(177)Lu-PSMA-617 versus docetaxel in chemotherapy-naïve metastatic castration-resistant prostate cancer: a randomized, controlled, phase 2 non-inferiority trial

PURPOSE: Lutetium-177 prostate-specific membrane antigen-617 ((177)Lu-PSMA-617) in end-stage metastatic castration-resistant prostate cancer (mCRPC) has reported favourable outcomes. In this study, we aimed to prospectively compare the efficacy and safety of (177)Lu-PSMA-617 and docetaxel in chemotherapy-naïve mCRPC patients. METHODS: This was a randomized, parallel-group, open-label, phase 2, and non-inferiority trial. Chemotherapy-naïve patients with mCRPC and high PSMA-expressing lesions on (68) Ga-PSMA-11 PET/CT were randomly assigned in 1:1 ratio to (177)Lu-PSMA-617 (6.0–7.4 GBq/cycle, every 8 weeks, up to 4 cycles) or docetaxel (75 mg/m(2)/cycle, every 3 weeks, up to 10 cycles). The primary end-point was best prostate-specific antigen response rate (PSA-RR), defined according to Prostate Cancer Clinical Trials Working Group-3 as proportion of patients achieving ≥ 50% decline in PSA from baseline. Non-inferiority margin of − 15% was pre-specified for PSA-RR. RESULTS: Between December 2019 and March 2021, 40 of the 45 patients assessed for eligibility underwent randomization. Fifteen of 20 patients in (177)Lu-PSMA-617 arm and 20/20 patients in docetaxel arm received treatment per protocol. Of these, best PSA-RR in the (177)Lu-PSMA-617 arm was 60% (9/15) versus 40% (8/20) in the docetaxel arm. The difference in the PSA-RRs between the two arms was 20% (95% confidence interval, CI: − 12–47, P = 0.25), meeting the pre-specified criterion for non-inferiority in per-protocol analysis. Further, progression-free survival rates at 6 months were 30% and 20% in the (177)Lu-PSMA-617 and docetaxel arms respectively (difference 10%, 95% CI: − 18–38, P = 0.50). Overall, treatment-emergent grade ≥ 3 adverse events occurred less frequently with (177)Lu-PSMA-617 than with docetaxel (6/20, 30% versus 10/20, 50%, respectively, P = 0.20). Quality-of-life outcomes improved significantly in (177)Lu-PSMA-617 arm compared to docetaxel arm (P < 0.01). CONCLUSION: (177)Lu-PSMA-617 was demonstrated to be safe and non-inferior to docetaxel in the treatment of mCRPC and could, thus, be potentially employed earlier in the disease course rather than being solely reserved for advanced end-stage disease. CLINICAL TRIAL REGISTRATION: Clinical Trials Registry-India, CTRI/2019/12/022282. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-021-05618-3.