New FDA Approval for Lutetium Therapy: It Can Now Be Used Earlier

On March 28, 2025, the United States Food and Drug Administration (FDA) expanded the indication for the radioactive therapeutic agent lutetium Lu 177 vipivotide tetraxetan (Pluvicto). The new approval also covers adults with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who have received an androgen receptor pathway inhibitor and are considered appropriate to delay taxane-based chemotherapy.

Castration-Resistant Prostate Cancer (CRPC), which refers to prostate cancer that continues to progress despite treatments that lower testosterone levels (castration), means that the cancer has developed resistance to treatment and continues to grow.

Metastatic Castration-Resistant Prostate Cancer (mCRPC) is a condition in which prostate cancer has spread (metastasized) to other parts of the body, such as bones or lymph nodes, and become resistant to castration therapy.

Approximately 10-20% of patients diagnosed with prostate cancer develop CRPC.

A New Era in Prostate Cancer

mCRPC is particularly challenging when treatment options are limited. Targeted radioactive therapies are emerging as a new source of hope for this disease group. One of the most noteworthy developments in this area concerns Pluvicto (lutetium Lu 177 vipivotide tetraxetan) and its FDA approval pathway.

Pluvicto had previously been approved in 2022for patients who had received an androgen receptor inhibitor (ARPI, Androgen Receptor Pathway Inhibitor) and taxane-based chemotherapy and had PSMA-positive mCRPC . Now, on March 28, 2025 , the FDA expanded its use to patients at an earlier stage who wish to delay chemotherapy. This development has the potential to improve both patient comfort and survival.

What Does the New Indication Mean?

Under the new FDA approval, Pluvicto can now also be used in patients with the following characteristics:

• PSMA-positive metastatic castration-resistant prostate cancer is present,
• Androgen receptor pathway inhibitor therapy (ARPI) has been received,
• But the adult male patient has not yet received taxane-based chemotherapy and wishes to delay it.

In other words, it will now be possible, without waiting for resistance to chemotherapy to develop, to treat the disease at an earlier stage using targeted radioactive molecules.

The PSMAfore Study: Efficacy and Safety Data

This new approval is based on PSMAfore (NCT04689828) , a multicenter, open-label, randomized clinical trial. The study enrolled 468 patients whose disease had progressed after a previous ARPI .

Study Design

• Patients were assigned to two arms in a 1:1 ratio:
  • One group received Pluvicto (7.4 GBq / 200 mCi) every 6 weeks.
  • The other group switched to a different ARPI.
• After disease progression, 60% of patients in the ARPI arm crossed over to the Pluvicto arm and benefited from this treatment.

Clinical Efficacy Results

Radiographic Progression-Free Survival (rPFS)

• Pluvicto arm: Median rPFS 9.3 months
• ARPI arm: Median rPFS 5.6 months
• Hazard ratio (HR): 0.41
  This shows that Pluvicto was 59% more effective at delaying disease progression. (p < 0.0001, statistically significant)

Overall Survival (OS)

• Pluvicto arm: Median OS 24.5 months
• ARPI arm: Median OS 23.1 months
• Hazard ratio: 0.91
  This difference was not statistically significant, but the treatment is considered to offer an important contribution in terms of tolerability and quality of life.

Safety: Known Risks Remain

Pluvicto's adverse effects were consistent with previous clinical experience. The most common were:

• Fatigue
• Dry mouth
• Anemia
• Decreased appetite
• Decreased lymphocyte and platelet counts
• Radiation-related bone marrow suppression (myelosuppression)
• Impaired kidney function (renal toxicity)

Dosing and Administration

Recommended dose: Every 6 weeks, 7.4 GBq (200 mCi) intravenously is administered.
A total of 6 doses are given, or treatment continues until disease progression or unacceptable toxicity.

Why Does It Matter?

This new approval provides an important alternative for patients who wish to avoid chemotherapy or seek a more tolerable treatment . Starting treatment earlier may also improve disease control. For PSMA-positive patients, appropriate selection using PET imagingis critical to treatment success.

Conclusion

The FDA's new approval for Pluvicto is an important milestone in prostate cancer treatment. A targeted, molecularly active option that could prolong survivalis now available to a broader group of patients.

Mechanism of Action of Targeted Molecular Radionuclide Therapy

Lutetium Lu 177 vipivotide tetraxetan binds to prostate-specific membrane antigen (PSMA) on prostate cancer cells to both visualize and destroy tumor cells.

Radioactive peptides (lutetium Lu 177 vipivotide tetraxetan) administered intravenously during treatment attach to the targeted cancer cells, emit large amounts of radiation, and can destroy them. Patients may need to remain in the hospital for several days after treatment. Treatment generally requires 4-6 cycles.

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