LUNAR Trial: Combining Radiopharmaceutical Therapy with SBRT
A phase II study known as the LUNAR trial investigated whether adding a PSMA-targeted radiopharmaceutical before high-precision radiation could improve outcomes for men with oligometastatic, hormone-sensitive recurrent prostate cancer. In this randomized study, 92 participants with one to five distant lesions visible on PSMA PET/CT were assigned to receive either metastasis-directed radiation therapy (SBRT) alone or SBRT preceded by two cycles of the investigational radiopharmaceutical 177Lu-PNT2002. Patients were followed for a median of 22 months to monitor disease progression and treatment response.
How Radiopharmaceuticals Work in Prostate Cancer
Radiopharmaceutical therapy combines a radioactive payload with a targeting molecule that homes in on cancer cells. In prostate cancer, the targeting molecule binds to PSMA, delivering radiation directly to tumors—including microscopic disease not detectable by imaging. While radiopharmaceuticals are approved for later-stage disease, the LUNAR trial explored their utility earlier in the disease course when coupled with SBRT aimed at visible lesions.
Key Findings: Progression-Free Survival and Hormone Therapy Delay
The addition of radiopharmaceutical therapy significantly extended progression-free survival (PFS). The median PFS was 18 months for the combination therapy vs 7 months for SBRT alone (p<0.001). After adjusting for PSA levels, prior hormonal therapy, and lesion number, the improved PFS with the radiopharmaceutical remained statistically significant. The results suggest that treating both visible tumors and microscopic disease can meaningfully delay progression in oligometastatic recurrence.
Another meaningful endpoint was the extension of time before starting androgen deprivation therapy (ADT). Patients receiving the radiopharmaceutical before SBRT could delay ADT by a median of 24 months, compared with 14 months for SBRT alone (p<0.0001). PSA declines of 50% or more were observed in 52% of patients in the combination arm vs 31% in the SBRT-alone arm (p=0.04). These findings highlight a potential quality-of-life benefit by postponing systemic hormone therapy, known for fatigue, metabolic changes, and other side effects.
Safety, Efficacy, and Local Control
Local tumor control was excellent in both groups, with 98% control in the SBRT arm and 100% in the combination arm. Most disease progression events were new metastases rather than regrowth at treated sites, underscoring the challenge of eradicating micrometastatic disease even with advanced imaging. In terms of safety, the combination did not increase severe adverse effects: grade 3 hematologic toxicity—low white blood cell counts—occurred in two patients on SBRT alone and three on the combination arm. Overall, the regimen was well-tolerated by participants.
Clinical Implications and Next Steps
These results reinforce the expanding role of definitive radiation therapy for oligometastatic disease and introduce a potential strategy to extend its benefits by addressing occult tumor cells. Delaying ADT is particularly appealing given its long-term side effects. Dr. Amar U. Kishan, lead investigator, noted that while hormone therapy remains a cornerstone of care, safely deferring it without compromising outcomes would be highly advantageous for patients’ quality of life. The LUNAR findings also emphasize that radiopharmaceuticals like 177Lu-PNT2002 can complement SBRT in earlier stages of disease when the goal is durable control and symptom relief.
It’s important to recognize that 177Lu-PNT2002 is still investigational in this setting, and SBRT with PSMA PET/CT is already FDA-approved and widely available. A separate trial using a different radiopharmaceutical targeting bone did not show a benefit, illustrating that not all radiopharmaceuticals have the same impact and that dosing, sequencing, and patient selection are critical areas for future research. As scientists refine these approaches, the prospect of combining targeted radiopharmaceutical therapy with metastasis-directed radiation could become a new standard for carefully selected patients facing recurrent oligometastatic prostate cancer.
