Background: ¹⁷⁷Lu‐PSMA-617 (Lu-PSMA) is a radiolabeled small-molecule that binds with high affinity to PSMA enabling highly targeted delivery of beta radiation to prostate cancer cells. In metastatic castration-resistant prostate cancer, Lu-PSMA showed superior activity to Cabazitaxel in the TheraP trial. Although androgen deprivation therapy (ADT) + Docetaxel is a standard of care for de novo high-volume mHNPC, outcomes remain sub-optimal for many patients. We hypothesize that Lu-PSMA prior to docetaxel will achieve a higher undetectable PSA rate at 12 months compared to docetaxel alone in men with newly-diagnosed high-volume mHNPC. Methods: UpFrontPSMA is an open label, randomized, stratified, 2-arm, multi-center, phase 2 clinical trial recruiting 140 patients at 11 Australian centers. Key eligibility criteria include histological diagnosis of prostate cancer within 12 weeks, PSA > 10ng/ml at diagnosis, < 4 weeks on ADT, and high-volume (≥ 4 bone metastases with ≥ 1 outside the axial skeleton, and/or visceral metastases), PSMA-avid disease on ⁶⁸Ga-PSMA-11 PET/CT with no major discordance on ¹⁸FDG-PET/CT. Patients will be randomized 1:1 to the experimental arm (Lu-PSMA 7.5 GBq q6w x 2 cycles followed 6 weeks later by docetaxel 75mg/m² q3w x 6 cycles), or standard-of-care Arm (docetaxel alone). All patients will receive continuous ADT. Assessments will be done every 3 weeks during study treatment, and then every 6-12 weeks until unequivocal disease progression. CT and whole body bone scan will be performed at baseline and every 12 weeks, ⁶⁸Ga-PSMA-11 PET/CT at baseline and 12 weeks, and ¹⁸FDG-PET/CT at baseline and 12 weeks (if applicable). Correlative samples will include optional tumour tissue (baseline and disease progression), and serial plasma/whole blood collection. The primary endpoint is undetectable PSA (≤ 0.2 ng/ml) at 12 months. Secondary endpoints are safety, time to castration resistance, PSA-progression-free-survival (PSA-PFS), radiographic PFS, radiographic response rates, early PSMA-PET response rates, quality of life and overall survival. Exploratory endpoints are prognostic and predictive value of PET-derived parameters and of biomarkers identified in plasma/whole blood/tumour tissue. The study will have 85% power to reject the null hypothesis if the true 12 month undetectable PSA rate in the experimental Arm is 50%. The power calculation assumes no more than 10 patients (7%) of the 140 patients will be unevaluable or lost to follow-up in 1 year, 5% alpha and two-sided test for proportions. As of October 13, 2020, accrual stands at 4. UpFrontPSMA is an investigator-led, academic trial sponsored by Peter MacCallum Cancer Centre in collaboration with ANZUP Cancer Trials Group with study coordination provided by the Centre for Biostatistics and Clinical Trials (BaCT) Clinical trial information: NCT04343885