What are the results of having more than 6 Pluvicto (Lutetium-177 PSMA) infusions for prostate cancer?

Extended Pluvicto Therapy Beyond 6 Cycles

Extended therapy with Lutetium-177 PSMA beyond the standard 6 cycles is safe and demonstrates preserved efficacy, with no increased risk of severe toxicity, and should be considered for patients who continue to respond to treatment. 1

Evidence for Extended Treatment

The FDA-approved regimen for Pluvicto (177Lu-PSMA-617) consists of 7.4 GBq administered intravenously every 6 weeks for up to 6 doses, based on the pivotal VISION trial which demonstrated a median overall survival of 15.3 months versus 11.3 months with best standard of care alone. 2 However, emerging real-world data challenges the limitation to only 6 cycles.

Safety Profile Beyond 6 Cycles

A German multicenter retrospective analysis of 111 patients who received extended 177Lu-PSMA therapy provides the most robust evidence for treatment beyond 6 cycles. 1 Key safety findings include:

• Hematologic toxicity remained manageable: Grade 3-4 anemia occurred in 16.3% of continuous treatment patients versus 19.1% in rechallenge patients (P=0.6), with no significant difference from standard 6-cycle protocols 1
• Thrombocytopenia rates were low: Grade 3-4 thrombocytopenia occurred in only 7.0% of continuous treatment versus 4.4% of rechallenge patients (P=0.3) 1
• Renal toxicity remained minimal: Grade 3-4 renal adverse events occurred in 4.7% versus 7.4% (P=0.2) 1
• No cumulative bone marrow toxicity: Unlike older radiopharmaceuticals such as strontium-89 and samarium-153, which caused problematic bone marrow toxicity with repeated treatments, extended 177Lu-PSMA therapy did not demonstrate increased severe toxicity 3, 1

Efficacy Outcomes

Overall survival from extended therapy is clinically meaningful:

• Median overall survival from first administration was 31.3 months for the entire extended treatment cohort 1
• Patients undergoing rechallenge treatment (therapy break followed by retreatment) demonstrated median survival of 40.2 months 1
• Continuous treatment patients showed median survival of 23.2 months 1

Biochemical response rates:

• PSA decline of ≥50% was observed in 37.1% of patients after first rechallenge, demonstrating preserved treatment efficacy even after a treatment break 1
• Initial PSA response rates were significantly higher in the rechallenge group (90.4%) compared to continuous treatment (61.9%, P=0.006), suggesting that treatment breaks may restore sensitivity 1

Treatment Strategies Beyond 6 Cycles

Continuous Treatment Approach

Patients received uninterrupted continuation beyond 6 cycles with median cumulative doses reaching 57.4 GBq (approximately 7-8 cycles). 1 This approach is appropriate for patients demonstrating ongoing response without significant toxicity.

Rechallenge Approach

The rechallenge strategy involves a treatment holiday followed by retreatment, with median cumulative doses of 60.8 GBq. 1 This approach demonstrated:

• Superior overall survival (40.2 months versus 23.2 months for continuous treatment) 1
• Higher initial PSA response rates (90.4% versus 61.9%) 1
• Preserved efficacy upon retreatment (37.1% PSA response after first rechallenge) 1

Ongoing Clinical Trial Evidence

The FLEX-MRT trial is currently investigating an extended and flexible dosing schedule allowing up to 12 cycles with potential treatment holidays, comparing this approach to the standard 6-cycle regimen. 4 Response assessment is based on SPECT/CT at each cycle and PSMA PET/CT during treatment holidays every 12 weeks. 4

Monitoring During Extended Therapy

PSA monitoring remains critical:

• A 66% PSA response rate with 177Lu-PSMA-617 is strongly associated with improved progression-free survival, overall survival, and quality of life 5
• Patients demonstrating PSA response should continue with planned treatment, as grade 3-4 adverse events with 177Lu-PSMA-617 (33%) are less frequent than alternative therapies like cabazitaxel (53%) 5
• Do not add concurrent systemic therapies based solely on PSA kinetics if the patient is demonstrating response and tolerating treatment well 5

Imaging surveillance:

• PSMA PET/CT is superior to conventional imaging for detecting low-volume metastatic disease and should be used for restaging evaluation 5
• Response assessment during treatment holidays should occur every 12 weeks using PSMA PET/CT 4

Common Pitfalls and Caveats

Avoid premature discontinuation: The standard 6-cycle limitation from the VISION trial was based on study design rather than safety or efficacy concerns. Patients continuing to respond without significant toxicity may benefit from extended treatment. 2, 1

Monitor for cumulative hematologic toxicity: While extended therapy has not shown increased severe toxicity, regular complete blood counts remain essential, particularly monitoring for anemia, thrombocytopenia, and leukopenia. 1

Consider treatment holidays: The rechallenge approach demonstrated superior survival outcomes compared to continuous treatment, suggesting that strategic treatment breaks may restore treatment sensitivity and improve long-term outcomes. 1

Patient selection matters: Extended therapy candidates demonstrated favorable median survival of 31.3 months from first administration, indicating that appropriate patient selection for extended treatment is crucial. 1