PROQURE-I: a phase I study adding concurrent [¹⁷⁷Lu]Lu-PSMA-617 to EBRT and ADT in curative intent treatment of N1 prostate cancer

Purpose: Current treatment of N1M0 prostate cancer (PCa) with locoregional external beam radiotherapy (EBRT) and long-term androgen deprivation therapy (ADT) has suboptimal five-year recurrence-free rates. Adding [¹⁷⁷Lu]Lu-PSMA-617 may improve tumour control and reduce reliance on long-term ADT. This phase-1 dose-escalation study explores the safety and tolerability of adding concurrent [¹⁷⁷Lu]Lu-PSMA-617 with EBRT and ADT. Methods: In the multi-centre phase-1 dose-escalation study (PROQURE-I), treatment-naïve cT1-4N1M0 PCa patients received standard locoregional EBRT (25–35 fractions) and 2–3 years ADT with concurrent [¹⁷⁷Lu]Lu-PSMA-617 to determine its maximum tolerated dose (MTD). Dose levels included one cycle (3, 6 or 9 GBq in week 2 of EBRT) or two cycles (2 × 7.4 GBq in week 2 and 4). Grade ≥ 3 toxicity (CTCAE v5.0) was dose-limiting. Tumour and organ dosimetry was performed with SPECT/CT and planar imaging at 4, 24 and 168 h post-injection. Results: Fourteen patients were included. No dose-limiting toxicity was observed and the MTD was not reached. Reported grade 1–2 toxicities were related to EBRT. Median absorbed dose to the primary tumour of 0.71 Gy/GBq (interquartile range (IQR) 0.5–2.9) at the 9 GBq; 0.91 Gy/GBq (IQR 0.6-1.0) at 7.4 GBq cycle 1; and 0.47 Gy/GBq (0.3–0.5) at cycle 2. Conclusions: Concurrent [¹⁷⁷Lu]Lu-PSMA-617 with EBRT and ADT is safe and well tolerated in treatment-naïve N1M0 PCa. Clinical efficacy should be evaluated in a subsequent phase 2 study.