The FDA has approved lutetium Lu 177 vipivotide tetraxetan (Pluvicto, Novartis) in combination with androgen receptor pathway inhibitor (ARPI) therapy for adults with prostate-specific membrane antigen (PSMA)-positive metastatic androgen pathway modulation-naive or -sensitive prostate cancer (formerly known as metastatic hormone-sensitive prostate cancer).

The radioligand was originally approved in 2022 for PSMA-positive metastatic castration-resistant prostate cancer after ARPI therapy and taxane-based chemotherapy. The indication expanded in 2025 to include patients after ARPI therapy considered appropriate to delay taxane chemotherapy.

The approval allows use earlier in the disease course, before development of castration-resistant disease. 

"This approval reflects a growing recognition that earlier treatment intensification matters," said Michael Morris, MD, Memorial Sloan Kettering Cancer Center, New York, the principal investigator on the approval trial for the new indication in a Novartis press release. 

Novartis said the new indication nearly doubles the patient population eligible for the drug. The FDA said patients should be selected based on tumor PSMA expression using PSMA-PET with Locametz or another approved imaging agent.

The approval was based on the randomized, multicenter, open-label PSMAddition trial, which randomly assigned 1144 men to receive either lutetium Lu 177 vipivotide tetraxetan (7.4 GBq every 6 weeks for six doses) in combination with investigators' choice of an ARPI and androgen deprivation therapy (ADT) or an ARPI plus ADT. ARPIs were continued until disease progression or unacceptable toxicity. Patients received a gonadotropin-releasing hormone agonist or antagonist concurrently or had a bilateral orchiectomy.

Median radiographic progression-free survival was not reached in either group after a median follow-up of nearly 2 years, but lutetium Lu 177 vipivotide tetraxetan was associated with a 28% lower risk for radiographic progression or death (hazard ratio, 0.72; P = .002). Overall survival also favored the experimental group, although the data remain immature

William Oh, MD, a prostate cancer medical oncologist at Yale School of Medicine in New Haven, Connecticut, said the approval is an advance for particularly aggressive prostate cancer, but was cautious about prescribing it for less aggressive disease.

For men who present with very high burdens of disease in their bone or lymph nodes or liver, "those patients may be very good candidates for upfront Pluvicto," Oh told Medscape Medical News. But for patients who don't have high disease burden, "the risk-benefit may not be worth it." 

Oh also questioned whether all patients will require six planned doses, given the effectiveness of ARPI therapy and the potential for cumulative toxicity.

In the trial, grade 3 or higher adverse events occurred in nearly 51% of patients receiving lutetium Lu 177 vipivotide tetraxetan compared with 43% of those receiving an ARPI plus ADT. Grade 3 or higher cytopenias occurred in 14.4% vs 5.0%, respectively. The most common adverse events with lutetium Lu 177 vipivotide tetraxetan included dry mouth, fatigue, nausea, hot flush, and anemia.

Labelling also includes warnings and precautions for radiation exposure, myelosuppression, renal toxicity, embryo-fetal toxicity, and infertility.

M. Alexander Otto is a physician assistant and award-winning journalist. He is also an MIT science journalism fellow. Email: aotto@medscape.net