131I-LNTH-1095 Plus Enzalutamide in Metastatic Castration-Resistant Prostate Cancer

Key Clinical Summary:

• Design/Population: The phase 2 ARROW study randomized 120 patients with PSMA-positive metastatic castration-resistant prostate cancer who progressed on abiraterone to receive ¹³¹I-LNTH-1095 plus enzalutamide or enzalutamide alone. The primary end point was PSA₅₀ response.
• Key Outcomes: The combination significantly improved PSA response rates compared with enzalutamide alone. Radiographic progression-free survival showed a numerical improvement but was not statistically significant.
• Clinical Relevance: PSMA-targeted radioligand therapy may enhance response when combined with androgen receptor–targeted therapy in metastatic castration-resistant prostate cancer. Increased hematologic toxicity highlights the need for careful patient selection and monitoring.

Results from the phase 2 ARROW study demonstrated that enzalutamide plus radioligand therapy (RLT) with ¹³¹I-LNTH-1095, an iodine-131-labeled small molecule targeting PSMA, significantly improved PSA₅₀ compared to enzalutamide alone among previously treated patients with metastatic castration-resistant prostate cancer, following progression on abiraterone treatment.

“Despite significant advances in treatment options, metastatic disease remains incurable,” stated Evan Yu, MD, Fred Hutchinson Cancer Center, Seattle, Washington, and coauthors. “In nonclinical studies, the combination of PSMA-directed treatment modalities plus antiandrogens had synergistic cytotoxic effects against prostate cancer cells.” 

In this open-label study, 120 patients who experienced disease progression on prior abiraterone therapy who were ineligible for or declined taxane-based chemotherapy were randomized 2:1 to receive 160 mg of once daily enzalutamide either alone (n = 40) or in combination with 3.7 GBq of  ¹³¹I-LNTH-1095 in 4 cycles every 8 weeks (n = 80). The primary end point was PSA₅₀ response. Key secondary end points included radiographic progression-free survival (rPFS) and safety.

At analysis, PSA₅₀ response was 62.9% in the ¹³¹I-LNTH-1095 plus enzalutamide arm and 31.3% in the enzalutamide monotherapy arm (P = .003). Median rPFS was 14 months and 11.5 months, respectively. 

Grade ≥ 3 treatment-emergent adverse events were reported in 65.8% of patients in the ¹³¹I-LNTH-1095 plus enzalutamide arm and 41% of patients in the enzalutamide monotherapy arm. Notably, grade ≥ 3 adverse events were more frequent with combination therapy, particularly hematologic toxicity. The most frequently reported treatment-emergent adverse events included fatigue (75%; 53.8%), nausea (59.2%; 33.3%), thrombocytopenia (51.3%; 0%), and decreased appetite (48.7%; 17.9%). Two treatment-related deaths were reported in the ¹³¹I-LNTH-1095 plus enzalutamide arm. 

“This study demonstrated ¹³¹I-LNTH-1095 to be an effective and tolerable PSMA-targeting small molecule when combined with an [androgen receptor pathway inhibitor],” concluded Dr Yu et al. “Additional studies may be warranted to evaluate long-term outcomes in chemo-naive [metastatic castration-resistant prostate cancer], provided they are within the context of a non-¹³¹I radioisotope and a further optimized dosing regimen.” 

Source: 

Yu EY, Narayan V, Esposito G, et al. ¹³¹I-LNTH-1095 radioligand therapy plus enzalutamide versus enzalutamide alone in men with PSMA-avid metastatic castration-resistant prostate cancer: A phase II study. Clin Can Res. Published online: March 26, 2026. doi:10.1158/1078-0432.CCR-25-4948