Radium-223 fails to improve skeletal event-free survival in metastatic RCC

Results from the phase 2 RadiCaL trial (Alliance A031801; NCT04071223) have been published in the Journal of Clinical Oncology, showing that adding radium-223 dichloride (Xofigo) to cabozantinib (Cabometyx) did not improve skeletal event-free survival (SSE-FS) compared with cabozantinib alone in patients with metastatic renal cell carcinoma (mRCC) and bone metastases.¹

The study, initially presented at the 2026 American Society of Clinical Oncology Annual Meeting, represents the first randomized trial of a radiopharmaceutical in kidney cancer. The trial was stopped early after a prespecified interim futility analysis indicated that the addition of radium-223 was unlikely to improve the primary end point.

Related: Rana McKay, MD, on radium-223 plus cabozantinib in renal cell carcinoma

“RadiCaL is the first randomized trial of a radiopharmaceutical in kidney cancer, and it tells us several important things,” said lead author Rana R. McKay, MD, professor of medicine at UC San Diego Health and principal investigator of the study, in a news release on the results.² “Skeletal complications were low across the board, which speaks to the effectiveness of modern bone-protective care, that in itself is reassuring news for patients. Radium-223 did not further reduce skeletal complications, but we did see numerically longer survival with the combination of radium-223 and cabozantinib. This finding is hypothesis-generating and needs further investigation. Together with a tolerable side effect profile showing these agents can be safely combined, it tells us that radiopharmaceuticals deserve continued, careful study in kidney cancer.”

RadiCaL trial findings

RadiCaL enrolled patients with mRCC of any histologic subtype who had at least 1 bone metastasis. Patients were randomly assigned 1:1 to cabozantinib with or without radium-223 and were stratified according to use of osteoclast-targeted therapy (OTT), previous therapy, opioid use, and International mRCC Database Consortium risk group. The primary end point was SSE-FS, with secondary end points including safety, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).

The investigators planned to enroll 124 evaluable patients and prespecified an interim futility analysis after approximately 50% of the expected SSE-FS events. The trial would be stopped if the stratified hazard ratio (sHR) for SSE-FS was greater than 1.0. The interim analysis was conducted after 90 patients had been enrolled and crossed the futility boundary (stratified HR, 1.24; 95% CI, 0.62 to 2.48), resulting in trial closure.

At baseline, the median patient age was 63 years, 82.7% had clear cell RCC, and 79.6% were receiving an OTT. IMDC risk was favorable in 18.4% of patients, intermediate in 67.3%, and poor in 14.3%. Median follow-up was 13.1 months.

Among all patients, 56 SSE-FS events were observed, including 27 in the cabozantinib plus radium-223 arm and 29 in the cabozantinib arm alone. The median SSE-FS was 16.7 months (90% CI, 13.5 to 39.6) with cabozantinib plus radium-223 compared with 17.6 months (90% CI, 11.5 to 24.5) with cabozantinib alone (sHR, 1.46; 90% CI, 0.86 to 2.51; one-sided P = .12). The median time to first SSE was not estimable in either arm (stratified HR, 1.47; 95% CI, 0.56 to 3.85; P = .43).

The study also reported a numerical difference in OS, although the trial was not designed or powered to establish an OS benefit. Median OS was 28.3 months (95% CI, 15.1 to NE) with the combination compared with 19.7 months (95% CI, 12.3 to NE) with cabozantinib alone (sHR, 1.40; 95% CI, 0.70 to 2.79; P = .34).

The median PFS was 10.3 months (95% CI, 5.5 to 16.8) in the cabozantinib plus radium-223 arm compared with 10.5 months (95% CI, 8.7 to 16.9) with cabozantinib alone (stratified HR, 1.37; 95% CI, 0.74 to 2.53; P = .32). ORR was also numerically lower with the combination, at 19.4% compared with 25.0% with cabozantinib alone (P = .78). The median time to subsequent anticancer therapy was 18.6 months (95% CI, 13.8 to NE) with cabozantinib plus radium-223 vs 19.2 months (95% CI, 15.1 to NE) with cabozantinib alone (stratified HR, 0.89; 95% CI, 0.40 to 1.96; P = .77).

Grade 3 or higher adverse events (AEs) occurred in 69.6% and 75.5% of patients, respectively. The most common grade 3 or higher AEs were diarrhea (13.0% v 6.1%), back pain (4.3% v 10.2%), hypertension (0% v 20.4%), palmar-plantar erythrodysesthesia syndrome (0% v 12.2%), sepsis (6.5% v 0%), thromboembolic events (8.7% v 6.1%), fatigue (2.2% v 6.1%), ALT increase (2.2% v 6.1%), anorexia (8.7% v 0.0%), and vomiting (6.5% v 2.0%).

“To our knowledge, RADICAL (Alliance A031801) represents the first randomized trial specifically designed to evaluate a bone-targeted therapeutic strategy in patients with mRCC and BM, and to our knowledge constitutes the largest prospective study of a therapeutic radiopharmaceutical agent in mRCC,” the authors concluded.¹ “Although the addition of radium-223 to cabozantinib did not improve SSE-FS, the combination demonstrated a manageable safety profile and the results of this trial provide a valuable foundation for the design of future bone-targeted therapeutic strategies in mRCC.”

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