SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 313,780 new cases of prostate cancer will be diagnosed in 2025 and 35,770 men will die of the disease.
Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) remains a challenging disease state, even with modern intensification strategies. Androgen-Deprivation Therapy (ADT) combined with an Androgen Receptor Pathway Inhibitor (ARPI) is a widely adopted standard of care. Yet many patients continue to progress and long-term disease control remains elusive.
Prostate-Specific Membrane Antigen (PSMA) is a Type II cell membrane glycoprotein that is selectively expressed in prostate cells, with high levels of expression in prostatic adenocarcinoma. PSMA is a therefore an excellent target for molecular imaging and therapeutics, due to its high specificity for prostate cancer. The emergence of PSMA-targeted radioligand therapy validated in metastatic Castration-Resistant Prostate Cancer (mCRPC) through the VISION and PSMAfore studies, has prompted investigation of earlier integration.
Lutetium Lu 177 vipivotide tetraxetan (PLUVICTO®) is a radiopharmaceutical that targets PSMA. It is comprised of Lutetium-177, a cytotoxic radionuclide, linked to the ligand PSMA-617, a small molecule designed to bind with high affinity to PSMA. Radioligand therapy with PLUVICTO® targets PSMA and releases its payload of lethal beta radiation into the prostate cancer cell.
The Phase III PSMAddition trial represents the first randomized effort to evaluate a targeted radionuclide therapy in the hormone-sensitive setting.
Study Design and Patient Population
PSMAddition enrolled 1,144 men with treatment-naïve or minimally treated (≤45 days of hormonal therapy) mHSPC. All patients had PSMA-positive metastatic disease confirmed by 68Ga-PSMA-11 PET/CT, defined as at least one lesion with uptake exceeding liver activity. Participants were randomized 1:1 to:
- Experimental arm: 177Lu-PSMA-617 (7.4 GBq every 6 weeks for up to six cycles) + ADT + an ARPI of physician’s choice
- Control arm: ADT + ARPI alone, with crossover to 177Lu-PSMA-617 permitted upon centrally confirmed radiographic progression
Baseline characteristics were well balanced. Half had de novo metastatic disease and more than two-thirds had high-volume disease by conventional imaging criteria. Abiraterone was the most commonly selected ARPI, followed by Apalutamide and Enzalutamide. In the experimental arm, treatment adherence was high, with 86% completing all six cycles.
This report reflects the second interim analysis for radiographic Progression-Free Survival (rPFS; data maturity 74%) and the first interim analysis for Overall Survival (OS; data maturity 47%) after a median follow-up of 23.6 months.
Efficacy Outcomes
Radiographic Progression-Free Survival: Primary Endpoint Achieved
The addition of 177Lu-PSMA-617 significantly prolonged rPFS compared with ADT + ARPI alone (HR 0.72; P=0.002). Median rPFS has not been reached in either arm. Importantly, benefit was observed across all predefined subgroups, including high- vs low-volume disease, de novo vs recurrent mHSPC, as well as varying ARPI backbones. These findings confirmed that PSMA-targeted radioligand therapy can improve disease control even in the presence of potent systemic hormonal intensification.
Early Overall Survival Trends
Although OS data are immature, there is a favorable trend for early 177Lu-PSMA-617 (HR 0.84). As nearly 60% of progressing control-arm patients crossed over to 177Lu-PSMA-617, subsequent analyses may be confounded, potentially attenuating the ability to detect an OS difference with further follow-up.
Secondary Efficacy Measures
Across all Secondary endpoints, outcomes favored the 177Lu-PSMA-617 arm:
- ORR: 85% vs 81%
- Complete responses: 57% vs 42%
- PSA endpoints:
- PSA <0.2 ng/mL rates at multiple prespecified time points were higher in the experimental arm
- PSA progression significantly delayed (HR 0.42)
- Time to mCRPC: HR 0.70
- Investigator-assessed PFS: HR 0.64
- Time to symptomatic skeletal events: Comparable between arms, but favored 177Lu-PSMA-617 numerically
Collectively, these findings indicate deeper and more durable disease responses with early radioligand therapy.
Safety and Tolerability
Overall toxicity was higher with the addition of 177Lu-PSMA-617 but consistent with the known safety profile of radioligand therapy. Common all-grade adverse events (experimental arm) included dry mouth (46%), fatigue (35%), nausea (34%), Hot flashes (29%) and anemia (27%). Grade ≥3 cytopenias occurred more often with 177Lu-PSMA-617 (14% vs 5%), though most were low grade and manageable. Importantly, no treatment-related deaths were reported. Despite higher toxicity rates, Quality-of-Life measures including FACT-P and EQ-5D were not adversely impacted, and time to worsening pain was similar between arms.
Clinical Implications
PSMAddition provides the first Phase III evidence supporting integration of PSMA-targeted radioligand therapy into initial systemic treatment for PSMA-positive mHSPC. While rPFS and multiple disease-control endpoints clearly favor the triplet approach, questions remain regarding long-term survival benefit, patient selection, and optimal treatment duration. Additional biomarker-driven analyses and longer follow-up will be critical in defining how broadly early LuPSMA-617 should be adopted in routine practice.
Phase 3 trial of [177Lu]Lu-PSMA-617 combined with ADT + ARPI in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (PSMAddition). Tagawa ST, Sartor O, Piulats JM, et al. Presented at: European Society for Medical Oncology (ESMO) Congress. October 17-21, 2025. Berlin, Germany. Abstract LBA6
