On July 31, 2026, the US Food and Drug Administration approved lutetium Lu 177 vipivotide tetraxetan, marketed as Pluvicto, in combination with androgen receptor pathway inhibitor (ARPI) therapy for adults with prostate-specific membrane antigen (PSMA)-positive metastatic androgen pathway modulation-naïve or -sensitive prostate cancer.
This disease setting was previously referred to as metastatic hormone-sensitive prostate cancer. The approval moves PSMA-targeted radioligand therapy into an earlier stage of metastatic prostate cancer, before the development of castration-resistant disease.
Patients should be selected for treatment based on PSMA expression in their tumors using Locametz, which contains gallium Ga 68 gozetotide, or another FDA-approved PSMA positron emission tomography product.
Approval Supported by PSMAddition
The approval was based on findings from the randomized, multicenter, open-label phase 3 PSMAddition trial, registered as NCT04720157.
The study enrolled 1,144 patients with PSMA-positive metastatic androgen pathway modulation-naïve or -sensitive prostate cancer. Patients were randomly assigned in a 1:1 ratio to receive lutetium Lu 177 vipivotide tetraxetan plus an ARPI or an ARPI alone, with 572 patients in each group. Lutetium Lu 177 vipivotide tetraxetan was administered at 7.4 GBq, equivalent to 200 mCi, every six weeks for six doses.
The ARPI was selected by the investigator and could include abiraterone, apalutamide, enzalutamide, darolutamide, or another ARPI. All patients received concurrent androgen deprivation with a gonadotropin-releasing hormone agonist or antagonist or had undergone bilateral orchiectomy.
The trial’s primary endpoint was radiographic progression-free survival assessed by blinded independent central review according to Prostate Cancer Working Group 3-modified RECIST version 1.1 criteria. Overall survival was an additional efficacy endpoint.
PSMAddition Results Presented at ESMO Congress 2025
The primary phase 3 results were presented as late-breaking abstract LBA6 at the ESMO Congress 2025 and published as an abstract in Annals of Oncology. Eligible patients had treatment-naïve or minimally treated metastatic hormone-sensitive prostate cancer and at least one PSMA-positive metastatic lesion identified using gallium Ga 68 PSMA-11 PET/CT. Patients in the control group could cross over to lutetium Lu 177 vipivotide tetraxetan following centrally confirmed radiographic progression if they remained eligible.
At the January 13, 2025, data cutoff, the median study follow-up was 23.6 months. Half of the enrolled patients had de novo metastatic disease, and 68.1% had high-volume disease. Among patients assigned to the lutetium Lu 177 vipivotide tetraxetan group, 85.6% completed all six planned cycles and 93.1% received at least four cycles.
The trial met its primary endpoint:
- Median radiographic progression-free survival was not reached in either treatment group
- Hazard ratio for radiographic progression or death: 0.72
- 95% confidence interval: 0.58–0.90
- p=0.002
These findings corresponded to a 28% relative reduction in the risk of radiographic progression or death with lutetium Lu 177 vipivotide tetraxetan plus ADT and an ARPI compared with ADT and an ARPI alone.
Overall survival data were immature. There were 85 deaths in the lutetium Lu 177 vipivotide tetraxetan group and 99 in the control group. Median overall survival was not estimable in either arm, with a hazard ratio of 0.84 and a 95% confidence interval of 0.63–1.13.
The objective response rate among patients with measurable disease was 85.3% with lutetium Lu 177 vipivotide tetraxetan plus standard therapy and 80.8% with standard therapy alone.
The investigators concluded that the addition of lutetium Lu 177 vipivotide tetraxetan significantly improved radiographic progression-free survival in the first phase 3 trial of radioligand therapy in metastatic hormone-sensitive prostate cancer. Time to worsening in quality of life, assessed using FACT-P and EQ-5D, did not differ meaningfully between the treatment groups.
Safety Findings
In the ESMO 2025 analysis, adverse events of any grade occurred in 98.4% of patients receiving lutetium Lu 177 vipivotide tetraxetan plus standard therapy and 96.6% of patients receiving standard therapy alone.
Grade 3 or higher adverse events occurred in:
- 50.7% of patients receiving lutetium Lu 177 vipivotide tetraxetan
- 43.0% of patients receiving standard therapy alone
- Serious adverse events were reported in 31.9% and 28.7% of patients, respectively.
Dry mouth was the most common adverse event and was limited to grade 1 or 2. Grade 3 or higher cytopenias occurred in 14.4% of patients receiving the radioligand therapy combination and 5.0% of patients in the control group.
According to the FDA, adverse reactions were consistent with previous experience with lutetium Lu 177 vipivotide tetraxetan. The prescribing information includes warnings and precautions regarding radiation exposure, myelosuppression, renal toxicity, embryo-fetal toxicity, and infertility.
May 2026 Analysis Showed Deeper PSA Responses
On May 17, 2026, Novartis announced an additional analysis from PSMAddition evaluating prostate-specific antigen outcomes. The results were presented as a rapid oral presentation at the American Urological Association Annual Meeting 2026.
The analysis showed that adding lutetium Lu 177 vipivotide tetraxetan to ARPI therapy and ADT reduced the risk of PSA progression by 58% compared with ARPI therapy and ADT alone:
- Hazard ratio for PSA progression: 0.42
- 95% confidence interval: 0.30–0.59
Novartis reported that the combination produced more frequent, deeper, and more durable PSA responses than standard therapy alone.
More than 98% of patients in both groups experienced substantial PSA reductions. However, a greater proportion of patients treated with lutetium Lu 177 vipivotide tetraxetan achieved PSA levels below 0.2 ng/mL at the assessed time points:
- At week 12: 47.6% versus 37.7%
- At week 24: 73.7% versus 59.7%
- At week 48: 87.4% versus 74.9%
At the time of the announcement, Novartis stated that regulatory submissions had been filed in the United States, China, and Japan, with the first decisions anticipated during the second half of 2026. The FDA approval followed on July 31, 2026.
Recommended Dose
The recommended dose of lutetium Lu 177 vipivotide tetraxetan in combination with an ARPI is:
- 7.4 GBq, or 200 mCi, administered intravenously every six weeks for six doses, or until disease progression or unacceptable toxicity.
ARPI therapy may continue until disease progression or unacceptable toxicity.
Expanding PSMA-Targeted Radioligand Therapy
Pluvicto was initially approved by the FDA on March 23, 2022, for adults with PSMA-positive metastatic castration-resistant prostate cancer previously treated with androgen receptor pathway inhibition and taxane-based chemotherapy. On March 28, 2025, the indication was expanded to include patients previously treated with ARPI therapy who were considered appropriate candidates to delay taxane-based chemotherapy.
The July 2026 approval extends its use to patients whose metastatic prostate cancer remains sensitive to androgen pathway modulation. It establishes lutetium Lu 177 vipivotide tetraxetan plus an ARPI as a new FDA-approved treatment option for appropriately selected patients with PSMA-positive metastatic androgen pathway modulation-naïve or -sensitive prostate cancer. In PSMAddition, patients also received ongoing medical castration or had undergone bilateral orchiectomy.
Read the full announcement on the FDA’s official website.