Phase 1, open-label, first-in-human study of ABBV-969, a dual variable antibody-drug conjugate, in patients with metastatic castration-resistant prostate cancer.

Background:

Metastatic castration-resistant prostate cancer (mCRPC) is an incurable disease with high unmet need. Six-transmembrane epithelial antigen of prostate 1 (STEAP1) is highly enriched in > 85% of prostate cancer (PC),1 and prostate-specific membrane antigen (PSMA) expression is > 100-fold higher in patients (pts) with mCRPC.2 These are well-established and actionable targets in mCRPC. ABBV-969, a dual variable domain IgG1 drug conjugate, targets STEAP1 and PSMA and includes a topoisomerase-1 inhibitor (Top1i) payload. Based on preclinical data, ABBV-969 is expected to have greater efficacy and wider activity than targeting either antigen alone. We describe a first-in-human study of ABBV-969 in pts with mCRPC.

Methods:

This phase 1 open-label study (NCT06318273) of ABBV-969 monotherapy evaluates safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Eligible pts, ≥ 18 years of age, have mCRPC treated with and progressed on ≥ 1 prior novel hormonal agent for mPC/CRPC and ≥ 1 taxane for PC (or have refused, are intolerant to, or unable to access taxanes). Pts must have a life expectancy > 6 months, serum testosterone levels ≤ 50 ng/dL, ≥ 1 metastatic lesion at baseline, and serum prostate-specific antigen (PSA) levels ≥ 1.0 ng/mL. Part 1 (dose escalation) of the study will enroll up to ~80 pts and is guided by the Bayesian optimal interval design primarily based on the dose-limiting toxicity rate. Part 2 (dose expansion) will randomize up to 60 pts in 2 (1:1) or 3 (1:1:1) dose levels (determined in part 1). Part 1 will enroll pts in US, Israel, Japan, and Australia with Canada, France, and Spain added in part 2. Optimal (recommended phase 2) dose will be determined by the totality of PK, PD, safety, and efficacy data. Pts will receive intravenous ABBV-969 until disease progression, intolerable toxicity, or other study discontinuation criteria are met. The study objectives and endpoints are shown in the Table. 1. Xu M, et al. Cancers 2022;14:4034. 2. Sweat SD, et al. Urology 1998;52:637–40.
Objectives and endpoints.

Objective

Endpoint

Primary

Safety and tolerability

Adverse events and dose-limiting toxicities

Clinical laboratory parameters, vital signs, ECG

Secondary

 

Preliminary efficacy

Primary

≥ 50% prostate-specific antigen (PSA) decrease from baseline

Secondary

Confirmed complete response(CR)/partial response (PR) per RECIST v1.1

PSA response duration

Duration of response for pts with CR or PR

Overall survival

Progression-free survival

Pharmacokinetic (PK) characterization

PK parameters including Cmax, Tmax, t1/2, and area under the curve using noncompartmental methods

Determination of antidrug antibodies

Dose optimization

Recommended phase 2 dose determined using all available information
Previously presented at ESMO 2024, FPN: 1660TiP, Raanan Berger et al - reused with permission.

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Author Details

Anthony Tolcher

NEXT Oncology San Antonio, San Antonio, TX

Abstract Details

Meeting

2025 ASCO Annual Meeting

Session Type

Poster Session

Session Title

Genitourinary Cancer—Prostate, Testicular, and Penile

Track

Genitourinary Cancer—Prostate, Testicular, and Penile

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Abstract Disclosure