High activity, pain reduction and low toxicity with Lutetium-177 PSMA617 theranostics in metastatic castrate-resistant prostate cancer (mCRPC): results of a phase II prospective trial

531 Background: Retrospective studies demonstrate high response rates of Lutetium-177 (177Lu)-PSMA617 (LuPSMA), a radiolabelled small molecule, that binds with high affinity to prostate specific membrane antigen (PSMA) in men with mCRPC. Methods. In this phase II prospective trial, 30 pts with PSMA-avid mCRPC who had failed standard therapies received up to 4 cycles of LuPSMA every 6 weeks. Patients were included if they had high uptake on 68Ga-PSMA PET/CT defined by tumor SUVmax greater than 1.5 times liver and were excluded if FDG PET/CT demonstrated sites of PSMA-negative disease. Administered activity (6 GBq ± 2 GBq) was adjusted according to tumor burden ( 20 sites), renal function (GFR 90 mL/min) and weight ( 90 Kg). The primary endpoints were PSA response (PCWG2) and toxicity (CTCAE v4). Other endpoints were imaging response (PCWG2 RECIST), quality of life (EORTC QLQ-C30, BPI), dosimetry, PFS and OS. Australian New Zealand Clinical Trials Registry, ACTRN12615000912583. Results. 47 men were screened to identify 30 patients eligible for treatment. 83% progressed after abiraterone and/or enzalutamide, and 87% progressed after chemotherapy including 47% following cabazitaxel. The mean administered activity was 7.5 GBq/cycle. The primary endpoint of PSA decline ≥ 50% was achieved in 17 of 30 patients (57%, 95% CI 37-75%), including 11 patients (37%, 95% CI 20-56%) with a PSA decline ≥ 80%. The most common toxicity was dry mouth in 87% of patients, all grade 1 in severity. Grade 3 or greater thrombocytopenia possibly attributed to LuPSMA occurred in 13% of patients. An objective imaging response was seen in 82% of the subgroup of 17 patients who had evaluable soft tissue disease. The overwhelming pattern of progression was seen in non-target marrow disease. Pain severity and interference scores improved significantly at all time points. Median PSA progression free survival was 7·6 months (95% CI 6·4-9·0) and median OS was 13·5 months (95% CI 10·4-22·7). Conclusions. This LuPSMA Phase II trial provides evidence of high response rates, pain reduction and low toxicity in men with mCRPC who progressed after conventional therapies. These compelling results indicate the need for randomised trials comparing LuPSMA to existing standard-of-care.