Will metastatic prostate cancer lesions that do not reduce after two Lutetium-177 (LU-177) infusions reduce after further Lutetium-177 (LU-177) infusions?

Response to Metastatic Prostate Cancer Lesions After Lu-177 Infusions

Metastatic prostate cancer lesions that do not respond to two Lu-177 infusions may still respond to additional cycles, as standard treatment protocols recommend three to six total cycles of Lu-177 therapy. 1, 2

Lu-177 Treatment Protocol for Metastatic Prostate Cancer

• Standard Lu-177-PSMA therapy typically consists of 3-5 cycles administered at 6-12 week intervals 1
• The VISION trial, which established Lu-177-PSMA as effective therapy for metastatic castration-resistant prostate cancer (mCRPC), utilized 4-6 cycles of treatment at 6-week intervals 1, 2
• Each Lu-177 cycle delivers 5.55-7.4 GBq (150-200 mCi) of radioactivity to PSMA-expressing tumor cells 1

Response Patterns to Lu-177 Therapy

• Tumor response to Lu-177 therapy can be heterogeneous, with some lesions responding after additional cycles even if no response was observed after initial treatments 2
• In the pivotal VISION trial, continued Lu-177 treatment provided cumulative benefit with median overall survival of 15.3 months versus 11.3 months in the control group 1, 2
• Response assessment should include both imaging (PSMA-PET/CT) and PSA measurements, as some lesions may show metabolic response before size reduction 3

Factors Affecting Response to Additional Cycles

• PSMA expression levels on tumor cells significantly impact treatment efficacy - higher expression generally correlates with better response to additional cycles 4
• Tumor burden and location of metastases can affect response rates to continued therapy 3
• Prior treatments (especially taxane chemotherapy and androgen receptor pathway inhibitors) may influence response to additional Lu-177 cycles 2

Clinical Evidence for Continued Treatment

• In clinical studies, some patients demonstrated continued tumor response with additional Lu-177 cycles beyond the initial two treatments 3, 2
• The LuPSMA trial showed that up to 57% of patients achieved PSA decline of 50% or more with multiple Lu-177 cycles 3
• Objective responses in nodal or visceral disease were reported in 82% of patients with measurable disease after completing the full treatment course 3

Treatment Considerations for Non-Responding Lesions

• For lesions not responding after two cycles, dosimetry studies may help determine if adequate radiation dose is being delivered to target tissues 1
• Consider evaluating for heterogeneity in PSMA expression with repeat PSMA-PET imaging before additional cycles 4
• Hyperfractionation (more frequent, lower dose treatments) has been studied but does not appear to offer advantages over standard fractionation for non-responding lesions 5

Monitoring During Additional Cycles

• Regular monitoring of hematologic parameters is essential as myelosuppression can be cumulative with additional cycles 6, 3
• Common side effects with continued Lu-177 therapy include fatigue, dry mouth, nausea, and potential for thrombocytopenia, anemia, and lymphopenia 6, 3
• Quality of life assessments should be performed throughout treatment, as maintaining QOL is a primary goal of therapy 3, 2

Conclusion for Clinical Practice

• Continuing Lu-177 therapy beyond two cycles is reasonable and recommended for patients who have not progressed, even if lesions have not yet shown significant reduction 1
• The full therapeutic benefit of Lu-177 may require completion of the recommended 3-5 cycles to achieve maximal tumor response 1, 2
• Treatment decisions should consider the overall response pattern, not just individual lesions, as the systemic effect of continued therapy may eventually impact initially non-responsive lesions 3, 2