Novartis announced on March 28, 2025, that the U.S. Food and Drug Administration (FDA) has approved Pluvicto® (lutetium Lu 177 vipivotide tetraxetan) for an expanded indication in prostate cancer treatment. The radioligand therapy is now approved for patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with an androgen receptor pathway inhibitor (ARPI) therapy and are considered appropriate to delay chemotherapy.
This expanded approval significantly broadens access to Pluvicto, approximately tripling the number of eligible patients who can benefit from this targeted therapy before requiring chemotherapy.
Clinical Trial Results Show Significant Efficacy
The FDA's decision was based on compelling data from the Phase III PSMAfore trial, which demonstrated that Pluvicto reduced the risk of radiographic progression or death by 59% (HR=0.41; 95% CI: 0.29, 0.56; p<0.0001) compared to a change in ARPI therapy in patients with PSMA-positive mCRPC.
An updated exploratory analysis revealed that Pluvicto more than doubled median radiographic progression-free survival to 11.6 months compared to 5.6 months with alternative ARPI therapy. While the final overall survival analysis numerically favored Pluvicto with a hazard ratio of 0.91 (95% CI: 0.72, 1.14), it did not reach statistical significance, likely due to the high crossover rate (60.3%) from the control arm to Pluvicto.
Dr. Michael Morris, Prostate Cancer Section Head at Memorial Sloan Kettering Cancer Center and Principal Investigator of the U.S. study, emphasized the significance of this approval: "The earlier indication for Pluvicto could really change our treatment paradigms for patients with mCRPC. It offers a targeted therapy that better delays disease progression compared to a second ARPI."
Addressing a Critical Treatment Gap
Prostate cancer remains a leading cause of cancer death among men, with more than 35,000 men dying from the disease annually in the United States. The disease burden is particularly concerning as approximately half of patients with mCRPC do not survive long enough to receive a second treatment after initial therapy failure.
"With worsening outcomes after each successive line of treatment, patients with this type of metastatic prostate cancer and their families have long faced limited options and uncertain outcomes," said Gina Carithers, CEO and President of the Prostate Cancer Foundation. "The now expanded approval of Pluvicto is an empowering development for the prostate cancer community."
Safety Profile and Treatment Administration
The PSMAfore study demonstrated a consistent and favorable safety profile for Pluvicto. The most frequently reported adverse events were primarily Grade 1-2 and included dry mouth (61%), fatigue (53%), nausea (32%), and constipation (22%). Importantly, Pluvicto did not impair patients' ability to receive subsequent chemotherapy if needed.
Dr. Oliver Sartor, Chair of Genitourinary Cancer Disease Group and Director of Radiopharmaceutical Clinical Trials at Mayo Clinic, noted: "The clinical development of PSMA-targeting radioligand therapy has provided important insights into the treatment of metastatic castration-resistant prostate cancer. The trial data demonstrated a clear clinical benefit in delaying disease progression in eligible patients, offering an additional therapeutic approach in this setting."
Mechanism of Action and Treatment Delivery
Pluvicto is an intravenous radioligand therapy that combines a targeting compound (ligand) with a therapeutic radionuclide (lutetium-177). After administration, it binds to target cells expressing PSMA, a transmembrane protein found on prostate cancer cells. The energy emissions from the radioisotope then damage these target cells and nearby cells, disrupting their ability to replicate or triggering cell death.
Novartis has established a robust infrastructure to ensure patient access to Pluvicto, with the ability to deliver the therapy to nearly 600 U.S. RLT treatment sites, typically within five days. The company offers multiple administration methods, including prefilled syringes, and has launched the RLT Institute to educate healthcare providers on radiation safety and treatment administration.
Future Directions
Beyond this expanded indication, Novartis is investigating Pluvicto in earlier stages of prostate cancer, including metastatic hormone-sensitive prostate cancer (PSMAddition trial) and oligometastatic prostate cancer (PSMA-DC trial). These studies aim to further define the role of radioligand therapy across the prostate cancer treatment landscape.
Victor Bultó, President US at Novartis, stated: "Today's approval for an expanded indication for Pluvicto brings more choice to nearly three times as many patients, enabling us to further establish radioligand therapies as a pillar in cancer care."
The expanded approval of Pluvicto represents a significant advancement in the treatment paradigm for metastatic castration-resistant prostate cancer, offering patients an effective targeted therapy option earlier in their treatment journey, potentially improving outcomes for this challenging disease.
