What are the results and recommendations for using Pluvicto (Lutetium-177 vipivotide tetraxetan) in clinical trials for patients with Prostate-Specific Membrane Antigen (PSMA)-positive metastatic castration-resistant prostate cancer?

Pluvicto (Lutetium-177 Vipivotide Tetraxetan) Clinical Trial Results for PSMA-Positive mCRPC

Pluvicto significantly improves survival in patients with PSMA-positive metastatic castration-resistant prostate cancer who have progressed on both androgen receptor pathway inhibitors and taxane chemotherapy, with a 3.6-month overall survival benefit and an 8.7-month radiographic progression-free survival advantage. 1, 2

FDA-Approved Indication and Patient Selection

Pluvicto is FDA-approved for adult patients with PSMA-positive mCRPC who have been treated with both androgen receptor (AR) pathway inhibition AND taxane-based chemotherapy. 1

Critical Patient Selection Requirements:

• PSMA-positive disease confirmed on PET imaging (using LOCAMETZ® or approved PSMA-11 imaging agent) with at least one tumor lesion showing uptake greater than normal liver 1
• Exclusion criterion: Any lesions exceeding size criteria (organs ≥1 cm, lymph nodes ≥2.5 cm, bones ≥1 cm) with uptake less than or equal to normal liver 1
• Prior treatment requirements: At least one AR pathway inhibitor AND 1-2 prior taxane-based chemotherapy regimens 1

VISION Trial: Pivotal Phase III Evidence

The VISION trial (NCT03511664) established Pluvicto's efficacy through a randomized 2:1, open-label study comparing Pluvicto plus best standard of care (n=551) versus best standard of care alone (n=280). 1, 2

Primary Efficacy Outcomes:

Overall Survival:

• Median OS: 15.3 months (Pluvicto + BSoC) vs 11.3 months (BSoC alone) 1, 2
• Hazard ratio: 0.62 (95% CI: 0.52-0.74, P<0.001) 1, 2
• Absolute survival benefit: 3.6 months 1

Radiographic Progression-Free Survival:

• Median rPFS: 8.7 months (Pluvicto + BSoC) vs 3.4 months (BSoC alone) 3, 1
• Hazard ratio: 0.40 (99.2% CI: 0.29-0.57, P<0.001) 3, 1
• Note: Interpretation of rPFS magnitude was limited by high censoring rates from early dropout in the control arm 1

Quality of Life and Symptomatic Benefits:

Time to First Symptomatic Skeletal Event:

• Median: 11.5 months (Pluvicto) vs 6.8 months (control) 4
• Hazard ratio: 0.50 (95% CI: 0.40-0.62) 4

Health-Related Quality of Life:

• Delayed time to worsening in FACT-P score (HR 0.54,95% CI: 0.45-0.66) 4
• Delayed time to worsening in pain intensity (BPI-SF score HR 0.52,95% CI: 0.42-0.63) 4
• Delayed time to worsening in EQ-5D-5L utility score (HR 0.65,95% CI: 0.54-0.78) 4

Treatment Protocol and Dosing

Standard dosing regimen: 7.4 GBq (200 mCi) intravenously every 6 weeks for up to 6 doses. 1

Treatment Administration Details:

• Typical course: 4-6 cycles at 6-week intervals 3, 5
• Continuation criteria: Patients with stable disease or partial response after 4 doses may receive up to 2 additional doses per investigator discretion 1
• Discontinuation triggers: Disease progression or unacceptable toxicity 1

Pre-Treatment Requirements:

• Complete blood counts must be performed before each cycle 3, 1
• Renal and hepatic function testing required before each treatment 3, 1
• Radioprotection precautions must follow national and local regulations 3

Safety Profile and Adverse Events

Most Common Adverse Reactions (≥20%):

• Fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation 1, 2
• Asthenia/fatigue and mild nausea are generally well tolerated 5

Laboratory Abnormalities (≥30%):

• Decreased lymphocytes (51% grade 3-4), decreased hemoglobin (15% grade 3-4), decreased leukocytes, decreased platelets (9% grade 3-4), decreased calcium, and decreased sodium 1, 2, 4

Serious Hematological Toxicity:

• Grade 3-4 events: Decreased hemoglobin (15% vs 6% control), lymphocyte concentrations (51% vs 19% control), platelet counts (9% vs 2% control) 4
• Myelosuppression is cumulative with additional cycles—requires vigilant monitoring 3, 5

Treatment-Related Deaths:

• Five deaths (1%) in Pluvicto arm: Pancytopenia (n=2), bone marrow failure (n=1), subdural hematoma (n=1), intracranial hemorrhage (n=1) 4
• Zero treatment-related deaths in control arm 4

Critical Safety Warnings and Management

Radiation Exposure Precautions:

• Minimize radiation exposure during and after treatment consistent with institutional radiation safety practices 1
• Patients must increase oral fluid intake and void frequently to reduce bladder radiation exposure 1
• Patients must limit close contact with others and use bathroom precautions in days following treatment 5

Dose Modifications:

• Dose interruption, reduction, or permanent discontinuation may be required based on adverse reaction severity 1
• Withhold, reduce dose, or permanently discontinue based on myelosuppression severity 1
• Withhold, reduce dose, or permanently discontinue based on renal toxicity severity 1

Renal Considerations:

• Lutetium Lu 177 vipivotide tetraxetan is primarily eliminated renally 1
• Exposure (AUC) increases with decreasing creatinine clearance 1
• Effect of baseline CLcr <54 mL/min has not been studied 1
• Patients must remain well hydrated and urinate frequently 1

Reproductive Toxicity:

• Embryo-fetal toxicity: Can cause fetal harm 1
• Male patients with female partners of reproductive potential must use effective contraception 1
• May cause temporary or permanent infertility 1

Clinical Trial Design Context

The VISION trial design aligns with contemporary PCWG3 recommendations for mCRPC trials, which emphasize: 6

• Time-to-event endpoints (OS, rPFS, symptomatic skeletal events) as primary measures 6
• Serial biologic profiling to identify resistance mechanisms 6
• Distinguishing progression in existing lesions from new lesions 6
• Concept of "no longer clinically benefiting" to guide treatment discontinuation 6

Positioning in Treatment Landscape

Pluvicto represents a theranostic approach using PSMA-targeted ligands linked to therapeutic radiopharmaceuticals (lutetium-177), following the established precedent of radium-223 for bone-predominant disease. 6

Key Distinctions from Other Radiopharmaceuticals:

• Unlike radium-223 (alpha emitter for bone-predominant disease), Pluvicto uses beta-minus emission targeting PSMA-expressing cells throughout the body 6, 1
• Radium-223 showed OS benefit in bone-predominant mCRPC but combination with abiraterone increased fracture risk 6
• Bone-targeted agents should be started before radium-223 based on ERA-223 trial results 6

Current Treatment Sequencing:

• Pluvicto is positioned after progression on AR pathway inhibitors and taxane chemotherapy 7, 3, 1
• Alternative options at this stage include cabazitaxel (if not previously received), PARP inhibitors (if DNA repair defects present), or clinical trial enrollment 8
• Radium-223 remains an option specifically for symptomatic bone metastases without visceral disease 8

Ongoing Research and Future Directions

Multiple ongoing trials are evaluating Pluvicto in earlier disease stages, different dosing strategies, and combination regimens. 5, 9

Areas of Active Investigation:

• Combination with other anticancer agents for mCRPC treatment 5
• Use in metastatic castration-sensitive prostate cancer 5
• Application in early-stage prostate cancer 5
• Alternative dosing strategies 5
• Biomarker development to predict which patients will benefit most 9

Unmet Needs:

• Predictive markers to facilitate patient selection for specific therapies or treatment sequences remain an unmet need 7
• Novel imaging methods claiming increased sensitivity/specificity have not been adequately tested in prospective trials 7

Administration Requirements

Pluvicto must only be administered by trained personnel in a designated clinical setting with existing radiation safety protocols. 5

• Multidisciplinary collaboration is recommended for optimal utilization 3
• Patient education is necessary to ensure safe daily practices post-treatment 5
• Institutional radiation safety practices must be followed 1, 5