When to use Pluvicto (Lutetium-177 psma) for treating castration-sensitive prostate cancer?

Pluvicto Should NOT Be Used for Castration-Sensitive Prostate Cancer

Pluvicto (lutetium-177 PSMA-617) is not indicated for castration-sensitive prostate cancer and should never be used in this setting. The drug is FDA-approved exclusively for metastatic castration-resistant prostate cancer (mCRPC) after failure of both androgen receptor pathway inhibitors AND taxane-based chemotherapy 1, 2.

Current FDA-Approved Indication

Pluvicto is approved only for adult patients with PSMA-positive mCRPC who have:

• Previously received androgen receptor pathway inhibition (abiraterone, enzalutamide, apalutamide, or darolutamide) 1, 3
• Previously received taxane-based chemotherapy (docetaxel or cabazitaxel) 1, 3
• PSMA-positive disease confirmed on PSMA PET imaging 4, 1

Evidence-Based Treatment Sequencing

For Castration-Sensitive Disease (What You Should Actually Use)

The current standard of care for metastatic castration-sensitive prostate cancer is treatment intensification with ADT plus additional agents, NOT Pluvicto 5:

• First-line triplet therapy: ADT + docetaxel + abiraterone/prednisone for fit patients with de novo metastatic disease, especially those with multiple bone metastases (>3) or visceral metastases [Level I, B evidence] 5
• Alternative triplet: ADT + docetaxel + darolutamide [Level I, B evidence] 5
• Doublet therapy: ADT + novel hormone agent (abiraterone, apalutamide, or enzalutamide) for patients who cannot tolerate triplet therapy [Level I, A evidence] 5
• ADT alone: Reserved only for vulnerable patients who cannot tolerate treatment intensification 5

When Pluvicto Actually Becomes an Option

Pluvicto enters the treatment algorithm only after progression through multiple prior lines 4, 6:

1. After castration-resistance develops (rising PSA or radiographic progression despite castrate testosterone levels) 5
2. After failure of androgen receptor pathway inhibitor (abiraterone, enzalutamide, apalutamide, or darolutamide) 4, 1
3. After failure of docetaxel chemotherapy 4, 1
4. With confirmed PSMA-positive disease on Ga-68 PSMA-11 PET/CT imaging 4, 1

Clinical Trial Evidence Supporting This Sequencing

The VISION trial, which led to FDA approval, specifically enrolled patients with mCRPC who had already failed both androgen receptor pathway inhibition and taxane-based chemotherapy 3. In this heavily pretreated population:

• Median overall survival: 15.3 months vs 11.3 months (HR 0.62, P<0.001) 5, 3
• Median progression-free survival: 8.7 months vs 3.4 months (HR 0.40, P<0.001) 5, 3

There is no evidence supporting Pluvicto use in castration-sensitive disease, and doing so would be off-label, potentially harmful, and would deprive patients of proven life-extending therapies 4.

Critical Pitfall to Avoid

Using Pluvicto before docetaxel failure is not supported by current guidelines and may limit future treatment options 4. The American Urological Association and Society of Urologic Oncology provide a strong recommendation (Evidence Level: Grade B) that Lu-177 PSMA-617 should only be used after disease progression on docetaxel 4.

Why This Sequencing Matters for Outcomes

• Switching from effective therapy prematurely compromises disease control and patient outcomes 4
• The survival benefit of treatment intensification in castration-sensitive disease (triplet therapy) is substantial and should not be bypassed 5
• Approximately 24.5% of mCRPC patients may have radiographic progression without PSA progression, highlighting the importance of continuing effective therapy until clear progression 4