Metastasis-directed therapy with stereotactic body radiotherapy (SBRT) has been shown to improve progression-free survival in patients with oligorecurrent hormone-sensitive prostate cancer (orHSPC). Although SBRT can provide effective local control of metastatic lesions, disease progression remains common, frequently occurring outside previously treated sites. This pattern of recurrence suggests that occult microscopic disease may contribute to subsequent progression despite treatment of all visible lesions.
The randomized phase II LUNAR trial investigated whether adding neoadjuvant prostate-specific membrane antigen (PSMA)-targeted radioligand therapy with ¹⁷⁷Lu-PNT2002 before SBRT could improve disease control. Following the previously reported primary analysis, investigators conducted an updated evaluation of efficacy and safety, including secondary and exploratory outcomes intended to assess longer-term disease progression.
The updated findings were published in European Urology on October 12, 2026, in a study titled “¹⁷⁷Lu-Prostate-specific Membrane Antigen Prior to Stereotactic Ablative Radiotherapy in Oligorecurrent Prostate Cancer: Secondary and Exploratory End Point Results from the Randomized Phase 2 LUNAR Trial.”
The study was authored by Amar U. Kishan, Holly Wilhalme, Carol Felix, Johanna Enke, Farzana Z. Ali, Rejah Nabong, Jesus E. Juarez-Casillas, Kevin Flores, T. Martin Ma, Vinicius Ludwig, Mariko Nakayama, Zachary Ells, Magnus Dahlbom, Michael Lauria, Catherine Meyer, Minsong Cao, Joanne B. Weidhaas, Donatello Telesca, Kristen McGreevy, Nicholas G. Nickols, Sophia Parmisano, Wayne Brisbane, Leonard Marks, Adam E. Singer, Matthew B. Rettig, Robert E. Reiter, Luca F. Valle, Martin Allen-Auerbach, Johannes Czernin, Michael L. Steinberg, and Jeremie Calais.
Study Design and Endpoints
LUNAR was a single-center, open-label, randomized phase II trial conducted at the University of California, Los Angeles. The study enrolled patients with PSMA PET/CT-detected orHSPC and one to five metastatic lesions amenable to SBRT. Between September 2022 and November 2023, 92 patients were randomized 1:1 to receive either SBRT alone (n = 47) or two cycles of neoadjuvant ¹⁷⁷Lu-PNT2002 followed by SBRT (n = 45).
Patients assigned to the experimental arm received ¹⁷⁷Lu-PNT2002 at a dose of 6.8 GBq (±10%) per cycle, administered approximately eight weeks apart. An interval PSMA PET/CT was performed four to six weeks after the second cycle, followed by SBRT one to two weeks later. Patients in the control arm received SBRT without preceding radioligand therapy.
Five patients assigned to SBRT alone withdrew immediately after randomization. Consequently, the efficacy and safety analyses included 87 evaluable patients: 42 in the SBRT-alone arm and 45 in the ¹⁷⁷Lu-PNT2002 plus SBRT arm. The primary endpoint was progression-free survival (PFS), defined as the time from randomization to PSMA PET/CT-defined progression, initiation of salvage hormonal therapy, or death.
Secondary endpoints included hormonal therapy-free survival (HT-FS), progression-free status at 24 months after SBRT, and overall survival (OS). Exploratory endpoints included polymetastatic PFS, castration-resistant disease-free survival (CRFS), and conventional imaging-based PFS (CT-PFS).
Updated Efficacy Results
At the May 15, 2026 data cutoff, median follow-up was 31.9 months. The updated analysis confirmed a sustained PFS benefit with the addition of neoadjuvant ¹⁷⁷Lu-PNT2002 to SBRT.
Median PFS was 17.6 months with ¹⁷⁷Lu-PNT2002 plus SBRT versus 7.4 months with SBRT alone (HR 0.38; 95% CI 0.23–0.61; p < 0.001). At 24 months after SBRT, a significantly greater proportion of patients in the combination arm remained free of detectable disease compared with SBRT alone (33% vs 12%; p = 0.02).
Hormonal therapy-free survival was also significantly improved with the addition of ¹⁷⁷Lu-PNT2002 (HR 0.57; 95% CI 0.34–0.95; p = 0.03). Salvage hormonal therapy was initiated in 29 of 45 patients in the combination arm and 31 of 42 patients in the SBRT-alone arm. During follow-up, 37 progression events were recorded in the SBRT-alone arm and 30 in the combination arm. All progression events in the SBRT-alone arm and 29 of 30 events in the combination arm involved new lesions outside previously treated fields on PSMA PET/CT. The remaining event involved initiation of salvage hormonal therapy for rising PSA without detectable disease.
Overall survival remained immature. Two deaths occurred in the SBRT-alone group and one in the combination group, with no statistically significant difference in OS (HR 0.45; 95% CI 0.04–5.00; p = 0.51).
Secondary and Exploratory Outcomes
The extended follow-up also provided information on disease progression beyond the appearance of new lesions on PSMA PET/CT. Polymetastatic PFS: Polymetastatic progression occurred in three patients receiving ¹⁷⁷Lu-PNT2002 plus SBRT and nine patients receiving SBRT alone. The estimated two-year polymetastatic PFS rate was 93% versus 79%, respectively (HR 0.28; 95% CI 0.08–1.03; log-rank p = 0.04).
Castration-resistant disease-free survival: Castration-resistant prostate cancer developed in one patient in the combination arm and seven patients in the SBRT-alone arm. The estimated two-year CRFS rate was 100% with ¹⁷⁷Lu-PNT2002 plus SBRT versus 88% with SBRT alone (HR 0.13; 95% CI 0.02–1.10; log-rank p = 0.03).
Conventional imaging-based PFS: New lesions detectable on CT were identified in eight patients receiving ¹⁷⁷Lu-PNT2002 plus SBRT and 14 patients receiving SBRT alone. Estimated two-year CT-PFS rates were 84% and 67%, respectively (HR 0.46; 95% CI 0.19–1.09; p = 0.07). Although the results numerically favored the combination arm, the difference did not reach conventional statistical significance.
These exploratory analyses suggested a potential benefit beyond delaying PSMA PET/CT-detected recurrence. However, the findings should be interpreted cautiously, particularly given the limited number of events, the confidence intervals crossing 1, and the exploratory nature of the analyses.
Updated Safety Findings
No new safety signals were identified during extended follow-up, and the investigators reported no significant differences in adverse event profiles between treatment arms. During extended follow-up, no grade 4–5 adverse events were reported except for one grade 4 neutropenia event in the SBRT-alone group, occurring in a patient who had subsequently initiated hormonal therapy for recurrent disease. The extended safety findings were consistent with the previously reported tolerability of the combined treatment approach, although follow-up remains relatively short in a disease setting with a long overall survival horizon.
Clinical Implications
The updated LUNAR analysis provides further evidence supporting the investigation of PSMA-targeted radioligand therapy before metastasis-directed SBRT in patients with oligorecurrent hormone-sensitive prostate cancer. An important consideration is that the initial PFS benefit was largely driven by delayed detection of new lesions on PSMA PET/CT. Although PSMA PET/CT offers greater sensitivity for detecting recurrent disease, the prognostic significance of isolated, low-volume progression identified through this modality remains incompletely established.
The exploratory evaluation of polymetastatic progression, development of castration-resistant disease, and progression on conventional imaging was therefore intended to provide additional information about potentially more clinically meaningful disease outcomes.
The results numerically favored the combination strategy across these endpoints, with statistically significant log-rank comparisons reported for polymetastatic PFS and CRFS. Nevertheless, these analyses were not designed to establish definitive treatment effects, and the conventional imaging-based PFS comparison did not achieve statistical significance.
Several limitations should be considered, including the single-center design, relatively small sample size, absence of blinded central image review, exclusion of five randomized patients from the analyzed population, and limited follow-up for evaluating long-term survival outcomes. Importantly, the study did not establish an overall survival advantage, and additional research is needed to identify which patients are most likely to benefit from radioligand treatment intensification rather than SBRT alone.
Conclusion
With extended follow-up, the randomized phase II LUNAR trial demonstrated sustained improvements in progression-free survival and hormonal therapy-free survival with two cycles of neoadjuvant ¹⁷⁷Lu-PNT2002 followed by SBRT compared with SBRT alone in patients with PSMA PET/CT-detected oligorecurrent hormone-sensitive prostate cancer.
Exploratory findings also suggested potential benefits in delaying polymetastatic progression, castration-resistant disease, and progression detectable on conventional imaging, without new safety signals. While these findings support further investigation of radioligand therapy combined with metastasis-directed SBRT, confirmation in larger studies with longer follow-up is needed to determine its impact on clinically meaningful long-term outcomes.
