Denosumab Displays Tolerability, Combination Potential in AYA Osteosarcoma

Although the RANKL-targeted monoclonal antibody denosumab (Prolia) did not produce clinical efficacy for the treatment of adolescent/young adult (AYA) patients with osteosarcoma in a phase 2 study (NCT02470091), the agent has potential to be used as a component of future combination regimens due to its tolerable safety profile, according to R. Lor Randall, MD, FACS.

“This is a pretty passionate topic of mine,” Randall said in an interview with OncLive^®. “It’s a Children’s Oncology Group [COG] trial. I’m the former chair of the Local Control Committee within COG, and I’m still involved with them. We recently published this study.”

Randall is the David Linn Endowed Chair for Orthopedic Surgery, the chair of the Department of Orthopedic Surgery, and a professor in the Department of Orthopedic Surgery at UC Davis Comprehensive Cancer Center in Sacramento, California.

In the interview, Randall discussed the background of the study, the key findings, and how these data could be used to inform future trials of denosumab for the treatment of AYA patients with osteosarcoma.

OncLive: What were the key design characteristics of this study?

Randall: This was a phase 2 study evaluating denosumab, which is a monoclonal antibody that targets RANKL, in AYA [patients] with recurrent or refractory osteosarcoma.¹ This trial was motivated by compelling preclinical evidence suggesting that RANKL blockade could suppress tumor growth and metastases in osteosarcoma models through inhibition of osteoclast-mediated bone resorption.

The study enrolled 2 patient cohorts between the ages of 11 and 49. Cohort 1 included patients with measurable, unresectable disease and cohort 2 included those who had undergone complete resection of recurrent disease.² Participants received denosumab at 120 mg subcutaneously every 4 weeks, with additional loading doses during the first cycle, along with calcium and vitamin D supplementation. Treatment duration extended up to 24 months, or 26 cycles.

We confirmed target engagement by measuring standard biochemical markers of bone turnover, including serum C-telopeptides and urinary N-telopeptides. Both are indicators of osteoclast bone resorption. Consistent with prior studies, these markers showed marked suppression following denosumab therapy, confirming effective RANKL inhibition.

What were the notable safety and efficacy findings from the study?

Despite clear pharmacodynamic activity, there was no corresponding clinical benefit in tumor control or survival outcomes, [which] was disappointing.¹ No objective responses were observed, and the study did not meet its prespecified efficacy end points. [The] event-free survival [rate] at 4 months was only 7% [95% CI, 0.4%-26%] for patients with measurable disease [n = 38], and 26% [95% CI, 14%-41%] of patients in the resected cohort [n = 15] remained event-free at 12 months.

It’s good to note that treatment was well tolerated overall. The most common grade 3 or higher adverse effects were hypocalcemia and hypophosphatemia, and no cases of osteonecrosis of the jaw were reported. Immunohistochemical analysis of tumor samples [n = 30] revealed that 40% expressed either RANK or RANKL, but expression did not correlate with therapeutic response, highlighting the biologically complex environment that is osteosarcoma.

Overall, [although] denosumab demonstrated biologic activity and an acceptable safety profile, it did not improve outcomes as a single agent in [patients with] recurrent or refractory osteosarcoma. These findings reinforce the disconnect between preclinical promise and clinical efficacy in this disease and suggest that future studies should explore combination strategies incorporating RANKL inhibition with chemotherapy or other targeted therapies.

[It should be] emphasized that this [study evaluated] denosumab alone, with no backbone chemotherapy. Given the preclinical evidence and the biologic activity we observed, if we were to combine it with conventional chemotherapy, we might see an additive effect. This also emphasizes the need for predictive biomarkers and translational research to better identify the subset of patients most likely to benefit from RANKL-directed treatment.

What is the challenge in finding preclinical signals that translate into clinical benefit?

It’s tough. This is where artificial intelligence [AI] and large language models may be able to help us. There are so much preclinical data now, and so much [is] known about biologic pathways, that we could use AI to see if there are potential combinations of some of these drugs that in isolation aren’t [effective], but [in combination might be].

What are the next steps for denosumab in this population?

We might consider a backbone trial [and/or] look at other agents to complement RANKL inhibition. There is so much preclinical evidence that [denosumab] does something, and given that this study also showed the agent was very well tolerated, I don’t believe we should throw the baby out with the bathwater. There might be some use for it.

References

1. Janeway KA, Chou AJ, Buxton A, et al. A phase 2 trial of RANKL antibody, denosumab, in two cohorts of patients with recurrent / refractory osteosarcoma, a report from the Children’s Oncology Group (COG). Clin Cancer Res. Published online October 29, 2025. doi:10.1158/1078-0432.CCR-24-2885
2. Denosumab in treating patients with recurrent or refractory osteosarcoma. ClinicalTrials.gov. Updated January 22, 2024. Accessed December 11, 2025. https://www.clinicaltrials.gov/study/NCT02470091