Bispecific antibodies are next generation monoclonal antibodies (mAbs) that recognizes two antigens and have the potential to simultaneously inhibit different proteins, this inhibition process plays a very vital role in cancer progression.

Six-transmembrane epithelial antigen of prostate 1 (STEAP1) is highly expressed in prostate cancers, representing an attractive target for treating mCRPC. STEAP1 is overexpressed in  approximately 80% of prostate cancers, including bone and lymph node metastases, representing an attractive target for treating metastatic castration-resistant prostate cancer (mCRPC).

Amgen’s bi-specific demonstrated significant antitumor activity in preclinical prostate cancer models. Data from the Phase I study of AMG 509 in heavily pretreated patients with mCRPC were presented in the Proffered Paper Session at the ESMO 2023. The study objectives were to evaluate safety, tolerability, antitumor activity, pharmacokinetics, and determine the maximum tolerated dose and recommended Phase II dose. As of March 23, 2023, 97 patients in 15 dose levels received ≥1 dose of xaluritamig. The maximum tolerated dose was identified as 1.5 mg IV weekly (3-step, D1 0.1 mg / D8 0.3 mg / D15 1.0 mg / D22+ 1.5 mg).  Prostate-specific antigen (PSA) and RECIST responses across cohorts were encouraging as shown below in the table.

 

All patients experienced adverse events that emerged during treatment, with 76% of these being of Grade 3 or higher severity. Furthermore, 97% of patients reported adverse events related to the treatment, with 55% with Grade 3 or higher category. Treatment-related adverse events leading to discontinuation occurred in 19% of patients. The most common adverse events were cytokine release syndrome (72.2%), fatigue (52.6%), anemia (45.4%), pyrexia (40.2%), and myalgia (39.2%). Preliminary PK showed dose-proportional increase in exposure with a mean terminal half-life of approximately 3-4 days.

AMG 509 (xaluritamig) displayed promising responses in terms of PSA and RECIST when compared to well-established historical treatments for late-line mCRPC patients. This study not only confirms the viability of T-cell engagers as a potential therapy for prostate cancer but also validates STEAP1 as a suitable target. 

KOL insights

"Xaluritamig was tolerable, with low-grade cytokine release syndrome, occurring primarily cycle 1, with encouraging preliminary efficacy in heavily pretreated patients with mCRPC," –MD, United states

Conclusion 

The interim results from the Phase I study of AMG 509 (xaluritamig) represent a significant step forward in the pursuit of effective therapies for heavily treated mCRPC patients. With a positive benefit-to-risk profile, robust anti-tumor activity, and notable response rates, AMG 509 holds promise as a potential treatment option. The preliminary efficacy results are encouraging, with a notable PSA50 (≥ 50% PSA decline) responses occurred in 43 patients (49%) and PSA90 (≥ 90% PSA decline) in 24 patients (28%). In Addition, overall, RECIST responses included 16 (24%) confirmed partial responses and 32 (48%) with stable disease. AE were generally consistent with the MOA and patient population with no Grade 4-5 events. The drug was tolerable with manageable adverse events. These findings suggest that AMG 509 holds promise as a potential therapeutic option for this challenging patient population.

Apart from Amgen, other key players such as Xencor, Merus, Regeneron, and Lava Therapeutics are also evaluating their bispecific antibody candidates for the treatment of mCRPC. However, these products may or may not be direct competitors to Amgen’s AMG 509, but have the potential to significantly impact the therapeutic space of prostate cancer. 

The below mentioned table represents the competitive landscape of bispecific antibodies in prostate cancer:

For more insight into the patient's burden/epidemiology, treatment, and changing market landscape-related advancements, refer to the Metastatic Castration-Resistant Prostate Cancer (mCRPC) Market Report