRPC with or without prior treatment with an ARPI (NCT04221542). Furthermore, other studies in prostate cancer are assessing BiTEs that target different tumor antigens. For example, GEM3PSCA BiTE, which targets prostate stem cell antigen (PSCA), is being tested in patients with PSCA-positive genitourinary cancers, including prostate cancer (NCT03927573) and tarlatamab (AMG 757) that targets DLL3 antigen in patients with neuroendocrine prostate cancer (NCT04702737). Furthermore, MT110 and GEN1044 BiTEs that bind epithelial cell adhesion molecule (EpCAM; NCT00635596) and 5T4 antigen (NCT04424641) on prostate cancer cells, respectively, are undergoing testing in clinical trials. BiTEs have finally emerged as a promising treatment option in patients with advanced prostate cancer.