BULLSEYE: 177Lu-PSMA-617 may delay disease progression in oligometastatic HSPC

Treatment with [¹⁷⁷Lu]Lu-prostate-specific membrane antigen (PSMA)-617 (¹⁷⁷Lu-PSMA-617; Pluvicto) may durably delay disease progression compared with deferred androgen deprivation therapy (ADT) in men with oligometastatic hormone-sensitive prostate cancer (HSPC), according to findings from the phase 2 BULLSEYE trial (NCT04443062) published in The Lancet Oncology.¹

The radioligand therapy was also associated with a manageable safety profile. According to the authors, these findings suggest that ¹⁷⁷Lu-PSMA-617 “could offer an alternative to hormonal agents as a first-line systemic treatment in oligometastatic HSPC.”

“More and more men want to avoid hormone therapy because of the unpleasant side effects that can occur,” explained senior author James Nagarajah, MD, PhD, a nuclear medicine physician at Radboud University Medical Center, in a news release on the results.² “We therefore wanted to investigate whether PSMA therapy could delay hormone therapy, and whether it might become a suitable alternative in the future.”

BULLSEYE was an open-label, randomized, phase 2 trial conducted across 3 academic centers in the Netherlands and 1 community hospital in Cyprus. The study enrolled 58 patients with biochemically recurrent, PSMA-expressing oligometastatic HSPC following prior definitive therapy. To be eligible for enrollment, patients needed to have an ECOG performance status of 0 to 1, a prostate-specific antigen (PSA) doubling time of less than 6 months, and PSA levels greater than 1.0 μg/L.

Participants were randomly assigned 1:1 to receive 2 cycles of 7.4 GBq ¹⁷⁷Lu-PSMA-617 (n = 29) or standard of care consisting of deferred ADT with active surveillance (n = 29). The co-primary end points were the proportion of patients with disease progression and the time to disease progression.

Disease progression within the first 30 weeks occurred in 7% of patients in the treatment group compared with 93% of patients in the control group (P < .0001). At a median follow-up of 27 months (IQR, 18 to 32), the median PFS was 25 months (IQR, 15 to NR) in the treatment arm vs 5 months (IQR, 3 to 7) in the control arm (HR, 0.07; 95% CI, 0.03 to 0.17; P < .0001).

The median PSA PFS was 17 months in the intervention arm compared with 3 months in the control arm (HR, 0.09, 95% CI, 0.04 to 0.20; P < .0001). The median time to next systemic therapy was 26 months (IQR, 18 to NR) among those who received ¹⁷⁷Lu-PSMA-617 vs 6 months (IQR, 5 to 8) among those in the control arm (HR, 0.09, 95% CI, 0.04 to 0.22; P < .0001).

Overall, 93% of patients in the control arm subsequently received ¹⁷⁷Lu-PSMA-617. At the time of data report, 41% of patients in the control group and 48% of patients in the intervention arm initiated ADT (HR, 1.62; 0.72 to 3.66; P = .23). The median time to ADT was 39 months (IQR, 24 to 53) in the control group vs 26 months in the intervention group (IQR, 18 to NR).

Further, 17% of patients in the intervention arm vs 14% of patients in the control arm developed castration-resistant disease (HR, 2.32; 0.55 to 9.87; P = .24). The median time to castration-resistant prostate cancer was 21 months in the intervention arm vs 29 months in the control arm. PSA declines of at least 50% were reported in 83% of patients in the ¹⁷⁷Lu-PSMA-617 cohort vs none in the control cohort.

The most common adverse events were grade 1 dry mouth (66%, intervention vs 10%, control), fatigue (55% vs 21%), and nausea (48% vs 10%). Grade 3 toxicities were infrequent and included lymphopenia (10%) and dry eye (3%), with no grade 4 treatment-related adverse events or deaths reported. No serious adverse events in the ¹⁷⁷Lu-PSMA-617 arm were reported.

Lead author Bastiaan Privé, MD, PhD, added in the news release, “We see that we can postpone more burdensome hormone therapy. In addition, PSMA therapy sometimes reduces the cancer enough for men to become once again eligible for targeted radiation. This may further contribute to delaying hormone treatment in the future.”

The authors acknowledged several study limitations, including the small sample size and the selection criterion of a PSA doubling time of 6 months or less, which enriched for patients with more rapidly progressing disease. Additionally, the primary endpoint—disease progression defined by PSA doubling time and next systemic therapy free survival—is not a validated surrogate for long-term oncologic outcomes, raising the possibility that treatment effects could be overestimated. Further, the crossover design, which allowed patients in the control group to receive ¹⁷⁷Lu-PSMA-617 at progression, precluded assessment of overall survival and time to castration-resistant disease.

Considering these limitations, the authors concluded, “These findings suggest that following surgery and radiotherapy, ¹⁷⁷Lu-PSMA-617 might provide an additional treatment option for patients with oligometastatic HSPC.”

REFERENCES

1. Privé BM, Noordzij W, Muselaers CHJ, et al. [177Lu]-PSMA-617-PSMA-617 in oligometastatic hormone sensitive prostate cancer (BULLSEYE): an open-label, randomised, phase 2 study. Lancet Oncol. 2026;27(4):461-469. doi:10.1016/S1470-2045(25)00762-4

2. PSMA therapy delays hormone therapy in prostate cancer. News release. Radboud University Medical Center. March 31, 2026. Accessed April 9, 2026. https://www.radboudumc.nl/en/news-items/2026/psma-therapie-stelt-hormoontherapie-bij-prostaatkanker-uit