A phase 1, first-in-human (FIH) study evaluating the safety, pharmacokinetics, and efficacy of ABBV-969 in patients with metastatic castration-resistant prostate cancer (mCRPC).

Abstract

5014 Background: Prostate-specific membrane antigen (PSMA) and six-transmembrane epithelial antigen of prostate 1 (STEAP1) are overexpressed in >80% of metastatic prostate cancer tumors. ABBV-969 is a first-in-class PSMA/STEAP1 dual-targeting antibody drug conjugate with a topoisomerase 1 inhibitor (Top1i) payload. We report results from the completed dose escalation part of the phase 1, FIH study (NCT06318273) evaluating ABBV-969 in patients (pts) with mCRPC. Methods: Pts were ≥18 years with confirmed metastatic prostate adenocarcinoma, had an ECOG performance score ≤1, a serum prostate-specific antigen (PSA) level ≥1.0 ng/mL, and hemoglobin ≥9 g/dL at study entry. Pts received ≥1 novel hormone agent (NHA) and ≥1 taxane (unless unable to receive or declined taxane), and progressed on prior NHA. Pts received 1 mg/kg–12.5 mg/kg of ABBV-969 monotherapy every 3 weeks until disease progression or intolerable toxicity. Primary objective was to determine safety and tolerability. Secondary objectives were preliminary efficacy, pharmacokinetics, and recommended phase 2 dose. Results: As of Jan 2026, 49 pts with mCRPC received ABBV-969 in the dose escalation part of the study. Median follow-up was 11.1 months (95% CI, 8.4–13.2), and median number of prior lines was 5 (range 1–9). Pt demographics and safety results are shown in Table 1. Thirty-one (63%) pts had Grade (G) ≥3 TEAEs, primarily G3 anemia (n=24). Dose and exposure responses were observed, with durable PSA and objective responses noted at all dose levels ≥3 mg/kg. At dose levels ≥3 mg/kg, confirmed PSA50 and PSA90 responses were 67% (95% CI, 52–81) and 28% (95% CI, 15–44), respectively. Among 29 pts with RECIST-evaluable disease, the confirmed ORR, as assessed by investigator, was 45% (95% CI, 26–64). At data cut, 26 pts were receiving ongoing treatment. Radiographic PFS will be presented. Conclusions: ABBV-969 demonstrated promising antitumor activity and a manageable safety profile in heavily pretreated pts with mCRPC. Dose optimization is ongoing. Clinical trial information: NCT06318273 . Pt demographics and safety. TotalN=49 Median age, years (range) 71 (57–84) Median PSA, µg/L (range) 74 (2–2879) Disease location, n (%)BoneLymph nodeLiverLungAdrenal gland 43 (88)20 (41)8 (16)7 (14)2 (4) Prior therapy, n (%) a Androgen-receptor pathway inhibitorDocetaxelCabazitaxel 177 Lu-PSMA-617 49 (100)41 (84)19 (39)23 (47) Any Grade TEAE of interest, n (%)Hematologic toxicityGastrointestinal toxicitySalivary gland toxicity 38 (78)33 (67)6 (12) TEAE leading to, n (%)Discontinuation b InterruptionReduction 3 (6)24 (49)16 (33) TEAE leading to death, n (%) c Pneumonitis c 1 (2)1 (2) DLT events, n (%) d 3 (6) a Only therapies of interest listed. b G3 pneumonitis and disease progression. c ABBV-969-related. d Anemia at ≥8 mg/kg doses. DLT, dose-limiting toxicity.