PROQURE-I: a phase I study adding concurrent [<sup>177</sup>Lu]Lu-PSMA-617 to EBRT and ADT in curative intent treatment of N1 prostate cancer.
Concurrent [177Lu]Lu-PSMA-617 with EBRT and ADT appears safe and well tolerated in treatment-naïve N1M0 prostate cancer patients, but clinical efficacy requires further investigation.
Where it sits
this study against the rest of the vipivotide corpusSummary and findings
This phase I study evaluated the safety and tolerability of adding concurrent [177Lu]Lu-PSMA-617 to external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT) in treatment-naïve N1M0 prostate cancer patients. Fourteen patients received standard EBRT and ADT along with varying doses of [177Lu]Lu-PSMA-617. No dose-limiting toxicity was observed, and the maximum tolerated dose was not reached.
Abstract
<h4>Purpose</h4>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 [<sup>177</sup>Lu]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 [<sup>177</sup>Lu]Lu-PSMA-617 with EBRT and ADT.<h4>Methods</h4>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 [<sup>177</sup>Lu]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.<h4>Results</h4>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.<h4>Conclusions</h4>Concurrent [<sup>177</sup>Lu]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.
Background
This study addresses the suboptimal five-year recurrence-free rates in N1M0 prostate cancer treated with locoregional EBRT and long-term ADT. Previous research indicated that adding [177Lu]Lu-PSMA-617 could potentially improve tumor control. This phase I study is significant as it explores the safety of this combination therapy.
Methods
The study was a multi-centre phase-1 dose-escalation trial involving treatment-naïve cT1-4N1M0 prostate cancer patients. A total of fourteen patients received standard locoregional EBRT (25-35 fractions) and 2-3 years of ADT, with concurrent doses of [177Lu]Lu-PSMA-617 at 3, 6, or 9 GBq in week 2 of EBRT or two cycles of 7.4 GBq.
Results
The primary endpoint showed that no dose-limiting toxicity was observed in the fourteen patients. The median absorbed dose to the primary tumor was 0.71 Gy/GBq at the 9 GBq dose level. Reported toxicities were grade 1-2 and related to EBRT, with the maximum tolerated dose not reached.
Interpretation
The findings suggest that concurrent administration of [177Lu]Lu-PSMA-617 with EBRT and ADT is safe, aligning with previous studies that have explored similar combination therapies. However, the lack of significant adverse effects does not necessarily imply clinical efficacy, which needs to be evaluated in future studies. The small sample size and absence of long-term follow-up data limit the conclusions that can be drawn.
Key findings
- No dose-limiting toxicity observed, n=14.
- Median absorbed dose to the primary tumour of 0.71 Gy/GBq (IQR 0.5-2.9) at 9 GBq.
- Median absorbed dose of 0.91 Gy/GBq (IQR 0.6-1.0) at 7.4 GBq cycle 1.
- Median absorbed dose of 0.47 Gy/GBq (IQR 0.3-0.5) at cycle 2.
Limitations
- small sample size, n=14
- no dose-limiting toxicity reached
- short follow-up duration
- lack of long-term efficacy data