131I-LNTH-1095 Plus Enzalutamide in PSMA-Avid mCRPC

Key Takeaways

• The combination was associated with a stronger primary PSA50 signal than enzalutamide alone.
• Radiographic progression-free survival was numerically longer with the combination, although the trial was not powered to detect rPFS or overall survival differences.
• Grade 3 or higher adverse events were more frequent with the combination, and two treatment-related deaths occurred in that arm.

The randomized phase II ARROW study showed a higher PSA50 response with 131I-LNTH-1095 plus enzalutamide than with enzalutamide alone. In men with PSMA-avid metastatic castration-resistant prostate cancer after prior abiraterone, rates were 62.9% versus 31.3%, with P = 0.003.

ARROW enrolled men aged 18 years or older with metastatic castration-resistant prostate cancer after documented progression on prior abiraterone therapy. Eligibility required PSMA-positive disease, defined by PSMA PET tracer uptake greater than 1 times liver SUVmean in all CT-measurable lesions. This threshold required uptake above background liver activity in all measurable lesions before randomization. Of 177 screened men, 120 were randomized 2:1, with 80 assigned to 131I-LNTH-1095 at 3.7 GBq every 8 weeks for 4 cycles plus daily enzalutamide, and 40 to enzalutamide alone.

Median radiographic progression-free survival was 14.0 months with the combination and 11.5 months with enzalutamide alone (P = 0.10). The corresponding 95% confidence intervals were 8.64 to 18.20 months for the combination and 2.79 to 18.43 months for monotherapy.

Grade 3 or higher treatment-emergent adverse events occurred in 65.8% of the combination arm and 41% of the enzalutamide-alone arm. Two deaths in the combination group were considered treatment-related. The most frequent adverse events were fatigue, nausea, thrombocytopenia, and decreased appetite across study arms. Each occurred more often with the combination, with thrombocytopenia showing the clearest contrast at 51.3% versus 0%.