Radium-223 Does Not Improve SSE-Free Survival With Cabozantinib in mRCC

According to results from the phase 2 RADICAL trial (Alliance A031801; NCT04071223), published in the Journal of Clinical Oncology, adding radium-223 dichloride (Xofigo) to cabozantinib (Cabometyx) did not improve symptomatic skeletal event-free survival (SSE-FS) compared with cabozantinib alone in patients with metastatic renal cell carcinoma (mRCC) and bone metastases.¹ The trial closed to accrual after crossing a prespecified futility boundary at interim analysis.²

In the final analysis of 98 patients, median SSE-FS was 16.7 months (90% CI, 13.5-39.6) with the combination vs 17.6 months (90% CI, 11.5-24.5) with cabozantinib alone (stratified HR, 1.46; 90% CI, 0.86-2.51; 1-sided P =.12).¹ Secondary end points numerically favored the monotherapy arm but showed wide confidence intervals: median overall survival (OS) was 28.3 months vs 19.7 months (stratified HR, 1.40; 95% CI, 0.70-2.79; P =.34), median progression-free survival (PFS) was 10.3 vs 10.5 months (stratified HR, 1.37; 95% CI, 0.74-2.53; P =.32), and confirmed objective response rate (ORR) was 19.4% vs 25.0% (P =.78).¹

Study Design

RADICAL enrolled patients with mRCC of any histology and at least 1 bone metastasis not previously irradiated, who were treatment-naive or had received prior systemic therapy but no prior cabozantinib or radium-223. Patients were randomly assigned 1:1 to cabozantinib plus radium-223 (n = 48) or cabozantinib alone (n = 50), stratified by International mRCC Database Consortium (IMDC) risk group, osteoclast-targeted therapy (OTT) use, prior treatment status, and baseline opioid use. All patients received concurrent OTT with a bisphosphonate or denosumab unless contraindicated. Radium-223 was given at 1.49 μCi/kg on day 1 of each 28-day cycle for up to 6 cycles; cabozantinib was initiated at 40 mg during cycle 1 and escalated to 60 mg from cycle 2 in the combination arm, vs the standard 60-mg daily dose in the monotherapy arm.

The data and safety monitoring board recommended closing accrual after a prespecified interim futility analysis at 90 patients (50 SSE-FS events) returned a stratified HR of 1.24 (95% CI, 0.62-2.48), crossing the Wieand-rule futility boundary. The final analysis included all 98 enrolled patients, with a median follow-up of 13.1 months.

Safety and Tolerability

Grade 3 or higher adverse events (AEs) occurred in 69.6% of patients in the combination arm vs 75.5% in the cabozantinib-alone arm. Hematologic toxicities were more frequent with the combination, including any-grade anemia (76.1% vs 59.2%), neutropenia (45.7% vs 14.3%), and lymphopenia (50.0% vs 34.7%; grade ≥3, 26.1% vs 14.3%). Among grade 3 or higher AEs occurring in at least 5% of either arm, rates were higher with the combination for diarrhea (13.0% vs 6.1%) and sepsis (6.5% vs 0%), and higher with cabozantinib alone for hypertension (0% vs 20.4%) and palmar-plantar erythrodysesthesia syndrome (0% vs 12.2%). Six on-treatment deaths were reported across both arms.

Clinical Context and Limitations

The study authors noted that stratified and unstratified estimates of the SSE-FS HR diverged substantially (1.46 vs 0.97 [90% CI, 0.62-1.51]), suggesting the 4-factor stratified model may have been overparameterized relative to the sample size—a discordance they said warrants caution in interpreting the primary end point.¹

RADICAL enrolled patients from December 2019 to December 2025, a period marked by growing first-line use of immune checkpoint inhibitor–based regimens, which the authors said may have introduced selection bias by excluding some patients who had already received cabozantinib. Cabozantinib previously showed a PFS benefit over everolimus (Afinitor), including in a bone-metastasis subgroup, in the phase 3 METEOR trial (NCT01865747).³ Radium-223 is approved in metastatic castration-resistant prostate cancer based on an OS benefit shown in the phase 3 ALSYMPCA trial (NCT00699751).⁴ RADICAL was designed to avoid the fracture signal seen when radium-223 was combined with abiraterone in the phase 3 ERA-223 trial (NCT02043678), mandating concurrent OTT and excluding patients with imminent fracture risk; no fracture signal emerged in the combination arm.¹^,⁵

"Both of these efforts warrant additional data using novel agents in replacement of radium-223,” wrote Andrea Necchi, MD, associate editor, Journal of Clinical Oncology, in a written commentary accompanying the publication.

REFERENCES

1. McKay RR, Ballman KV, Atherton PJ, et al. Phase II randomized trial of radium-223 dichloride and cabozantinib in patients with renal cell carcinoma with bone metastases: RADICAL (Alliance A031801). J Clin Oncol. 2026;44(24):2341-2352. doi:10.1200/JCO-26-01135

2. Phase II Randomized Trial of Radium-223 Dichloride and Cabozantinib in Patients With Renal Cell Carcinoma With Bone Metastases (RADICAL). ClinicalTrials.gov. Updated July 31, 2026. Accessed August 24, 2026. https://clinicaltrials.gov/study/NCT04071223

3. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(7):917-927. doi:10.1016/S1470-2045(16)30107-3

4. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223. doi:10.1056/NEJMoa1213755

5. Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(3):408-419. doi:10.1016/S1470-2045(18)30860-X