131I-LNTH-1095 Radioligand Therapy Plus Enzalutamide vs. Enzalutamide Alone in Men With PSMA-Avid Metastatic Castration-Resistant Prostate Cancer: A Phase 2 Study

Purpose: The phase 2 ARROW study was designed to evaluate radioligand therapy with 131I-LNTH-1095, an iodine-131–labeled small molecule targeting PSMA, in combination with enzalutamide in subjects with metastatic castration-resistant prostate cancer after progression on prior abiraterone therapy. Patients and Methods: Men ≥18 years with PSMA-positive prostate cancer (PSMA PET tracer uptake >1× liver SUVmean in all CT-measurable lesions) were randomized 2:1 to 131I-LNTH-1095 (4 cycles of 3.7 GBq/dose every 8 weeks)+enzalutamide (160 mg po qd) vs. enzalutamide alone. The primary endpoint was PSA50 response. Secondary endpoints included rPFS, ORR, OS, and safety. Results: Of 177 screened subjects, 120 were randomized (80: 131I-LNTH-1095+enzalutamide; 40: enzalutamide-monotherapy). PSA50 response was 62.9% (95% CI, 50.5-74.1) for 131I-LNTH-1095+enzalutamide vs. 31.3% (16.1-50.0) for enzalutamide alone (P=.003). Median rPFS was 14.0 months (95% CI: 8.64-18.20) for 131I-LNTH-1095+enzalutamide vs. 11.5 months (2.79–18.43) for enzalutamide alone (P=.10). Incidence of grade ≥3 treatment-emergent adverse events (TEAEs) was 65.8% for 131I-095+enzalutamide vs. 41.0% for enzalutamide-monotherapy; the most frequent TEAEs were fatigue (75.0 vs. 53.8%), nausea (59.2 vs. 33.3%), thrombocytopenia (51.3 vs. 0%), and decreased appetite (48.7 vs. 17.9%), respectively. Two deaths in the 131I-LNTH-1095+enzalutamide group were considered treatment-related. The study was not powered to detect rPFS and OS differences. Conclusions: 131I-LNTH-1095+enzalutamide was associated with a statistically significant improvement in PSA50 response compared to enzalutamide alone despite a lower dosing schedule (4 cycles of 3.7 GBq/dose every 8 weeks) than the other approved PSMA RLT agents. Grade ≥3 adverse events were more frequent with combination therapy, particularly hematologic toxicity. NCT03939689