What is the efficacy of Pluvicto (Lutetium-177 vipivotide tetraxetan) in treating visceral prostate cancer?

Pluvicto Efficacy in Visceral Metastatic Prostate Cancer

Pluvicto (lutetium-177 vipivotide tetraxetan) is NOT recommended for patients with visceral metastatic castration-resistant prostate cancer (mCRPC), as these patients were explicitly excluded from the pivotal VISION trial that led to FDA approval. 1

Critical Exclusion Criteria

The FDA label for Pluvicto clearly states that patients were excluded from the VISION trial if they had tumor lesions exceeding size criteria (organs ≥1 cm, lymph nodes ≥2.5 cm, bones with soft tissue component ≥1 cm) that demonstrated PSMA uptake less than or equal to normal liver uptake. 1 This exclusion criterion effectively eliminated patients with significant visceral disease, particularly those with PSMA-negative or poorly PSMA-expressing visceral metastases.

Guideline Recommendations Specifically Exclude Visceral Disease

• ESMO 2015 guidelines explicitly state that radium-223 is recommended only for men with bone-predominant, symptomatic metastatic CRPC WITHOUT visceral metastases. 2 While this refers to radium-223, it establishes the precedent that radiopharmaceuticals have limited utility in visceral disease.

• ESMO 2023 updated guidelines recommend 177Lu-PSMA-617 for men with cancer expressing PSMA on PET imaging and specifically note "without PSMA non-expressing lesions." 2 Visceral metastases frequently demonstrate heterogeneous or absent PSMA expression, making them unsuitable targets.

• The NCCN guidelines emphasize that patients must have at least one PSMA-positive metastatic lesion and NO dominant PSMA-negative metastatic lesions, with PSMA-negative lesions defined as solid organ metastases ≥1.0 cm lacking PSMA uptake. 3

Clinical Trial Evidence

The VISION trial demonstrated improved outcomes in highly selected patients:

• Overall survival: 15.3 vs 11.3 months (HR 0.62,95% CI 0.52-0.74, P<0.001) 2, 1
• Radiographic progression-free survival: 8.7 vs 3.4 months (HR 0.40,99.2% CI 0.29-0.57, P<0.001) 2, 1

However, these results apply ONLY to patients with PSMA-positive disease without significant PSMA-negative visceral lesions. 1

Patient Selection Algorithm for Pluvicto

Before considering Pluvicto, patients must meet ALL of the following criteria:

1. Prior treatment requirements: 3, 4, 1

   • At least one androgen receptor pathway inhibitor (abiraterone, enzalutamide, apalutamide, or darolutamide)
   • At least one taxane-based chemotherapy regimen (typically docetaxel)

2. PSMA imaging requirements: 3, 4

   • Ga-68 PSMA-11, F-18 piflufolastat, or F-18 flotufolastat PET imaging
   • At least one PSMA-positive metastatic lesion with uptake greater than normal liver
   • NO visceral metastases ≥1.0 cm with PSMA uptake less than or equal to liver

3. Disease characteristics: 1

   • Metastatic castration-resistant prostate cancer with documented progression
   • Adequate organ function (renal, hepatic, hematologic)

Alternative Treatment Options for Visceral mCRPC

For patients with visceral metastatic disease who are ineligible for Pluvicto, consider:

• Cabazitaxel after docetaxel progression (ESMO-MCBS score: 3) 2
• Olaparib for patients with BRCA1/2 alterations after androgen receptor axis inhibitor failure (ESMO-MCBS score: 3) 2
• Continued androgen receptor pathway inhibitor if not previously used or switching to an alternative agent 2

Common Pitfalls to Avoid

• Do not assume all mCRPC patients are candidates for Pluvicto - visceral disease, particularly liver and lung metastases, often demonstrates poor or heterogeneous PSMA expression. 3, 1

• Do not proceed with Pluvicto without confirmatory PSMA PET imaging showing adequate PSMA expression in ALL significant disease sites. 3, 4

• Do not use Pluvicto in patients with dominant PSMA-negative visceral lesions - these patients were excluded from VISION and lack evidence of benefit. 1