ETCTN 10302: A randomized phase II trial of radium-223 dichloride in combination with paclitaxel in patients with bone metastatic breast cancer.

3096 Background: Radium-223 dichloride is an alpha particle emitting radiopharmaceutical that mimics calcium and localizes bone metastases inducing double-strand DNA breaks. Tumor cells in M-phase cell cycle arrest from paclitaxel are highly sensitive to alpha-emitting radionuclides. ETCTN 10302 tested the hypothesis that addition of radium-223 to paclitaxel will improve outcomes for bone-dominant metastatic breast cancer. Methods: ETCTN 10302 was a randomized, two-arm, multicenter, open-label phase II trial. Patients (pts) were randomized to receive either radium-223 (1.49 microcurie/kg iv day 1 x 6 doses) and paclitaxel (80 mg/kg iv on days 1,8 and 15) of each 28-day cycle (Arm A) or paclitaxel alone (Arm B). Inclusion criteria included HER2-negative metastatic breast cancer with ≥2 bone lesions and limited visceral metastases (five or less and ≤4 cm in size). Primary endpoint was median progression-free survival (PFS). Exploratory analyses included whole exome sequencing and serum alkaline phosphatase dynamics. Results: 70 pts were randomized from August 2020 to May 2024. Median age was 58.5 years, 100% were female, 60% were non-Hispanic whites, 14% had triple negative breast cancer, 37% had bone only disease. In the intent-to-treat analysis (37 Arm A, 33 Arm B), there was no significant difference in median PFS (5.8 vs 5.6 months; HR 0.92 p=0.80) but there was a numeric improvement in median OS in radium-223 plus paclitaxel arm (20.2 vs 16.6 months; HR 0.74 p=0.40). Overall response rate (ORR) was 5% in Arm A vs 9% in Arm B. There was no difference in median OS and PFS when analysis was limited to efficacy evaluable pts who completed at least one cycle (37 Arm A, 24 Arm B). Common treatment-related adverse events (TRAE) with the combination of radium-223 plus paclitaxel vs paclitaxel were anemia (78% vs 54%), neutropenia (76% vs 45%), fatigue (49% vs 50%), nausea/vomiting (46% vs 21%), diarrhea (32% vs 25%), peripheral sensory neuropathy (33% vs 30%) and increased ALT (22% vs 4%). Most common ≥grade 3 TRAE was neutropenia in Arm A (43% vs 8% in Arm B). Treatment discontinuation rate due to TRAE was 3%. Conclusions: Combination of radium-223 and paclitaxel can be administered safely as most adverse events observed were grade 1 to 2 except for higher incidence of ≥ grade 3 neutropenia. The trial did not meet the primary PFS endpoint but there was a numerical improvement observed in median OS with the combination. Clinical trial information: NCT04090398 .