Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases.
OBJECTIVE
Denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor-kappaB ligand, suppresses bone resorption. In this study, we evaluated the efficacy and safety of five dosing regimens of denosumab in patients with breast cancer-related bone metastases not previously treated with intravenous bisphosphonates (IV BPs).


METHODS
Eligible women (n = 255) with breast cancer-related bone metastases were stratified by type of antineoplastic therapy received and randomly assigned to one of six cohorts (five denosumab cohorts [blinded to dose and frequency]; one open-label IV BP cohort). Denosumab was administered subcutaneously every 4 weeks (30, 120, or 180 mg) or every 12 weeks (60 or 180 mg). The primary end point was percentage of change in the bone turnover marker urine N-telopeptide corrected for urine creatinine (uNTx/Cr) from baseline to study week 13. The percentage of patients achieving more than 65% uNTx/Cr reduction, time to more than 65% uNTx/Cr reduction, patients experiencing one or more on-study skeletal-related events (SRE), and safety were also evaluated.


RESULTS
At study week 13, the median percent reduction in uNTx/Cr was 71% for the pooled denosumab groups and 79% for the IV BP group. Overall, 74% of denosumab-treated patients (157 of 211) achieved a more than 65% reduction in uNTx/Cr compared with 63% of bisphosphonate-treated patients (27 of 43). On-study SREs were experienced by 9% of denosumab-treated patients (20 of 211) versus 16% of bisphosphonate-treated patients (seven of 43). No serious or fatal adverse events related to denosumab occurred.


CONCLUSIONS
Subcutaneous denosumab may be similar to IV BPs in suppressing bone turnover and reducing SRE risk. The safety profile was consistent with an advanced breast cancer population receiving systemic therapy.
Lipton
Allan
A
Penn State Milton S. Hershey Medical Center, Hershey, PA 17033-0850, USA. alipton@psu.edu
Steger
Guenther G
GG
Figueroa
Jazmin
J
Alvarado
Cristina
C
Solal-Celigny
Philippe
P
Body
Jean-Jacques
JJ
de Boer
Richard
R
Berardi
Rossana
R
Gascon
Pere
P
Tonkin
Katia S
KS
Coleman
Robert
R
Paterson
Alexander H G
AH
Peterson
Mark C
MC
Fan
Michelle
M
Kinsey
Amy
A
Jun
Susie
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers / Q000378:metabolism; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D001862:Bone Resorption / Q000517:prevention & control*; D001943:Breast Neoplasms / Q000473:pathology*; D024042:Collagen Type I / Q000187:drug effects / Q000378:metabolism; D003198:Computer Simulation; D000069448:Denosumab; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D010455:Peptides / Q000187:drug effects / Q000378:metabolism; D053245:RANK Ligand