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.
OBJECTIVE
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.


CONCLUSIONS
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.
University of Arizona Cancer Center, Tucson, AZ, USA. Alison.Stopeck@stonybrookmedicine.edu.
Alison T
AT
Stopeck
Institut Gustave Roussy, University of Paris Sud, Villejuif, France.
Karim
K
Fizazi
Centre Hospitalier Universitaire Brugmann, Université Libre de Bruxelles, Brussels, Belgium.
Jean-Jacques
JJ
Body
Cancer Research UK Experimental Cancer Medicine Centres, St James's University Hospital, Leeds, UK.|Weston Park Hospital, University of Sheffield, Sheffield, UK.
Janet E
JE
Brown
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
Michael
M
Carducci
Center for Comprehensive Gynecology Clinic, Mannheim, Germany.
Ingo
I
Diel
National Cancer Center Hospital, Tokyo, Japan.
Yasuhiro
Y
Fujiwara
Instituto de Investigación Sanitaria General Gregorio Marañón, Universidad Complutense, Madrid, Spain.
Miguel
M
Martín
Tom Baker Cancer Centre, Calgary, AB, Canada.
Alexander
A
Paterson
Cross Cancer Institute, Edmonton, AB, Canada.
Katia
K
Tonkin
Carolina Urologic Research Center, Myrtle Beach, SC, USA.
Neal
N
Shore
Lancaster Urology, Lancaster, PA, USA.
Paul
P
Sieber
Urology Associates, Christchurch, New Zealand.
Frank
F
Kueppers
The Urology Center of Colorado, Denver, CO, USA.
Lawrence
L
Karsh
Sarah Cannon Research Institute, Nashville, TN, USA.
Denise
D
Yardley
Amgen Inc., Thousand Oaks, CA, USA.
Huei
H
Wang
Amgen Inc., Thousand Oaks, CA, USA.
Tapan
T
Maniar
Amgen Inc., Thousand Oaks, CA, USA.
Jorge
J
Arellano
Amgen Inc., Thousand Oaks, CA, USA.
Ada
A
Braun
D000279:Administration, Cutaneous; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D001943:Breast Neoplasms; D000069448:Denosumab / Q000008:administration & dosage* / Q000009:adverse effects; D004164:Diphosphonates / Q000008:administration & dosage / Q000009:adverse effects; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects; D007262:Infusions, Intravenous; D008134:Long-Term Care; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms; D016896:Treatment Outcome; D000077211:Zoledronic Acid
D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000069448:Denosumab; D000077211:Zoledronic Acid
Bone metastases; Breast cancer; Denosumab; Osteonecrosis of the jaw; Prostate cancer; Zoledronic acid