Tolerability of Concurrent EBRT + Lu-PSMA for Node-positive Prostate Cancer (PROQURE-1)

Rationale: In the past, prostate cancer patients with nodal metastases (clinically N1M0) were not considered for curative treatment, based on the hypothesis that these patients are affected by systemic disease. Today, patients with primary diagnosed N1M0 prostate cancer increasingly receive curative intent high-dose external beam radiotherapy (EBRT) to the prostate and regional nodes combined with up to 3 years androgen deprivation therapy (ADT). This aggressive and lengthy multimodal treatment can achieve long-term disease-free and overall survival, but it also comes with significant toxicity and failure rates of up to 47% within 5 years with locoregional recurrence within radiotherapy fields and/or distant progression. A new strategy is needed to (1) enhance EBRT to better control macroscopic tumor in the prostate and involved nodes, (2) better treat undetected microscopic disease inside and outside EBRT fields, and (3) potentially reduce or obviate the long use of ADT with its toxicity and associated poor quality of life. Radioligand therapy (RLT) with Lutetium-177 labeled PSMA-ligands (177Lu-PSMA-617) can selectively deliver radiation dose to both macroscopic and microscopic tumor locations throughout the body, with limited systemic toxicity. Based on radiobiologic considerations, the hypothesis is that complementing EBRT with concurrent 177Lu-PSMA-617 can provide synergistic anti-tumor effects, without prolonging overall treatment time and with limited toxicity. The feasibility of this innovative use of "RLT as the ultimate radiosensitizer for EBRT" now needs to be explored.

Objective: Primary: To determine the maximum tolerated dose (MTD) of 1 or 2 cycles 177Lu-PSMA-617 when given concurrent with EBRT+ADT. Secondary: To demonstrate acceptable late toxicity at 6 months, superior dosimetric efficacy, anti-tumor efficacy at 6 months, feasibility of QoL evaluation and favorable pharmacokinetics.

Study design: Multicenter prospective phase I dose-escalation study, using a BOIN design, with 4 dose levels for 177Lu-PSMA-617 and a maximum of 24 patients.

Study population: Patients with primary diagnosed prostate cancer, clinical stage T2-T4N1M0 based on MRI and PSMA PET/CT, with a PSMA-positive index tumor within the prostate and involved nodes all within EBRT fields (highest node below the level of the aortic bifurcation).

Intervention: Standard of care treatment (EBRT of prostate and pelvic nodes with concurrent ADT) is complemented with 1 or 2 concurrent cycles dose-escalated 177Lu-PSMA-617 in week 2 (and 4).