Radioligand Therapy Moves Earlier: FDA Expands Pluvicto for Metastatic Prostate Cancer

Radioligand therapy is no longer only an option for later-line treatment of prostate cancer. The U.S. Food and Drug Administration (FDA) approved Novartis’ Pluvicto (lutetium Lu 177 vipivotide tetraxetan) in combination with an androgen receptor pathway inhibitor for the treatment of prostate-specific membrane antigen (PSMA)-positive metastatic hormone-sensitive prostate cancer, allowing eligible patients to receive treatment while their disease is still responsive to hormonal control.

Pluvicto uses a PSMA-targeting molecule to carry the radioactive isotope lutetium-177, thereby delivering radiation more selectively to cancer cells that express PSMA. This strategy was previously used mainly for metastatic castration-resistant disease; the expansion of the indication to an earlier setting means that the timing of treatment has extended from later-stage disease after hormonal therapy has failed to the initial metastatic treatment setting. Novartis estimates that the newly approved indication could nearly double the number of people eligible for Pluvicto treatment.

The approval was based on the open-label, randomized Phase 3 PSMAddition trial. The study evenly assigned 1,144 patients whose disease had been confirmed by PSMA imaging and who were either treatment-naive or had received only short-term treatment to receive Pluvicto plus androgen deprivation therapy and an androgen receptor pathway inhibitor, or the latter two standard treatments alone. The planned Pluvicto dose was 7.4 GBq every six weeks for a total of six cycles.

In the prespecified interim analysis with a data cutoff of January 13, 2025, adding Pluvicto significantly improved centrally reviewed radiographic progression-free survival, with a hazard ratio of 0.72 for radiographic disease progression or death, corresponding to a 28% relative risk reduction. In its approval announcement, the company separately stated that an updated analysis showed a 33% risk reduction; the two figures came from different data cutoff points and should not be viewed directly as conflicting results. The direction of effect was generally consistent across key subgroups, including patients with high or low tumor burden and those with de novo metastatic disease or metastases following recurrence.

The principal trade-off in efficacy was hematologic toxicity. Grade 3 or higher adverse events occurred in 50.7% of the Pluvicto group and 43.0% of the control group, respectively, while Grade 3 or higher cytopenia occurred in 14.4% and 5.0%; dry mouth, fatigue, nausea, hot flashes, and anemia were also common reactions. The quality-of-life scale used in the trial showed no meaningful deterioration, but this does not mean that the treatment burden can be disregarded. Bone marrow function and the practical requirements for administering radiopharmaceutical therapy must still be assessed in clinical practice.

The most important caveat at present is that overall survival remains inconclusive. At the interim analysis, the hazard ratio for overall survival was 0.84, with the confidence interval crossing no difference and not reaching statistical significance. Follow-up is ongoing, and the study is expected to be completed in 2027. This approval establishes a pathway for earlier use of PSMA-directed radioligand therapy, but whether it can prolong life and how it should be sequenced with existing intensified hormonal therapy remain questions for mature data to answer.