¹⁷⁷Lu-Prostate-Specific Membrane Antigen Neoadjuvant to Stereotactic Ablative Radiotherapy for Oligorecurrent Prostate Cancer (LUNAR): An Open-Label, Randomized, Controlled, Phase II Study.

Abstract

Progression after metastasis-directed therapy via stereotactic body radiotherapy (SBRT) for oligorecurrent hormone-sensitive prostate cancer (orHSPC) is common. We aimed to assess whether the addition of neoadjuvant prostate-specific membrane antigen (PSMA)-targeting radioligand therapy to SBRT would improve outcomes. The LUNAR trial was a single-center, randomized, open-label, controlled phase II trial conducted at the University of California, Los Angeles. Eligible participants had orHSPC as determined by the presence of one to five lesions identified on PSMA positron emission tomography/computed tomography (PET/CT). After stratifying by stage (N1/M1a <i>v</i> M1b) and lesion count (1 <i>v</i> 2-3 <i>v</i> 4-5), we randomly assigned patients 1:1 to receive SBRT to all lesions or two cycles of ¹⁷⁷Lu-PNT2002 (6.8 GBq/cycle, 2 weeks apart) followed by SBRT to all lesions. The primary end point was progression-free survival (PFS), defined by PSMA PET/CT, salvage hormonal therapy, or death. PSMA PET/CT was acquired systematically at prostate-specific antigen progression and/or 12 months after SBRT. All analyses were done in the intention-to-treat population. The study is registered with ClinicalTrials.gov (identifier: NCT05496959). From September 2, 2022, to November 9, 2023, 92 patients were randomly assigned (SBRT n = 47 and ¹⁷⁷Lu + SBRT n = 45), with 87 evaluable patients (SBRT n = 42 and ¹⁷⁷Lu + SBRT n = 45). At a median follow-up of 22 months, the addition of ¹⁷⁷Lu to SBRT significantly improved PFS (17.6 months [95% CI 15 months to not reached] <i>v</i> 7.4 months [95% CI, 6.0 to 13.5 months]; hazard ratio, 0.37 [95% CI, 0.22 to 0.61], <i>P</i> < .0001). The only grade 3 adverse events were lymphopenia (two patients [4.8%] in the SBRT group and three patients [6.7%] in the ¹⁷⁷Lu + SBRT group). Prognostic biomarkers for PFS were identified. Compared with SBRT alone, the addition of ¹⁷⁷Lu-PNT2002 to SBRT significantly improved PFS in patients with orHSPC without an attendant increase in toxicity.