ProTACT: Preliminary data from a first-in-human, phase 1 study evaluating the safety, tolerability, and anti-tumor activity of [ ²²⁵ Ac]Ac-FL-020, a PSMA-targeted radioconjugate, in patients with mCRPC.

Abstract

5050 Background: [ 225 Ac]Ac-FL-020 is a next-generation, prostate-specific membrane antigen (PSMA) alpha radioconjugate developed using the proprietary UniRDC linker-chelator technology designed to optimize biodistribution. [ 225 Ac]Ac-FL-020 is intended for treating patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and aims to enhance tumor uptake while sparing radiosensitive organs, such as salivary glands, thus potentially leading to an improved therapeutic window. Methods: ProTACT (FL-020-001) is a first-in-human, open-label, multicenter Phase 1 study investigating the safety, tolerability, and preliminary anti-tumor activity of [ 225 Ac]Ac-FL-020 in pts with advanced PSMA-positive mCRPC. This study consists of: Bayesian dose escalation (Part 1) and dose expansion (Part 2). Eligible pts must have: histologically confirmed mCRPC, evidence of disease progression, and ≥1 PSMA-positron emission tomography positive lesion (uptake higher than liver). Prior androgen receptor signaling inhibitors or CYP17 inhibitors and ≥1 taxane-based chemotherapy is required, unless declined by the pt. Prior Lu-177 is allowed. Pts with extensive PSMA-negative disease are excluded. Dose cohorts of 1 to 3 pts (for Cohorts 1 and 2) and dose cohorts of 3 to 6 pts (for Cohorts 3+) will evaluate ascending dose levels from 1 to 10 MBq (intravenous; every 6 weeks; x 6 cycles) to determine the maximum tolerated dose and/or recommended Phase 2 dose (RP2D). Once the RP2D is established, 18 additional pts will be enrolled in Part 2 to further assess safety and early signals of efficacy. Results: As of 2 Jan 2026, 15 eligible pts have received [ 225 Ac]Ac-FL-020 (maximum dose/cycle: 5 MBq). No dose-limiting toxicities have been observed. Most frequent adverse events (AEs) were fatigue (10 pts), nausea and dry mouth (7 pts each), constipation and anemia (4 pts each). Grade (G)3+ AEs were reported for 6 pts, all G3+ AEs occurred in one pt each. One pt at 1 MBq had G3 anemia and 1 pt at 5 MBq had G3 anemia and G3 thrombocytopenia, both considered related to disease progression with bone marrow infiltration and unrelated to [ 225 Ac]Ac-FL-020. As of the cutoff date, 11 pts remain on treatment and 4 pts discontinued treatment prematurely, 3 due to disease progression and 1 due to G2 dry mouth. Another 6 pts reported dry mouth, all were G1. No renal toxicities or decline in renal function was observed. As of 6 Jan 2026, 1 of 3 pts at 3 MBq showed a reduction in baseline prostate-specific antigen (PSA) > 80% after 3 cycles and 2 of 6 pts at 5 MBq showed a reduction in PSA > 50% after 1 cycle. Conclusions: These initial findings support the feasibility and tolerability of [ 225 Ac]Ac-FL-020 administration in heavily pretreated pts with mCRPC with a few notable PSA responses. The RP2D has not yet been reached, and dose escalation continues. Clinical trial information: NCT06492122 .