Can more than 6 Lutetium-177 (LU-177) infusions improve overall survival (OS) in patients with castration-resistant metastatic prostate cancer?

Extended LU-177 PSMA Therapy Beyond 6 Infusions in Castration-Resistant Metastatic Prostate Cancer

Currently, there is insufficient evidence to support that more than 6 LU-177 infusions improve overall survival in patients with castration-resistant metastatic prostate cancer, as clinical trials have typically used 4-6 cycles of treatment.

Evidence for LU-177 PSMA Therapy in Metastatic CRPC

• Lutetium-177 PSMA-617 (LU-177) therapy has been established as an effective treatment for metastatic castration-resistant prostate cancer (mCRPC) in patients who have progressed after at least one taxane and one novel androgen receptor axis inhibitor 1
• The VISION trial, which led to regulatory approval, demonstrated that LU-177 PSMA-617 plus best standard of care significantly improved overall survival compared to standard of care alone (median 15.3 vs 11.3 months; HR 0.62,95% CI 0.52-0.74) 2
• In the VISION trial protocol, patients received 4-6 cycles of LU-177 PSMA-617 at 7.4 GBq per cycle administered every 6 weeks 2, 3
• The standard treatment regimen established by clinical trials consists of 4-6 cycles of LU-177 PSMA-617 2, 3

Safety and Efficacy Considerations

• LU-177 PSMA-617 therapy is associated with specific toxicities that may limit extended use, including:
  • Grade 3-4 hematological adverse events such as decreased hemoglobin (15%), lymphocyte concentrations (51%), and platelet counts (9%) 3
  • Treatment-related deaths occurred in 1% of patients in the VISION trial 3
• Smaller studies have shown promising results with varying numbers of cycles:
  • The LuPSMA trial used up to 4 cycles of LU-177 PSMA-617 and demonstrated a PSA decline of ≥50% in 57% of patients 4
  • Real-world data analysis of patients receiving 1-5 cycles showed median overall survival of 12 months 5

Quality of Life Impact

• LU-177 PSMA-617 therapy has demonstrated significant benefits in quality of life metrics:
  • Delayed time to worsening in Functional Assessment of Cancer Therapy-Prostate (FACT-P) scores 3
  • Improved pain control as measured by Brief Pain Inventory-Short Form (BPI-SF) 3
  • Delayed time to first symptomatic skeletal event (median 11.5 vs 6.8 months) 3

Current Recommendations and Limitations

• Current ESMO guidelines recommend LU-177 PSMA-617 for men with mCRPC pretreated with at least one taxane and at least one novel androgen receptor axis inhibitor 1
• The guidelines do not specify recommendations for extended therapy beyond the standard 4-6 cycles used in clinical trials 1
• There is a lack of prospective randomized trials specifically evaluating the efficacy and safety of extended LU-177 PSMA therapy beyond 6 cycles 1

Clinical Implications

• The decision to extend LU-177 PSMA therapy beyond 6 cycles must carefully weigh potential benefits against cumulative toxicity risks, particularly hematological toxicities 3
• Patients who have responded well to initial therapy with minimal toxicity may theoretically benefit from additional cycles, but this approach lacks evidence from randomized controlled trials 5
• Monitoring for bone marrow suppression, particularly thrombocytopenia, is essential if considering extended therapy 4, 3

In conclusion, while LU-177 PSMA-617 therapy has demonstrated significant survival benefits in mCRPC patients, the current evidence base from clinical trials is limited to 4-6 cycles of treatment. Until further studies specifically evaluate extended treatment protocols, clinicians should adhere to the established regimen that has demonstrated proven survival benefits.