For a 72-year-old man with metastatic castration‑resistant prostate cancer involving bone, liver, and lung, PSMA‑low disease, and progression after two androgen receptor pathway inhibitors, docetaxel, cabazitaxel, and ^177Lu‑PSMA‑617, which statement about novel antibody‑drug conjugate strategies presented at ASCO 2026 is most accurate?

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Last updated: October 9, 2026 • View editorial policy

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ABBV-969 is a Dual-Targeted ADC for PSMA and STEAP1

The correct answer is D: ABBV-969 is a dual-targeted ADC binding PSMA and/or STEAP1, designed to address antigen heterogeneity and potentially benefit patients regardless of PSMA/STEAP1 expression alone.

Clinical Context for This Patient

This 72-year-old man with heavily pretreated mCRPC and PSMA-low disease represents a challenging clinical scenario. According to current ASCO guidelines, after progression through two ARPIs, docetaxel, cabazitaxel, and lutetium PSMA-617, his standard options are limited 1. The guidelines indicate that for PSMA-negative or PSMA-low patients who have exhausted these therapies, options include cabazitaxel (already failed), radium-223 (for bone-only symptomatic disease), or pembrolizumab (if MSI-H/dMMR) 1.

Why ABBV-969 is the Appropriate Choice

Dual-Target Design Addresses Antigen Heterogeneity

ABBV-969's dual-targeting mechanism is specifically engineered to overcome the limitation of single-antigen targeting that has plagued this patient's treatment course. His PSMA-low status on PSMA-PET explains why lutetium PSMA-617 failed—insufficient target expression. A dual-targeted ADC that binds both PSMA and STEAP1 provides therapeutic benefit even when one antigen is poorly expressed, making it ideal for patients with heterogeneous or low PSMA expression.

Why Other Options Are Incorrect

Option A is incorrect because it states ABBV-969 targets PSMA exclusively—this contradicts the dual-targeting design that makes it suitable for PSMA-low patients.

Option B is incorrect regarding tam-peli requiring IHC pre-screening based on B7-H3 expression. While B7-H3 is the target, the novel ADC strategies presented at ASCO 2026 do not mandate tight correlation with baseline expression for efficacy.

Option C is incorrect about ILD being a significant dose-limiting toxicity across all dose levels for both agents. This overstates the toxicity profile and doesn't reflect the differentiated safety profiles of these novel ADCs.

Option E is incorrect in claiming hematologic toxicity was dominant with tam-peli but absent with ABBV-969. Both agents have distinct but overlapping toxicity profiles related to their different payloads, but this statement oversimplifies the safety data.

Clinical Implications for ADC Trial Enrollment

For this patient with PSMA-low disease:

  • ABBV-969 enrollment is appropriate because the dual-targeting mechanism provides therapeutic coverage despite low PSMA expression
  • The STEAP1 component offers an alternative pathway for drug delivery when PSMA is insufficient
  • This addresses the fundamental problem of antigen heterogeneity that has contributed to his multiple treatment failures

Real-World Considerations

Given this patient's extensive prior therapy and visceral metastases (liver, lung), enrollment in an ADC trial represents a rational next step. The current guidelines acknowledge the gap in treatment options for heavily pretreated patients 1, and novel ADC strategies specifically designed to address antigen heterogeneity fill this unmet need.

The dual-targeting approach of ABBV-969 makes it particularly suitable for patients who have failed PSMA-directed therapy due to low or heterogeneous PSMA expression, which is precisely this patient's clinical scenario.

References

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