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 <50 ng/dL), ECOG performance status 0–1, and high PSMA uptake on 68-Galium-PSMA PET/CT (SUVmax ≥20 in ≥1 lesion and >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.