The RADICAL Trial: Radium-223 Plus Cabozantinib in Bone Metastases From Kidney Cancer

KEY FINDINGS

• Trial: RADICAL (Alliance A031801; NCT04071223), the first randomized trial testing a radiopharmaceutical in kidney cancer; published in the Journal of Clinical Oncology.
• The primary endpoint was not met: Adding radium-223 dichloride to cabozantinib did not improve skeletal event-free survival (SSE-FS) - 16.7 months versus 17.6 months (sHR 1.46; 90% CI 0.86-2.51).
• Early stopping: The trial was stopped at a prespecified interim futility analysis; the futility boundary was crossed when 90 patients had been enrolled and accrual was closed at 98 patients.
• Skeletal events were fewer than expected: Symptomatic skeletal events remained low in both arms - reflecting the effectiveness of modern bone-protective therapy (osteoclast-targeted agents).
• Safety: The combination showed a manageable safety profile; a numerical difference in overall survival (28.3 versus 19.7 months) was observed but the trial was not designed for this endpoint - the finding is hypothesis-generating only.

Background: The Problem of Bone Metastasis in Kidney Cancer

Bone metastases develop in approximately 30% of patients with metastatic renal cell carcinoma (mRCC). Bone involvement in mRCC is not simply a question of localisation; it is independently associated with worse survival, a lower response to systemic therapy and symptomatic skeletal events (SSEs). SSEs are defined as pathological fracture, spinal cord compression, or the need for radiotherapy or surgery to bone, and they directly threaten the patient's functional independence.

Radium-223 dichloride is an alpha-emitting radiopharmaceutical that localises selectively to areas of increased osteoblastic activity in bone metastases. The hypothesis that this agent, approved with a survival advantage in bone metastases from castration-resistant prostate cancer, might also provide benefit in mRCC with its similar bone microenvironment biology formed the starting point for the RADICAL trial.

Study Design

RADICAL is a phase 2, randomized, multicentre trial conducted by the Alliance for Clinical Trials in Oncology. The results were first presented at the 2026 ASCO Annual Meeting and subsequently published in full in the Journal of Clinical Oncology. The lead author is Dr Rana R. McKay (UC San Diego Health).

Key Results

The interim futility analysis was performed when 90 patients had been enrolled and the futility boundary was crossed (stratified HR 1.24; 95% CI 0.62-2.48). Accrual was therefore closed and the final analysis was performed on a total of 98 patients (56 SSE-FS events in total: 27 combination / 29 control).

Note on interpretation: The numerical difference in overall survival favouring the combination (28.3 versus 19.7 months) should be interpreted bearing in mind that the trial was neither designed nor powered for this endpoint, that the number of events was small, that the confidence intervals were wide and that the reported hazard ratio did not reach significance. The investigators explicitly describe this finding as hypothesis-generating.

Safety

Grade ≥3 adverse events occurred in 69.6% of the combination arm and 75.5% of the cabozantinib monotherapy arm.

The toxicity profile shows that the two agents can be combined safely; this provides an important foundation for future radiopharmaceutical combination trials.

Implications for Clinical Practice

1. Bone-protective therapy is doing its job

That skeletal complications remained low in both arms is perhaps the most practical message of the trial. In a population in which approximately 80% of patients were receiving osteoclast-targeted therapy, a median SSE-FS remaining in the 16-18 month band in both arms points to the effectiveness of modern bone-protective care. The use of zoledronic acid or denosumab should be maintained as standard practice as recommended in current guidelines.

2. Success in prostate cancer cannot be transferred directly to the kidney

RADICAL shows that the efficacy of radium-223 cannot be assumed independently of tumour biology. Bone metastases in RCC are predominantly osteolytic in character; unlike the osteoblastic lesions of prostate cancer, the increased osteoblastic activity that radium-223 requires in order to bind to hydroxyapatite may be more limited in this environment. This mechanistic difference stands out as the biological explanation for the result.

3. Negative trials also advance the field

RADICAL is the first randomized trial evaluating a bone-targeted therapeutic strategy in mRCC and is the largest prospective study conducted with a therapeutic radiopharmaceutical in this field. Early stopping based on a futility rule is an exemplary application of contemporary trial design that prioritises patient safety and efficiency of resources.

4. Patient selection and the need for biomarkers

That the trial covered all histological subtypes and a broad IMDC risk spectrum increased its real-world representativeness while making it harder to identify subgroups that might respond. In future trials, patient selection based on the phenotype of bone lesions (osteoblastic/osteolytic) or on bone turnover biomarkers may reveal the true potential of the radiopharmaceutical approach.

Conclusion

The RADICAL trial has established that adding radium-223 to cabozantinib does not improve skeletal event-free survival in patients with bone metastases from metastatic kidney cancer. This result does not lead to a change in our current clinical practice; but it brings three important messages: modern bone-protective therapy is effective, radiopharmaceutical efficacy is specific to tumour type and these two agents can be combined safely.

As lead investigator Dr Rana McKay has stated, the findings show that radiopharmaceuticals deserve careful and continued investigation in kidney cancer. Progress in our field is possible not only through what positive trials teach us but also through what well-designed negative trials do.

References

• 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. doi:10.1200/JCO-26-01135
• Clarke H. Radium-223 fails to improve skeletal event-free survival in metastatic RCC. Urology Times, 18 August 2026.
• UroToday. RADICAL (Alliance A031801) study summary.
• Alliance for Clinical Trials in Oncology. Alliance reports results from first randomized trial of a radiopharmaceutical in kidney cancer. Press release, 17 August 2026.
• ClinicalTrials.gov. NCT04071223 - RADICAL / Alliance A031801.