Lu-177 PSMA Therapy for Metastatic Castration-Resistant Prostate Cancer
Yes, Lu-177-PSMA-617 will reduce lesions in metastatic castration-resistant prostate cancer that expresses PSMA, with objective response rates of 82% in measurable disease and PSA reductions of ≥50% in 57-66% of patients. 1, 2
Patient Selection Requirements
Before initiating Lu-177-PSMA-617, confirm the following criteria are met:
- PSMA-positive disease on PET imaging (68Ga-PSMA-11 or equivalent) with no PSMA non-expressing lesions 3, 4
- Prior treatment with at least one androgen receptor pathway inhibitor (abiraterone, apalutamide, darolutamide, or enzalutamide) 3, 5
- Prior treatment with docetaxel chemotherapy 3, 5
- Adequate organ function: check complete blood count, renal function, and hepatic function before each cycle 4, 5
Evidence for Lesion Reduction
The landmark VISION trial demonstrated clear tumor reduction with Lu-177-PSMA-617:
- Median radiographic progression-free survival: 8.7 months versus 3.4 months with standard care alone (HR 0.40, P<0.001) 2
- Overall survival benefit: 15.3 months versus 11.3 months (HR 0.62, P<0.001) 2
- Objective response rate in measurable nodal or visceral disease: 82% 1
- PSA decline ≥50%: 57% of patients in the LuPSMA trial 1
The TheraP trial showed even higher response rates, with 66% PSA response compared to 37% with cabazitaxel in docetaxel-pretreated patients 4, 5
Treatment Protocol
Administer Lu-177-PSMA-617 using this standardized approach:
- 4-6 cycles at 6-week intervals 4, 5
- Dose: 7.4 GBq (200 mCi) per cycle 2
- Continue treatment even if lesions have not yet shown significant reduction after 2 cycles, provided there is no progression 4
- Monitor PSA levels before each cycle 5
- Check blood counts, renal, and hepatic function before each treatment cycle 4
Expected Timeline for Response
- PSA response typically occurs within 2-4 cycles 4
- Imaging response assessment should occur at 8 weeks after cycle 1 and 12 weeks after cycle 2 6
- Clinical progression-free survival in elderly patients (≥80 years): median 8.7 months 7
Safety Profile and Toxicity
Lu-177-PSMA-617 has a favorable toxicity profile compared to chemotherapy alternatives:
- Grade 3-4 adverse events: 52.7% versus 38.0% with standard care alone 2
- Most common side effects: grade 1 dry mouth (87%), grade 1-2 nausea (50%), grade 1-2 fatigue (50%) 1
- Grade 3-4 thrombocytopenia: 3.8-13% 7, 1
- Grade 3-4 anemia: 5% 7
- No grade 4 non-hematologic toxicities reported 7
Critical caveat: A rare but serious delayed toxicity is therapy-related myeloid neoplasm (t-MN), occurring in approximately 1.3% of patients, with median time to diagnosis of 33.6 months after starting treatment 8. This risk must be weighed against the survival benefit, particularly in patients with longer life expectancy.
Special Populations
Chemotherapy-naïve patients show superior outcomes:
- PSA response rate: 51% versus 38.7% in chemotherapy-pretreated patients 7
- Median clinical progression-free survival: 10.5 months versus 6.5 months 7
- Median overall survival: 20.7 months versus 11.8 months 7
Elderly patients (≥80 years) tolerate treatment well, with comparable efficacy to younger cohorts and low rates of high-grade toxicities 7
Quality of Life Benefits
Beyond lesion reduction, Lu-177-PSMA-617 provides meaningful clinical benefits:
- 37% of patients experienced ≥10 point improvement in global health score by cycle 2 1
- Clinically meaningful improvements in pain severity and interference scores at all timepoints 1
- Quality of life was not adversely affected despite higher adverse event rates 2
Guideline Recommendations
ESMO guidelines assign Lu-177-PSMA-617 the highest benefit score (ESMO-MCBS v1.1 score: 4) for mCRPC patients with PSMA-expressing tumors who have received prior androgen receptor axis inhibitor and docetaxel 3, 4