ABBV-969 in mCRPC: Dual‑Targeting ADC Shows Robust PSA and Objective Responses in Heavily Pretreated Patients

ABBV-969, a first-in-class dual-targeting antibody-drug conjugate (ADC), is emerging as a promising new therapeutic candidate for patients with metastatic castration-resistant prostate cancer (mCRPC), particularly in the late-line setting where treatment options are limited and outcomes remain poor. Designed to simultaneously target prostate-specific membrane antigen (PSMA) and six-transmembrane epithelial antigen of prostate 1 (STEAP1), both highly expressed in the majority of advanced prostate tumors, ABBV-969 delivers a potent topoisomerase I inhibitor payload directly to cancer cells, aiming to improve tumor coverage and overcome resistance associated with single-target therapies.

Data from the completed dose-escalation phase of an ongoing first-in-human phase 1 trial provide an early but compelling signal of clinical activity. The study enrolled 49 heavily pretreated patients with mCRPC, with a median of five prior lines of therapy, all of whom had previously received at least one novel hormonal agent and typically a taxane. Patients received escalating doses of ABBV-969 ranging from 1 mg/kg to 12.5 mg/kg administered every three weeks.

Despite the advanced disease setting, the treatment demonstrated notable antitumor activity. At dose levels of 3 mg/kg and above, prostate-specific antigen (PSA) responses were particularly encouraging, with 67% of patients achieving a PSA decline of at least 50% and 28% achieving a decline of at least 90%. Among patients with RECIST-evaluable disease, the confirmed objective response rate reached 45%, suggesting meaningful tumor shrinkage in a population where response rates are typically modest.

Importantly, responses were observed across multiple dose levels and appeared durable at the time of analysis, with over half of the patients remaining on treatment at the data cutoff. These findings support a clear exposure-response relationship and reinforce the biological rationale behind dual targeting, which may enable more comprehensive tumor cell engagement in heterogeneous disease.

The safety profile of ABBV-969 was consistent with expectations for ADCs carrying topoisomerase I inhibitor payloads. Grade 3 or higher treatment-emergent adverse events occurred in 63% of patients, with anemia representing the most common severe toxicity. While the incidence of high-grade adverse events is not negligible, the overall safety profile was described as manageable, and no unexpected safety signals were reported.

The dual-targeting mechanism may represent a meaningful advance in ADC design for prostate cancer. By binding both PSMA and STEAP1, ABBV-969 has the potential to address tumor heterogeneity more effectively than single-antigen approaches, potentially reducing the likelihood of antigen escape and improving payload delivery across diverse tumor cell populations.

Source.