The phase 2 randomized LUNAR trial previously demonstrated that neoadjuvant [177]Lu-PNT2002 before stereotactic body radiotherapy (SBRT) significantly improved progression-free survival (PFS) in patients with oligorecurrent hormone-sensitive prostate cancer (orHSPC). We report updated efficacy and safety outcomes with extended follow-up. Patients with prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT)-detected orHSPC and one to five metastatic lesions amenable to SBRT were randomized 1:1 to SBRT alone or two cycles of neoadjuvant [177]Lu-PNT2002 followed by SBRT. The primary end point was PFS, defined as new lesions on PSMA PET/CT, initiation of salvage hormonal therapy, or death. Secondary end points included hormonal therapy-free survival (HT-FS) and 24-mo progression-free status. Exploratory end points included polymetastatic PFS (poly-PFS), castration-resistant disease-free survival (CRFS), and conventional imaging progression-free survival (CT-PFS). Between September 2022 and November 2023, 92 patients were randomized to SBRT alone (n = 47) or [177]Lu-PNT2002 plus SBRT (n = 45). At a median follow-up of 31.9 mo, [177]Lu-PNT2002 significantly improved PFS (median 17.6 vs 7.4 mo; hazard ratio [HR] 0.38, 95% confidence interval [CI] = 0.23-0.61; p < 0.001) and HT-FS (HR 0.57, 95% CI = 0.34-0.95; p = 0.03). Exploratory analyses demonstrated improved poly-PFS (HR 0.28, 95% CI = 0.08-1.03; p = 0.04), CRFS (HR 0.13, 95% CI = 0.02-1.10; p = 0.03), and CT-PFS (HR 0.46, 95% CI = 0.19-1.09; p = 0.07). No new safety signals were observed. With extended follow-up, neoadjuvant [177]Lu-PNT2002 before SBRT produced durable improvements in PFS and HT-FS. While poly-PFS, CRFS, and CT-PFS were exploratory end points, their improvement provides hypothesis-generating evidence that the addition of radioligand therapy to SBRT may alter disease trajectory beyond delaying PSMA PET/CT-detected recurrence.

Accumulating data support nectin-4, particularly membranous expression, as a predictive biomarker of enfortumab vedotin activity. Low expression identifies patients with poorer outcomes but not absence of benefit, underscoring the need for standardized prospective validation before clinical implementation.