131I-LNTH-1095 Radioligand Therapy plus Enzalutamide versus Enzalutamide Alone in Men with PSMA-Avid Metastatic Castration-Resistant Prostate Cancer: A Phase II Study.

PURPOSE: The phase II ARROW study was designed to evaluate radioligand therapy (RLT) with 131I-LNTH-1095, an iodine-131-labeled small molecule targeting prostate-specific membrane antigen (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 randomly assigned 2:1 to 131I-LNTH-1095 (4 cycles of 3.7 GBq/dose every 8 weeks) + enzalutamide (160 mg orally once daily) versus enzalutamide alone. The primary endpoint was PSA50 response. Secondary endpoints included radiographic progression-free survival (rPFS), objective response rate, overall survival (OS), and safety.

RESULTS

Of 177 screened subjects, 120 were randomly assigned (80: 131I-LNTH-1095 + enzalutamide; 40: enzalutamide monotherapy). PSA50 response was 62.9% [95% confidence interval (CI), 50.5-74.1] for 131I-LNTH-1095 + enzalutamide versus 31.3% (16.1-50) for enzalutamide alone (P = 0.003). The median rPFS was 14.0 months (95% CI, 8.64-18.20) for 131I-LNTH-1095 + enzalutamide versus 11.5 months (2.79-18.43) for enzalutamide alone (P = 0.10). The incidence of grade ≥3 treatment-emergent adverse events (TEAE) was 65.8% for 131I-LNTH-1095 + enzalutamide versus 41% for enzalutamide monotherapy; the most frequent TEAEs were fatigue (75% 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 with 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.