Background: Lutetium-177 (¹⁷⁷Lu)-PSMA617 (LuPSMA) is a radiolabelled small molecule that binds with high affinity to prostate specific membrane antigen (PSMA) enabling tumor-targeted delivery of beta-radiation. We previously reported favourable activity and toxicity in 30 patients with mCRPC and now report updated safety and efficacy results including an additional 20 patient expansion cohort. Methods: In this phase II trial, 50 patients with PSMA-avid mCRPC who had progressed after conventional therapies received up to 4 cycles of LuPSMA every 6 weeks. The primary endpoints were 50% PSA response rate (PCWG2) and toxicity (CTCAE v4.3). Other endpoints were objective response rate (ORR), quality of life (EORTC QLQ-C30, BPI), PSA progression free survival (PFS) and overall survival (OS). Results: 50 patients (median age 71, range: 50-87) were eligible for treatment. 90% had progressed after abiraterone and/or enzalutamide, and 88% progressed after chemotherapy (84% post docetaxel and 48% following docetaxel and cabazitaxel). A median of 4 (range: 1-4) cycles and mean radioactivity of 7.5 GBq/cycle was administered. At this interim analysis (cut-off: 19 Jan 2018), the primary endpoint of PSA decline ≥ 50% was achieved in 31 of 50 patients (62%, 95% CI 47-75%), including 22 patients (44%, 95% CI 30-59%) with a PSA decline ≥ 80%. Common toxicities included dry mouth (68%), fatigue (38%), nausea (48%) and pain flare (10%). These were all Grade 1-2, self-limiting or manageable. G3-4 hematological toxicities attributed as possibly related to LuPSMA included thrombocytopenia (10%), anemia (10%), and neutropenia (6%). Median PSA PFS was 7.0 months (95% CI 5.7-8.8) and median OS was 12.0 months (95% CI 10.0-18.7). Conclusions: This LuPSMA Phase II trial suggests high response rates and low toxicity in men with mCRPC who progressed after multiple conventional therapies. These compelling results have justified a randomized trial comparing LuPSMA to carbazitaxel (NCT03392428). Updated QOL, ORR, PSA-PFS and OS data will be presented. Clinical trial information: 12615000912583.