Background
Phase III, open-label RCT. 468 patients with mCRPC who had received one or two prior ARPIs (abiraterone or enzalutamide) but were taxane-naïve. PSMA PET-positive tumors required (PSMA+ by 68Ga-PSMA-11 or 18F-DCFPyL). Lu-PSMA-617 compared to physician's choice of ARPI switch (the other ARPI not previously received) — first phase III trial of Lu-PSMA-617 in the post-ARPI, taxane-naïve setting.
Interventions and follow up
Arm A: [177Lu]Lu-PSMA-617 7.4 GBq IV q6wk × up to 6 cycles
Arm B: Abiraterone 1000mg/day + prednisone OR enzalutamide 160mg/day (investigator choice)
Primary endpoint: Radiographic PFS (rPFS)
mFollow up: 13.0 mo
Arm B: Abiraterone 1000mg/day + prednisone OR enzalutamide 160mg/day (investigator choice)
Primary endpoint: Radiographic PFS (rPFS)
mFollow up: 13.0 mo
Results
rPFS: 9.30 vs 5.55 mo, HR 0.41, P<.0001
PSA response (≥50% decline): 57.0% vs 20.0%
OS: Immature at primary analysis; crossover to Lu-PSMA-617 permitted at progression
Objective response rate (soft tissue): 36% vs 14%
PSA response (≥50% decline): 57.0% vs 20.0%
OS: Immature at primary analysis; crossover to Lu-PSMA-617 permitted at progression
Objective response rate (soft tissue): 36% vs 14%
Adverse events
Overall: Grade ≥3 AEs 35.3% (Lu-PSMA) vs 38.5% (ARPI); myelosuppression requiring dose modification 17%; no secondary malignancies reported
Hematologic: Anemia grade ≥3 12.6% vs 11.6%; thrombocytopenia grade ≥3 7.7% vs 2.3%
GI/constitutional: Dry mouth (any) 46.7% vs 3.5%; nausea (any) 32.3% vs 11.0%; fatigue (any) 39.2% vs 31.5%
Hematologic: Anemia grade ≥3 12.6% vs 11.6%; thrombocytopenia grade ≥3 7.7% vs 2.3%
GI/constitutional: Dry mouth (any) 46.7% vs 3.5%; nausea (any) 32.3% vs 11.0%; fatigue (any) 39.2% vs 31.5%
Conclusions
Lu-PSMA-617 significantly improved rPFS versus ARPI switch in taxane-naïve, post-ARPI, PSMA-positive mCRPC with a large effect size (HR 0.41). This trial established Lu-PSMA-617 as a viable pre-taxane option and expanded its use beyond the post-docetaxel setting demonstrated in VISION.
Key Limitations
Key Limitations: ARPI comparator has limited efficacy post-prior ARPI (CARD demonstrated ~14% PSA response rate with ARPI switch) — this is a favorable comparator for Lu-PSMA-617. OS data were immature and crossover confounds survival analysis. PSMA PET selection (positive tumors only) enriches for the population most likely to benefit, limiting generalizability to all mCRPC. The optimal sequencing of Lu-PSMA-617 relative to taxane chemotherapy, PARP inhibitors, and radioligand therapy combinations (e.g., PARP + lutetium) remains under investigation.
Clinical Context
PSMAfore complemented VISION (Lu-PSMA-617 post-docetaxel, NEJM 2021, n=141 in DB) by establishing efficacy in the earlier taxane-naïve post-ARPI setting. FDA approved the expanded indication in 2024. PSMAfore, combined with VISION, makes Lu-PSMA-617 a flexible option across multiple lines in PSMA-positive mCRPC. Access to PSMA PET imaging and radiopharmaceutical availability remain practical constraints.
References
References: Morris MJ et al, Lancet 2024