UpFrontPSMA: A Randomised Phase 2 Study of Sequential 177 Lu-PSMA617 and Docetaxel versus Docetaxel in Metastatic Hormone-Naïve Prostate Cancer.

OBJECTIVE To assess the activity and safety of sequential 177 Lu-PSMA-617 and docetaxel versus docetaxel on a background of androgen deprivation therapy (ADT) in men with de novo metastatic hormone-naive prostate cancer (mHNPC). 177 Lu-PSMA-617 is a novel targeted radioligand therapy directed against prostate specific membrane antigen (PSMA). We hypothesise that 177 Lu-PSMA-617 will be effective and safe when given sequentially with docetaxel in mHNPC. PATIENTS AND METHODS UpFrontPSMA (NCT04343885) is an open-label, randomised, multicentre, phase two trial recruiting 140 patients at 12 Australian centres. Key eligibility criteria include: prostate cancer with a histological diagnosis within 12 weeks of screening commencement; PSA >10ng/mL at diagnosis; ≤ 4 weeks on ADT; evidence of metastatic disease on CT and/or bone scan; high-volume PSMA-avid disease with the maximum standardised uptake value (SUVmax) greater than 15; and absence of extensive discordant FDG-positive, PSMA-negative disease. 68 Ga-PSMA-11 and 18 F-FDG PET/CT undergo central review to determine eligibility. Patients are randomised 1:1 to experimental treatment, Arm A, (177 Lu-PSMA-617 7.5GBq q6w x 2 cycles followed by docetaxel 75 mg/m2 q3w x 6 cycles) or standard-of-care treatment, Arm B, (docetaxel 75 mg/m2 q3w x 6 cycles). All patients receive continuous ADT. Patients are stratified based on disease volume on conventional imaging and duration of ADT at time of registration. The primary endpoint is the proportion of patients with undetectable PSA (≤ 0.2ng/L) at 12 months after study treatment commencement. Secondary endpoints include safety, time to castration resistance, overall survival, PSA and radiographic progression-free survival (PFS), objective tumour response rate, early PSMA PET response, health-related quality of life, and frequency and severity of adverse events. Enrolment commenced in April 2020. RESULTS AND CONCLUSIONS The results of this trial will generate data on the activity and safety of 177 Lu-PSMA-617 in men with de novo mHNPC in a randomised phase 2 design.