e17543 Background: 177Lu-labelled prostate-specific membrane antigen (LuPSMA) radionuclide therapy of metastatic castration-resistant prostate cancer (mCRPC) is currently under investigation in phase III trial (VISION). However, patients with diffuse bone involvement, diagnosed with a superscan by bone scintigraphy at baseline, were excluded due to lack of efficacy and safety data. We therefore aimed to investigate the feasibility of LuPSMA in patients with diffuse bone marrow involvement on baseline PSMA-targeted PET/CT. Methods: Patients with progressive mCRPC treated with LuPSMA at six centers in Germany, USA and Australia were considered for inclusion.Eligible patients had 50% or greater bone involvement of the axial skeleton on the baseline PSMA PET. The primary endpoints were PSA response (PCWG3), toxicity (CTCAE v4.02), and overall survival (OS). Secondary endpoints included quality of life (assessed with Brief Pain Inventory-Short Form questionnaires) and radiological response (as measured by CT using RECIST 1.1). Results: 43 of 352 (12%) screened patients met inclusion criteria and were retrospectively analyzed. Median baseline PSA was 1000 (IQR 431-2151) ng/ml. PSA decline ≥50% was achieved in 26/43 (65%) patients, while median PSA progression-free survival was 4.8 (95%CI 2.4–7.1) mo. 15/42 (36%) evaluable patients exhibited pain progression with a median time-to-pain progression of 8.3 (95%CI 5.4–11.3) mo. After a median follow-up of 18.9 mo, median OS was 11.6 (95%CI 8.8-14.3) mo. Objective response in nodal or visceral disease was reported in 7/18 (39%) patients with evaluable target lesions on CT. Grade 3/4 anemia, thrombocytopenia and neutropenia occurred in 9/43 (21%), 10/43 (23%) and 3/43 (8%) patients, respectively. Of note, all patients had grade 1 anemia at baseline, with a median hemoglobin of 9.6 g/dl. 2/43 (5%) patients experienced an adverse event that required a reduction to the LuPSMA activity beginning with the third cycle. Conclusions: Patients with diffuse bone marrow involvement demonstrate similar LuPSMA efficacy and safety when compared to phase II evidence. Acceptable safety outcomes do not support exclusion of patients with a superscan from future LuPSMA treatment protocols.