Canadian Cancer Trials Group (CCTG) study PR21 (PLUDO): Results of crossover treatment from a randomized trial of ¹⁷⁷ Lu-PSMA-617 (LuP) vs docetaxel (DOC) in patients with metastatic castration-resistant prostate cancer (mCRPC).

Abstract

5019 Background: The PLUDO trial randomized patients with mCRPC to receive either LuP or DOC, with cross-over permitted at radiographic progression (RP). At the primary analysis, there was no significant difference in the primary endpoint of 1 st line radiographic progression free survival (rPFS) (HR 1.01, 90% CI: 0.77, 1.31). However, overall survival (OS) was in favor of patients randomized to receive docetaxel first (HR 1.64, 95% CI: 1.14, 2.35) (KN Chi, et al. ESMO Congress, 2025). To provide insights into potential reasons for the survival difference, we report the prespecified secondary objective of rPFS after cross-over therapy. Methods: Multi-centre open-label randomized phase II trial. 199 patients with chemotherapy-naïve, PSMA-PET positive mCRPC progressing after ARPI therapy were randomized 1:1 to receive either LU-P 7.4 GBq IV q6 weeks or DOC 75 mg/m2 IV q3 weeks, with cross-over permitted at progression. rPFS2 was measured from randomization to RP or death after cross-over therapy, “2 nd line rPFS” was from time of start of cross-over therapy to RP or death, OS was defined from time of initial randomization to death, and “2 nd line OS” was from time of cross-over therapy to death. Results: 159 patients had an rPFS event on 1 st line therapy (LuP: n = 79, DOC: n = 80) including 24 deaths (LuP: n = 16, DOC: n = 8). At the time of 1 st rPFS, there were no substantive differences between arms for grade 3-4 adverse events, but patients on LuP reported better quality of life (FACT-P). Of the 135 patients alive, 104 received cross-over therapy (LuP → DOC: 42, DOC → LuP: 62). There were no clinically relevant differences in baseline characteristics of patients who had cross-over therapy between treatment arms. OS was worse for patients that did not cross-over compared to those who did cross-over (LuP arm: HR 3.18 (95% CI 1.93, 7.42); DOC arm: HR 4.73 (95% CI 1.96, 11.38)). For the 104 patients who received both lines of therapy, there was no differences in efficacy outcomes for 2 nd line rPFS, rPFS2, OS, or 2 nd line OS (TABLE). PSA decline ≥ 50% was higher with cross-over Doc than LuP (69% vs 40%, P = 0.004). There were 9 grade 3 adverse events related to cross-over therapy in each arm. Conclusions: In the PLUDO study, there was no difference in first-line or cross-over rPFS between LuP and DOC. In patients who received cross-over therapy, this analysis shows no OS difference, suggesting that imbalance in cross-over from LuP to Doc likely impacted the OS difference in the ITT population and emphasizes the importance of both treatments on efficacy outcomes. Clinical trial information: NCT04663997 . LuP → DOC(median, months)n = 42 DOC → LuP(median, months)n = 62 HR(DOC → LuP/LuP → DOC) 2 nd line rPFS 4.8 5.4 0.86 (90% CI: 0.58, 1.26) rPFS2 18.5 15.8 0.91 (90% CI: 0.61, 1.35) 2 nd line OS 8.1 8.3 0.94 (95% CI: 0.53-1.64) OS 23.2 20.0 0.88 (95% CI: 0.50, 1.53)