Radioligand 177Lu-PSMA-617 Delays Radiographic Progression in PSMA-Positive Hormone-Sensitive Metastatic Prostate Cancer, Phase 3 Trial Shows

A phase 3 trial published in The Lancet found that adding the radioligand therapy 177Lu-PSMA-617 to standard first-line hormonal treatment significantly delayed radiographic progression in men with PSMA-positive metastatic hormone-sensitive prostate cancer, a result that could move the targeted therapy into an earlier stage of disease.

The study, called PSMAddition, enrolled 1,144 patients and showed a 28% reduction in the risk of radiographic progression or death for patients who received 177Lu-PSMA-617 on top of androgen-deprivation therapy, or ADT, plus an androgen receptor pathway inhibitor, or ARPI. The hazard ratio for radiographic progression-free survival was 0.72, with a 95% confidence interval of 0.58 to 0.90 and a p-value of 0.002. The finding matters because Pluvicto, the brand name for the lutetium-based PSMA-targeted radioligand therapy, is already used in more advanced prostate cancer after the disease has become castration-resistant. PSMAddition tested whether the approach works earlier, while the cancer is still hormone-sensitive.

PSMAddition, identified as NCT04720157, was an international, prospective, open-label, randomized phase 3 trial conducted across about 20 countries. Men with untreated or minimally treated metastatic hormone-sensitive prostate cancer were eligible if they had at least one PSMA-positive metastatic lesion on a gallium-68 PSMA-11 PET/CT scan, a form of imaging used to identify tumors expressing the PSMA target. Patients were randomly assigned 1:1, with 572 receiving 177Lu-PSMA-617 plus ADT and an ARPI and 572 receiving ADT plus an ARPI alone. The experimental treatment was given at 7.4 GBq, plus or minus 10%, every six weeks for up to six cycles.

At the interim analysis, based on a Jan. 13, 2025, data cutoff and a median follow-up of 23.6 months, radiographic progression-free survival events had occurred in 139 patients, or 24.3%, in the 177Lu-PSMA-617 group, compared with 172 patients, or 30.1%, in the control group. The primary endpoint was assessed by a blinded independent radiology committee using PCWG3-modified RECIST version 1.1 criteria or death.

Overall survival, however, was not yet statistically significant at this analysis. The hazard ratio for overall survival was 0.84, with a 95% confidence interval of 0.63 to 1.13 and a p-value of 0.125. There were 85 deaths in the 177Lu-PSMA-617 arm and 99 in the control arm. The study also allowed crossover, meaning patients in the control group could receive 177Lu-PSMA-617 after centrally confirmed radiographic progression if they were eligible, a factor that can complicate later survival comparisons.

“In metastatic prostate cancer, choosing the most efficacious treatment early is crucial, even at initial diagnosis,” Scott T. Tagawa said in a Novartis press release. “These findings suggest that combining 177Lu-PSMA-617 with standard of care hormonal therapy offers patients more time without disease progression.”

Safety was worse in the experimental arm, but investigators reported no new safety signal. Any-grade adverse events occurred in 98.4% of patients receiving 177Lu-PSMA-617, compared with 96.6% in the control group. Grade 3 or higher adverse events were reported in 50.7% versus 43.0%, and serious adverse events in 31.9% versus 28.7%. Grade 3 or higher cytopenias, or low blood cell counts, were more common with the radioligand therapy, at 14.4% compared with 5.0%. Common side effects included dry mouth, fatigue, nausea, hot flush and anemia.

Among patients with measurable disease, the overall response rate was numerically higher with 177Lu-PSMA-617, at 85.3% versus 80.8%. Quality-of-life measures, including FACT-P and EQ-5D, showed no meaningful difference in time to worsening between the groups. In the treatment arm, 85.6% of patients received all six planned cycles and 93.1% received at least four.

“Combining 177Lu-PSMA-617 with ADT + ARPI significantly improved rPFS in this first phase 3 trial of radioligand therapy in mHSPC,” investigators said in the ESMO late-breaking abstract. “Safety findings were consistent with the known profile and QoL was not adversely affected.”

Pluvicto is already established for PSMA-positive metastatic castration-resistant prostate cancer, based on earlier trials including VISION and PSMAfore. What makes PSMAddition notable is its timing: It is the first phase 3 trial of a PSMA-targeted radioligand therapy to meet its primary endpoint in metastatic hormone-sensitive disease, suggesting the treatment may have a role earlier in selected patients whose tumors are PSMA PET-positive.