SAN FRANCISCO, September 28, 2025 — A new clinical trial finds that people with a limited number of metastases from recurrent prostate cancer lived significantly longer without disease progression when they received a radiopharmaceutical drug before targeted radiation, compared with radiation alone.
The phase II LUNAR trial is the first randomized study to show that a treatment established for later-stage prostate cancer can delay progression and defer hormone therapy when added to high-precision radiation therapy for patients with early metastatic disease. Results will be presented today at the American Society for Radiation Oncology (ASTRO) Annual Meeting .
"When we pair external-beam radiation directed to tumors we can see with a radiopharmaceutical to reach microscopic disease we can't see, patients can experience a notably longer interval before progression," said Amar U. Kishan, MD, principal investigator of the trial and a professor and executive vice chair of radiation oncology at the University of California, Los Angeles. "Our study suggests radiopharmaceutical therapy may be beneficial even in the relatively early disease stage of recurrent prostate cancer, when patients can also benefit from metastasis-directed radiation therapy."
The LUNAR study involved patients with oligometastatic prostate cancer, a state of limited metastatic disease where the cancer grows in one to five sites outside the prostate region after initial therapy. Oncologists increasingly treat these patients with a precise, high-dose form of radiation therapy known as stereotactic body radiation therapy (SBRT) to achieve longer-lasting cancer control than with systemic therapies alone and to delay androgen deprivation therapy, which can cause side effects that undermine quality of life. But for most patients, the cancer ultimately returns, likely due to microscopic disease that scans cannot detect.
"Metastasis-directed radiation therapy delays progression, but many patients still recur. That tells us there must be disease present that we can't see even with today's advanced imaging," Dr. Kishan said.
Radiopharmaceuticals are a type of specialized medicine that link a small amount of radiation to a ligand — a molecule that homes in on cancer cells throughout the body. In prostate cancer, radiopharmaceuticals typically target prostate specific membrane antigen (PSMA), a protein found on cancer cells, delivering precise doses of radiation directly to tumors.
These medicines are currently approved for later-stage prostate cancer. The LUNAR trial tested whether a PSMA-targeted radiopharmaceutical could also benefit patients with earlier-stage oligometastatic disease when added to SBRT, to reach both visible and undetectable tumors.
Researchers enrolled 92 patients with hormone-sensitive, oligometastatic prostate cancer and one to five distant lesions visible on a PSMA PET/CT scan. Participants were randomly assigned to receive either SBRT alone (n=47) or two cycles of the investigational PSMA-targeting drug 177Lu-PNT2002 followed by SBRT (n=45). Researchers followed participants for a median of 22 months to track PSA, with low thresholds for follow-up scans to detect recurrence and a pre-planned scan at one year for patients who had not yet progressed.
Adding radioligand therapy significantly improved progression-free survival, with a median survival of 18 months with the combined treatment compared to 7 months with SBRT (p<0.001). On multivariable analysis adjusted for PSA, prior hormonal therapy and number of lesions, the addition of 177Lu-PNT2002 remained significantly associated with improved progression-free survival.
Patients who received the radiopharmaceutical before SBRT were also able to delay hormone therapy by 24 months, compared to 14 months without SBRT alone (p<0.0001). PSA declines of 50% or greater were seen in 52% of patients on the combination arm, compared to 31% on the SBRT arm (p=0.04).
Nearly all instances of disease progression (98%) were new metastases rather than regrowth at previously treated sites. SBRT resulted in very high local control for both groups: 98% in the SBRT arm and 100% in the combination arm. Dr. Kishan noted that there were more progression events than they expected, likely due to the trial's use of highly sensitive PSMA imaging and protocol-mandated scans that could detect changes earlier than in prior studies with different criteria and older imaging methods.
Both groups tolerated treatment well, and there was no increase in severe side effects with the addition of the radiopharmaceutical. The only severe (grade 3) side effects were low white blood cell counts (2 patients on the SBRT arm, 3 on the combination arm).
The results reinforce the growing role of definitive radiation therapy for oligometastatic disease and point to a potential new strategy to extend its benefits. Because androgen deprivation therapy (ADT) remains effective but is associated with side effects such as fatigue, metabolic changes, bone loss and cardiovascular risks, approaches that safely delay its use are of high interest, said Dr. Kishan. "Hormone therapy remains a cornerstone of care, but if we can safely keep people off ADT without compromising outcomes, that's a meaningful quality-of-life win."
LUNAR is the first randomized trial to show that radiopharmaceutical therapy can delay progression when added to metastasis-directed SBRT for recurrent prostate cancer. A similar trial reported earlier this year did not find a benefit when using a different type of radiopharmaceutical that targets bone rather than tumor tissue.
Despite the survival benefit of adding radiopharmaceutical therapy to standard-of-care radiation, 64% of patients in that group still ultimately experienced disease progression. Dr. Kishan said this highlights that residual microscopic disease remains a significant clinical challenge in recurrent prostate cancer and the need for future research into optimal dosing, sequencing and therapeutics.
He also noted that 177Lu-PNT2002 remains investigational in this setting. While SBRT and PSMA PET/CT are FDA-approved and increasingly accessible across the country, this agent is not yet available outside of a clinical trial.
