Bone metastases occur in approximately 30% of patients with renal cell carcinoma and are associated with poor survival and symptomatic skeletal events. Radium-223 is an alpha-emitting, bone-seeking radioisotope that has prolonged survival in advanced prostate cancer. A previous pilot study combining radium-223 with VEGF tyrosine kinase inhibitors in renal cell carcinoma with bone metastases showed safety and early efficacy.
Cabozantinib is a tyrosine kinase inhibitor with reported efficacy in bone metastases. The RADICAL trial evaluated cabozantinib with or without radium-223 in patients with renal cell carcinoma and bone metastases.
The original abstract, titled “A phase 2 randomized trial of radium-223 dichloride and cabozantinib in patients with renal cell carcinoma with bone metastases: RADICAL (Alliance A031801),” was presented at the 2026 ASCO Annual Meeting and published in the Journal of Clinical Oncology on May 27, 2026.
Authors: Rana R. McKay, Pamela J. Atherton, Karla V. Ballman, Heather Jacene, Ronald C. Chen, Atish Dipankar Choudhury, Joshua Michael Lang, Suzanne Cole, Tareq Al Baghdadi, Young Kwok, Alan Tan, Stephanie A. Berg, Himisha Beltran, Michael J. Morris, Bradley Alexander McGregor, Tian Zhang, Matthew D. Galsky, Jonathan E. Rosenberg, Daniel J. George, and Toni K. Choueiri.
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Study Design
RADICAL, also known as Alliance A031801, was an open-label, multicenter, randomized phase 2 trial. The study enrolled patients with renal cell carcinoma who had at least one symptomatic bone metastasis that had not previously been irradiated. Patients were required to have a Karnofsky performance status of at least 60%. Prior therapies were allowed, and the non-clear cell renal cell carcinoma population was limited to 20%.
Patients were randomized 1:1 to cabozantinib plus radium-223 or cabozantinib alone. Randomization was stratified by osteoclast-targeted therapy, prior therapy, baseline opioid use, and IMDC risk.
In the combination arm, cabozantinib was given at 40 mg daily during cycle 1 and increased to 60 mg thereafter if tolerated. Radium-223 was given intravenously every 28 days for 6 doses. In the cabozantinib-alone arm, cabozantinib was given at 60 mg daily. The primary endpoint was symptomatic skeletal event-free survival. Secondary endpoints included safety, objective response rate, progression-free survival, and overall survival.
Patient Population
From December 2019 to September 2025, 90 patients were enrolled and evaluable for the interim analysis. The median age was 63 years. Most patients were male, 74.4%, and 83.3% had clear cell histology. Overall, 11.1% were treatment-naïve, 80.0% had received osteoclast-targeted therapy, and 51.1% had baseline opioid use. By IMDC risk, 16.7% of patients had favorable-risk disease, 68.9% had intermediate-risk disease, and 14.4% had poor-risk disease.
Efficacy Results
At a median follow-up of 13.1 months, 50 events had occurred. These included 17 symptomatic skeletal events, with 10 in the cabozantinib plus radium-223 arm and 7 in the cabozantinib-alone arm. There were also 33 deaths, with 13 in the combination arm and 20 in the cabozantinib-alone arm. Median stratified symptomatic skeletal event-free survival was 17.9 months with cabozantinib plus radium-223 and 17.6 months with cabozantinib alone. The stratified hazard ratio was 1.24.
Median unstratified symptomatic skeletal event-free survival was also 17.9 months in the combination arm and 17.6 months in the cabozantinib-alone arm, with a hazard ratio of 0.90. Median progression-free survival was 11.0 months with cabozantinib plus radium-223 and 11.2 months with cabozantinib alone. The stratified hazard ratio was 1.39.
Among 71 patients evaluable for response, the objective response rate was 22.2% in the combination arm and 22.9% in the cabozantinib-alone arm. Median overall survival was 32.2 months with cabozantinib plus radium-223 and 21.3 months with cabozantinib alone. The hazard ratio was 0.77.
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Safety
Treatment-related adverse events of any grade occurred in 97.7% of patients receiving cabozantinib plus radium-223 and 93.2% of patients receiving cabozantinib alone. Grade 3 or higher treatment-related adverse events occurred in 65.9% and 56.8% of patients, respectively. The median cabozantinib dose was 31.4 mg in the combination arm and 40.0 mg in the cabozantinib-alone arm. The median number of radium-223 cycles was 6.
Takeaway
In RADICAL, cabozantinib plus radium-223 did not improve symptomatic skeletal event-free survival compared with cabozantinib alone in patients with renal cell carcinoma and bone metastases. Overall survival was numerically longer with the combination, but the trial closed after interim analysis because symptomatic skeletal event-free survival did not meet the prespecified futility boundary.
The original abstract is available in the Journal of Clinical Oncology.