Lutetium-177-PSMA-617 in oligo-metastatic hormone sensitive prostate cancer (BULLSEYE trial).

5009 Background: [ 177 Lu]Lu-PSMA-617 (Pluvicto) is a novel treatment for patients with metastatic castration resistant prostate cancer. In a phase 1 dosimetry study, we previously showed that [ 177 Lu]Lu-PSMA-617 could be offered to patients with PSMA-expressing, recurrent, oligometastatic hormone-sensitive prostate cancer (oHSPC) with encouraging outcomes (Privé et al, CCR 2021). We here report the results of the following randomized phase 2 trial. Methods: This was an investigator initiated, international, multicenter, open-label, randomized phase 2 trial (NCT04443062). Fifty-eight oHSPC patients ineligible for salvage treatments, were randomized in a 1:1 fashion to [ 177 Lu]Lu-PSMA-617 vs. the standard of care (SoC) of deferred androgen deprivation therapy (ADT). Eligibility consisted of fast-progressing oHSPC (prostate specific antigen [PSA] doubling time <6 months) following radical prostatectomy or radiotherapy, with a maximum of 5 metastases on PSMA-PET/CT. Patients received 2 (+2 optional) cycles of 7.4 GBq [ 177 Lu]Lu-PSMA-617. The primary outcome was progression-free survival (i.e. time without ADT). Progressive disease (PD) was defined as a 100% increase in PSA since randomization, radiographic or clinical progression or earlier necessitation of subsequent therapy (e.g. ADT). Secondary outcomes were PSA response, adverse events and quality of life. Results: Between April 20, 2020 and July 29 2024, 58 of 78 screened men were eligible. Data cut-off was set on December 24 th 2024. Median age was 72 years (range 51-82) with a median baseline PSA of 3.6 (1.2-29). Two patients received 2 cycles whereas 27 patients underwent 4 cycles of [ 177 Lu]Lu-PSMA-617. At a median follow-up time of 7 months (range 1-31), 93% (27/29) and 38% (11/29) of the SoC and arm, respectively, reached the definition for PD. The median progression free survival was 5 months (95% CI 4-6 months) for the SoC group whereas the median progression free survival was not reached for the [ 177 Lu]Lu-PSMA-617 group (HR, 0.07 [95% CI, 0.02 to 0.19]; P <.001). The median percentage PSA change was +125% vs. -91% in the SoC vs. [ 177 Lu]Lu-PSMA-617 arm, respectively. Twenty-one percent (6/29) of [ 177 Lu]Lu-PSMA-617 arm patients had a complete remission. The most common treatment-related adverse events were grade (G) 1 dry mouth (59%), G 1 fatigue (55%), G 1 nausea (48%), G 1 bone marrow toxicity (24-30%) which generally normalized during follow-up. G ≥2 adverse events were seldom observed (<15%) and not clinically relevant. Conclusions: [ 177 Lu]Lu-PSMA-617 showed promising efficacy as monotherapy in oligometastatic hormone sensitive prostate cancer patients to defer from androgen deprivation therapy, with minimal and mostly transient side effects. Following surgery and external beam radiotherapy, could become a third metastases-directed therapeutic option for oligometastatic prostate cancer patients to prolong ADT-free interval. Clinical trial information: NCT04443062 .