FDA Approves Lutetium Lu 177 Vipivotide Tetraxetan for PSMA+ mHSPC

The FDA has approved lutetium Lu 177 vipivotide tetraxetan (Pluvicto) plus an androgen receptor pathway inhibitor (ARPI) for the treatment of adult patients with prostate-specific membrane antigen (PSMA)–positive metastatic androgen pathway modulation–naive/sensitive prostate cancer, commonly known as metastatic hormone-sensitive prostate cancer (mHSPC).^1,2

This regulatory decision was based on data from the phase 3 PSMAddition trial (NCT04720157), in which treatment with lutetium Lu 177 vipivotide tetraxetan in combination with standard-of-care ARPI plus androgen deprivation therapy (ADT) led to a 28% reduction in the risk of progression or death vs standard-of-care therapy alone (HR, 0.72; 95% CI, 0.58-0.90). Findings from an updated analysis showed that the lutetium Lu 177 vipivotide tetraxetan regimen further reduced the risk of progression or death (HR, 0.67; 95% CI, 0.55-0.82), and showed a positive trend toward improved overall survival (OS) outcomes (HR, 0.80; 95% CI, 0.63-1.01). Data will continue to mature before the final OS analysis. ^1,2

Eligibility for lutetium Lu 177 vipivotide tetraxetan in patients with mHSPC should be determined using gallium Ga 68 gozetotide (Locametz) or another PET product based on tumor PSMA expression levels.²

“The treatment landscape for mHSPC is evolving, and this approval reflects a growing recognition that earlier treatment intensification matters,” Michael Morris, MD, section head of prostate cancer and genitourinary oncology at Memorial Sloan Kettering Cancer Center in New York, New York, as well as a principal investigator of PSMAddition, stated in a news release.¹ “Having a radioligand therapy available at this stage meaningfully expands the options for physicians and represents real progress for patients.”

What is the mechanism of action of lutetium Lu 177 vipivotide tetraxetan?

Lutetium Lu 177 vipivotide tetraxetan is a PSMA-targeted radioligand therapy that binds PSMA-expressing prostate cancer cells and delivers beta-particle radiation, causing DNA damage and cell death. The agent is already approved for PSMA-positive metastatic castration-resistant prostate cancer following ARPI therapy in both the taxane-naive and post-taxane settings, and PSMAddition is the first phase 3 evaluation of a targeted radioligand therapy in the hormone-sensitive setting.³ The approval adds a radioligand therapy option to an mHSPC treatment-intensification landscape, in which PARP inhibitor–based combinations are also under FDA review.⁴

How was PSMAddition designed?

PSMAddition was a randomized, multicenter, open-label phase 3 trial that enrolled 1144 patients with PSMA-positive mHSPC. Eligible patients had untreated or minimally treated disease, an ECOG performance status of 0 to 2, at least 1 PSMA-positive metastatic lesion on Ga-68 gozetotide PET/CT, and were suitable for treatment with ADT plus an ARPI.³

Patients were randomly assigned 1:1 to lutetium Lu 177 vipivotide tetraxetan at 7.4 GBq every 6 weeks for 6 cycles plus ADT and an ARPI (n = 572) or ADT plus an ARPI alone (n = 572), with crossover to the radioligand therapy permitted upon blinded independent central review (BICR)–confirmed radiographic disease progression. The ARPI was selected at the investigator’s discretion and included abiraterone acetate (Zytiga), apalutamide (Erleada), enzalutamide (Xtandi), or darolutamide (Nubeqa).

The primary end point was rPFS by BICR per Prostate Cancer Working Group 3–modified RECIST 1.1 criteria, and OS was a key secondary end point evaluated in the intent-to-treat population. Other secondary end points included PSA80 response rate, time to castration resistance, overall response rate (ORR), and time to symptomatic skeletal event. At the January 13, 2025, data cutoff, the median study follow-up was 23.6 months.

What additional efficacy data were reported?

The rPFS benefit was consistent across prespecified subgroups, including patients with high-volume (HR, 0.72; 95% CI, 0.56-0.92) and low-volume disease (HR, 0.73; 95% CI, 0.42-1.27), as well as those with de novo (HR, 0.74; 95% CI, 0.54-1.01) and recurrent (HR, 0.74; 95% CI, 0.53-1.04) metastatic disease. Among patients with measurable soft tissue disease, the confirmed ORR was 85.3% (95% CI, 79.9%-89.6%) with the radioligand therapy regimen vs 80.8% (95% CI, 74.8%-85.8%) with ADT plus an ARPI, with complete response rates of 57.1% and 42.3%, respectively.

The investigational regimen also prolonged time to prostate-specific antigen (PSA) progression (HR, 0.42; 95% CI, 0.30-0.59) and time to castration-resistant disease (HR, 0.70; 95% CI, 0.58-0.84) vs ADT plus an ARPI alone. A PSA level below 0.2 ng/mL at 48 weeks was achieved by 87.4% (95% CI, 83.6%-90.6%) of patients in the investigational arm vs 74.9% (95% CI, 70.3%-79.1%) of those in the control arm. At a prespecified interim analysis, OS numerically favored the radioligand therapy regimen, although these data remained immature and follow-up is ongoing.

What is the safety profile of lutetium Lu 177 vipivotide tetraxetan?

Any-grade adverse effects (AEs) occurred in 98.4% of patients in the lutetium Lu 177 vipivotide tetraxetan arm and 96.6% of those in the control arm, with grade 3 or higher AEs reported in 50.7% and 43.0% of patients, respectively. AEs led to discontinuation of any study treatment in 16.1% of patients in the investigational arm vs 9.0% in the control arm, and 8.0% discontinued radioligand therapy specifically. AEs led to death in 15 patients (2.7%) in the investigational arm and 14 patients (2.5%) in the control arm; none of these deaths were treatment related.³

The most common any-grade AEs in the investigational arm were dry mouth (45.7%), fatigue (34.6%), and nausea (34.2%), consistent with the established profile of the radioligand therapy. Among safety topics of interest, cytopenias were reported in 44.0% of patients in the investigational arm vs 20.4% in the control arm—including anemia in 28.0% vs 14.0%—and no clinically meaningful differences between arms were observed in time to worsening in patient-reported health-related quality of life or pain.³

References

1. FDA approves Pluvicto for PSMA+ metastatic hormone-sensitive prostate cancer (mHSPC), advancing potential new standard of care across metastatic disease. News release. Novartis. July 31, 2026. Accessed July 31, 2026. https://www.novartis.com/news/media-releases/fda-approves-pluvicto-psma-metastatic-hormone-sensitive-prostate-cancer-mhspc-advancing-potential-new-standard-care-across-metastatic-disease
2. FDA approves lutetium Lu 177 vipivotide tetraxetan with androgen receptor pathway inhibitor therapy for metastatic androgen pathway modulation-naïve or -sensitive prostate cancer. FDA. July 31, 2026. Accessed July 31, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lutetium-lu-177-vipivotide-tetraxetan-androgen-receptor-pathway-inhibitor-therapy
3. Tagawa ST, Sartor O, Piulats JM, et al. Phase 3 trial of [177Lu]Lu-PSMA-617 combined with ADT + ARPI in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (PSMAddition). Presented at: 2025 European Society for Medical Oncology Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA6.
4. FDA grants priority review to talazoparib plus enzalutamide in HRR-altered mCSPC. OncLive. July 23, 2026. Accessed July 31, 2026. https://www.onclive.com/view/fda-grants-priority-review-to-talazoparib-plus-enzalutamide-in-hrr-altered-mcspc