Patients with recurrent prostate cancer experienced a significant delay in disease progression when treated with a new PSMA-targeted radioligand therapy before undergoing stereotactic body radiotherapy (SBRT), according to results presented at the 2025 American Society for Radiation Oncology Annual Meeting in San Francisco.
The clinical trial found that men who received the radioligand drug went a median of 17.6 months without their disease worsening, compared to 7.4 months for those who received SBRT alone. This also resulted in a longer period before starting hormone therapy, which is commonly used to treat recurrent prostate cancer but can have side effects such as fatigue and bone loss.
“This is the first randomized trial to show that PSMA-targeting radioligand can significantly delay progression when added to metastasis-directed radiation,” said the executive vice chair of radiation oncology at the David Geffen School of Medicine at UCLA and first author of the study. “It gives patients more time before needing hormonal therapy, which can carry significant side effects such as fatigue and bone loss. Avoiding or delaying hormonal therapy consistently benefits quality of life. Moreover, the trial results establish that radioligand therapy agents, which thus far have only been studied in more advanced disease, have a role to play earlier in the disease course.”
Prostate cancer remains one of the most common cancers among men worldwide. In some cases, it returns years after initial treatment as oligorecurrent disease—where only a few new lesions appear.
SBRT has become an increasingly common approach for these cases by targeting visible lesions while sparing healthy tissue. However, many patients eventually relapse due to microscopic disease not detected on imaging scans. Radioligand therapy delivers targeted radiation directly to cancer cells and may help address this challenge.
The phase 2 LUNAR trial tested whether adding PNT2002—a molecule targeting PSMA on prostate cancer cells—before SBRT could control hidden tumors better than SBRT alone.
“This trial is especially exciting because it showcases the full potential of PSMA-based theranostics technologies,” said the senior author of the study, director of the Ahmanson Translational Theranostics Division’s clinical research program and associate professor at UCLA’s department of molecular and medical pharmacology. “We leveraged PSMA PET imaging technology to guide SBRT targeting, which is more precise than other imaging methods. And we combined it with PSMA radioligand therapy to treat PSMA expressing sites of disease, both the ones visible by PET but also the microscopic sites too small to be detected by PET.”
Researchers enrolled 92 men with recurrent prostate cancer into two groups: one received SBRT alone; the other got two doses of 177Lu-PNT2002 followed by SBRT. Patients were monitored using PSA blood tests and PSMA PET scans.
Results showed that adding 177Lu-PSMA before SBRT more than doubled progression-free survival—from 7.4 months up to 17.6 months—and reduced risk of recurrence, need for hormone therapy, or death by 63%. These outcomes were consistent across all patient subgroups regardless of stage or number of lesions and occurred with minimal side effects. Men receiving combination treatment waited a median 24.3 months before starting hormone therapy versus 14.1 months for those given only SBRT.
The team also identified biological markers linked to better outcomes: patients with stronger immune responses after SBRT fared better, and certain gene sets related to immune function and DNA repair helped identify those at higher or lower risk for progression.
Despite these benefits, researchers noted that microscopic cancer remains difficult to eliminate completely since about two-thirds still experienced progression during follow-up.
“This is an important proof of principle,” said Kishan, co-director of UCLA Health Jonsson Comprehensive Cancer Center’s cancer molecular imaging, nanotechnology and theranostics program. “It suggests we may be able to intervene earlier with radioligand therapy and meaningfully change the course of disease. And, importantly, we didn’t see significantly worse side effects with the addition of the drug. Further research is needed to track longer-term outcomes, and we will also be actively looking at other ways of optimizing response rates.”
“This work is a great example of true collaboration between radiation oncology and nuclear medicine, leveraging theranostics at its best, a mix of imaging and therapy,” Calais added.
Other authors from UCLA participated in this research project funded by Lantheus.
