A phase 1 study of docetaxel in combination with 177-lutetium-PSMA-I&T in patients with metastatic castration-resistant prostate cancer.

TPS281 Background: Radioligand therapy targeting prostate-specific membrane antigen (PSMA) with 177-Lutetium-labeled ligands has demonstrated meaningful antitumor activity and a manageable safety profile in patients with mCRPC. Preclinical and clinical data support combining 177-Lutetium-PSMA with other systemic agents to enhance efficacy through complementary mechanisms. Docetaxel remains a standard first-line chemotherapy for mCRPC, and the ongoing DORA trial is evaluating its combination with the alpha-emitter radium-223, highlighting the clinical interest in integrating chemotherapy with radiopharmaceuticals. However, the optimal and safe dose of docetaxel when combined with beta-emitting agents such as 177-Lutetium-PSMA-I&T has not yet been established. Methods: This investigator-initiated, single-center, open-label phase 1 study is evaluating the safety and tolerability of docetaxel in combination with 177-Lutetium-PSMA-I&T in chemotherapy-naïve patients with mCRPC. A standard 3+3 dose-escalation design is used to determine the recommended phase 2 dose (RP2D) of docetaxel. Patients receive fixed-dose 177-Lutetium-PSMA-I&T (7.4 GBq IV every 6 weeks, up to 4 cycles) combined with escalating docetaxel doses (50, 60, and 75 mg/m² IV every 3 weeks, up to 10 cycles). Continuous androgen deprivation therapy is required. Eligible patients must have histologically confirmed prostate adenocarcinoma, metastatic disease on conventional imaging, castration resistance (testosterone 10 in other lesions). Key exclusion criteria include prior chemotherapy or radiopharmaceuticals in the castration-resistant setting, neuroendocrine histology, discordant lesions on 18F-FDG PET/CT, or active secondary malignancies. The primary endpoint is determination of the RP2D of docetaxel in combination with 177-Lutetium-PSMA-I&T. Secondary endpoints include incidence of dose-limiting toxicities (DLTs), treatment completion rates, and late toxicities up to 24 weeks after therapy completion. Exploratory endpoints include PSA decline ≥50%, radiographic progression-free survival per PCWG3, and metabolic response by PERCIST on PSMA PET/CT. Planned enrollment is 2–15 patients, accounting for an estimated 30% screening failure rate.