The addition of neoadjuvant Lutetium-177 (Lu-177) therapy to metastasis-directed stereotactic body radiation therapy (SBRT) more than doubled progression-free survival (PFS) in men with oligometastatic, hormone-sensitive prostate cancer.

The primary endpoint median PFS rose from 7.4 months with standard SBRT to 17.6 months with the addition of Lu-177 therapy. The patients included in the LUNAR trial had recurrent, progressive disease limited to one to five sites outside of the prostate region after initial treatment.

This type of recurrent disease is common, occurring in an estimated 30%-45% of patients depending on how it is defined — one to three sites or one to five sites. SBRT is the current standard of care for patients with oligometastatic prostate cancer (involving up to five metastatic sites) and allows patients to avoid hormone-deprivation treatments that can significantly impair quality of life.

“Adding two cycles of [this treatment] to SBRT significantly improved PFS in men with oligorecurrent prostate cancer…without attendant increase in toxicity,” said principal investigator Amar U. Kishan, MD, at American Society for Radiation Oncology (ASTRO) 2025 Annual Meeting in San Francisco.

The improvement is “presumably by action against occult metastatic disease,” added Kishan, who is a professor and executive vice chair of radiation oncology at the University of California, Los Angeles. Lu-177 PNT2002 (Lu-177) is the radioligand therapy under investigation.

Methods and Results

The phase 2 study randomized 92 patients with one to five lesions outside of the prostate or prostate bed (the anatomical site where the prostate is or once was) to receive either standard SBRT given to all disease sites either alone or after Lu-177. In both groups, sites of disease were defined using prostate-specific membrane antigen (PSMA) PET/CT. Patients were stratified by stage (N1/M1a vs M1b) and number of disease sites (one, two to three, or four to five).

The targeted radiotherapy Lu-177 was given intravenously at a dose of 6.8 GBq in two cycles given 8 weeks apart. Imaging was performed 4-6 weeks after the second cycle. Progression was defined as PSMA-avid lesions seen at the time of biochemical progression or on a scheduled PSMA PET/CT performed 12 months after SBRT treatment, initiation of salvage therapy, or death.

The researchers also looked at hormone therapy-free survival. Patients who received Lu-177 and SBRT had improved survival without hormone treatment — 24.3 months vs 14.1 months with SBRT alone. 

The findings have important quality of life implications for these patients, according to invited discussant Chad Tang, MD, who is a radiation oncologist at the University of Texas MD Anderson Cancer Center, Houston.

“No man likes hormone therapy, so the obviation of hormone therapy in this subgroup is a very interesting idea and deserves further investigation,” Tang said. He added that LUNAR opens the door to avoiding hormone therapy even longer than with SBRT alone. 

Side effects associated with hormone treatment — hot flashes, loss of libido/erectile dysfunction, fatigue, weight gain, loss of muscle mass, and cognitive/mood changes — significantly impair quality of life.

T-cell receptor rearrangement is a marker of immune function, and patients who had better return of immune function (immune reconstitution) at 90 days were less likely to have progression regardless of the treatment group. The researchers also found that germline single nucleotide polymorphisms (SNPs) in 22 genes were predictive of whether a patient would have progression.

What’s Next?

Tang mentioned that two anticipated studies, one looking at 177Lu treatment before and after SBRT, and a Novartis-run study looking at 177Lu treatment after SBRT will provide additional detail.

“We’re going to eagerly see how all of these results fit together, and I think that the field…is going to be totally changed in the next 5 years,” he said during a press briefing.

There were no significant differences in side effects experienced by patients in the two treatment groups. The only severe (grade 3) side effect was low white blood cell count, which was seen in two patients in the SBRT group and three in the combination group.

Even with these additional studies, further research will be needed, both Kishan and Tang noted. In LUNAR, 98% (64/65) of progression events were due to new lesions.

“Ultimately, while this intervention [the addition of Lu-177] worked well, 64% even in the investigational arm still had some progression. So we could further optimize the dose, cycle, and other variables for these patients,” Kishan said.

Kishan noted that SBRT represents the standard of care for patients with metastasis to only a few sites (up to five), and that Lu-177 is not indicted for the treatment of recurrent disease in this patient group.

This study was supported by funding from Lantheus. Kishnan reported receiving honoraria, consulting fees, and/or participating on the advisory boards of Varian Medical Systems, Accuray, Boston Scientific, Lantheus, Novartis.

Tang reported no relevant disclosures.