Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer.

Abstract

PURPOSE:

Zoledronic acid (ZA) or denosumab treatment reduces skeletal-related events; however, the safety of prolonged therapy has not been adequately studied. Here, we describe safety results of extended denosumab therapy in patients with bone metastases from the open-label extension phase of two phase 3 trials.

METHODS:

Patients with metastatic breast or prostate cancer received subcutaneous denosumab 120 mg Q4W or intravenous ZA 4 mg Q4W in a double-blinded fashion. Denosumab demonstrated superior efficacy in the blinded treatment phase; thus, patients were offered open-label denosumab for up to an additional 2 years.

RESULTS:

Cumulative median (Q1, Q3) denosumab exposure was 19.1 (9.2, 32.2) months in the breast cancer trial (n = 1019) and 12.0 (5.6, 21.3) months in the prostate cancer trial (n = 942); 295 patients received denosumab for >3 years. No new safety signals were identified during the open-label phase, or among patients who switched from ZA to denosumab. During the blinded treatment phase, exposure-adjusted subject incidences of osteonecrosis of the jaw (ONJ) were 49 (1.9%) and 31 (1.2%) in the denosumab and ZA groups, respectively. In total, 32 (6.9%) and 25 (5.5 %) new cases of ONJ (not adjusted for exposure) were reported for patients continuing and switching to denosumab, respectively. The incidences of hypocalcemia were 4.3 and 3.1%, in patients continuing and switching to denosumab, respectively.

CONCLUSION:

These results describe the safety profile of denosumab after long-term exposure, or after switching to denosumab from ZA. No new safety signals were identified. Hypocalcemia rates were similar in the blinded treatment and open-label phases. ONJ rates increased with increasing exposure to antiresorptives, consistent with previous reports.

• Authors: Alison T Stopeck, Karim Fizazi, Jean-Jacques Body, Janet E Brown, Michael Carducci, Ingo Diel, Yasuhiro Fujiwara, Miguel Martín, Alexander Paterson, Katia Tonkin, Neal Shore, Paul Sieber, Frank Kueppers, Lawrence Karsh, Denise Yardley, Huei Wang, Tapan Maniar, Jorge Arellano, Ada Braun
• Journal: Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer (Support Care Cancer) Vol. 24 Issue 1 Pg. 447-455 (Jan 2016) ISSN: 1433-7339 [Electronic] Germany
• PMID: 26335402 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Bone Density Conservation Agents
• Diphosphonates
• Imidazoles
• Denosumab
• Zoledronic Acid

Topics

• Administration, Cutaneous
• Aged
• Antibodies, Monoclonal, Humanized (administration & dosage, adverse effects)
• Bone Density Conservation Agents (administration & dosage, adverse effects)
• Bone Neoplasms (drug therapy, secondary)
• Breast Neoplasms
• Denosumab (administration & dosage, adverse effects)
• Diphosphonates (administration & dosage, adverse effects)
• Double-Blind Method
• Drug Administration Schedule
• Female
• Humans
• Imidazoles (administration & dosage, adverse effects)
• Infusions, Intravenous
• Long-Term Care
• Male
• Middle Aged
• Prostatic Neoplasms
• Treatment Outcome
• Zoledronic Acid