Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates

Karim Fizazi, Allan Lipton, Xavier Mariette, Jean Jacques Body, Yasmin Rahim, Julie R. Gralow, Guozhi Gao, Ling Wu, Winnie Sohn, Susie Jun

Research output: Contribution to journalArticle

410 Citations (Scopus)

Abstract

Purpose Patients with bone metastases and elevated urinary N-telopeptide (uNTx), representing excessive bone resorption, are at increased risk for skeletal-related events (SREs), cancer progression, and death. Osteoclast-mediated bone resorption is regulated by RANKL. We evaluated the effect of denosumab, a fully human monoclonal antibody against RANKL, in patients with bone metastases and elevated uNTx levels despite ongoing intravenous (IV) bisphosphonate (BP) therapy. Patients and Methods Eligible patients had histologically confirmed malignancy, ≥ 1 bone metastases, and uNTx levels higher than 50 nmol/L bone collagen equivalents (BCE)/mM creatinine despite IV BPs. They were stratified by tumor type and screening uNTx levels (50 to 100 or > 100 nmol/L BCE/mM creatinine), and randomly assigned to continue IV BPs every 4 weeks or receive subcutaneous denosumab 180 mg every 4 weeks or every 12 weeks. Results Among 111 patients accrued, the primary end point of uNTx levels lower than 50 nmol/L BCE/mM creatinine (uNTx < 50) at week 13 was achieved by 49 (71%) of 69 patients in the denosumab arms, compared with 10 (29%) of 35 patients in the IV BP arm (P <.001). The proportion of patients with uNTx lower than 50 was maintained at week 25 (64% denosumab arms; 37% IV BP arm; P =.01). The incidence of SREs was six (8%) of 73 and six (17%) of 35 in the denosumab group and IV BP group, respectively. Rates of adverse events were similar between treatment groups. Conclusion Among patients with elevated uNTx despite ongoing IV BP therapy, denosumab normalized uNTx levels more frequently than the continuation of IV BP. Fewer patients receiving denosumab experienced on-study SREs than those receiving IV BPs.

Original languageEnglish (US)
Pages (from-to)1564-1571
Number of pages8
JournalJournal of Clinical Oncology
Volume27
Issue number10
DOIs
StatePublished - Apr 1 2009

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Diphosphonates
Prostatic Neoplasms
Breast Neoplasms
Neoplasm Metastasis
Bone and Bones
Neoplasms
Creatinine
Collagen
Bone Resorption
Denosumab
Osteoclasts
Therapeutics
Monoclonal Antibodies
Incidence

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Fizazi, Karim ; Lipton, Allan ; Mariette, Xavier ; Body, Jean Jacques ; Rahim, Yasmin ; Gralow, Julie R. ; Gao, Guozhi ; Wu, Ling ; Sohn, Winnie ; Jun, Susie. / Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. In: Journal of Clinical Oncology. 2009 ; Vol. 27, No. 10. pp. 1564-1571.
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title = "Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates",
abstract = "Purpose Patients with bone metastases and elevated urinary N-telopeptide (uNTx), representing excessive bone resorption, are at increased risk for skeletal-related events (SREs), cancer progression, and death. Osteoclast-mediated bone resorption is regulated by RANKL. We evaluated the effect of denosumab, a fully human monoclonal antibody against RANKL, in patients with bone metastases and elevated uNTx levels despite ongoing intravenous (IV) bisphosphonate (BP) therapy. Patients and Methods Eligible patients had histologically confirmed malignancy, ≥ 1 bone metastases, and uNTx levels higher than 50 nmol/L bone collagen equivalents (BCE)/mM creatinine despite IV BPs. They were stratified by tumor type and screening uNTx levels (50 to 100 or > 100 nmol/L BCE/mM creatinine), and randomly assigned to continue IV BPs every 4 weeks or receive subcutaneous denosumab 180 mg every 4 weeks or every 12 weeks. Results Among 111 patients accrued, the primary end point of uNTx levels lower than 50 nmol/L BCE/mM creatinine (uNTx < 50) at week 13 was achieved by 49 (71{\%}) of 69 patients in the denosumab arms, compared with 10 (29{\%}) of 35 patients in the IV BP arm (P <.001). The proportion of patients with uNTx lower than 50 was maintained at week 25 (64{\%} denosumab arms; 37{\%} IV BP arm; P =.01). The incidence of SREs was six (8{\%}) of 73 and six (17{\%}) of 35 in the denosumab group and IV BP group, respectively. Rates of adverse events were similar between treatment groups. Conclusion Among patients with elevated uNTx despite ongoing IV BP therapy, denosumab normalized uNTx levels more frequently than the continuation of IV BP. Fewer patients receiving denosumab experienced on-study SREs than those receiving IV BPs.",
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Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. / Fizazi, Karim; Lipton, Allan; Mariette, Xavier; Body, Jean Jacques; Rahim, Yasmin; Gralow, Julie R.; Gao, Guozhi; Wu, Ling; Sohn, Winnie; Jun, Susie.

In: Journal of Clinical Oncology, Vol. 27, No. 10, 01.04.2009, p. 1564-1571.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates

AU - Fizazi, Karim

AU - Lipton, Allan

AU - Mariette, Xavier

AU - Body, Jean Jacques

AU - Rahim, Yasmin

AU - Gralow, Julie R.

AU - Gao, Guozhi

AU - Wu, Ling

AU - Sohn, Winnie

AU - Jun, Susie

PY - 2009/4/1

Y1 - 2009/4/1

N2 - Purpose Patients with bone metastases and elevated urinary N-telopeptide (uNTx), representing excessive bone resorption, are at increased risk for skeletal-related events (SREs), cancer progression, and death. Osteoclast-mediated bone resorption is regulated by RANKL. We evaluated the effect of denosumab, a fully human monoclonal antibody against RANKL, in patients with bone metastases and elevated uNTx levels despite ongoing intravenous (IV) bisphosphonate (BP) therapy. Patients and Methods Eligible patients had histologically confirmed malignancy, ≥ 1 bone metastases, and uNTx levels higher than 50 nmol/L bone collagen equivalents (BCE)/mM creatinine despite IV BPs. They were stratified by tumor type and screening uNTx levels (50 to 100 or > 100 nmol/L BCE/mM creatinine), and randomly assigned to continue IV BPs every 4 weeks or receive subcutaneous denosumab 180 mg every 4 weeks or every 12 weeks. Results Among 111 patients accrued, the primary end point of uNTx levels lower than 50 nmol/L BCE/mM creatinine (uNTx < 50) at week 13 was achieved by 49 (71%) of 69 patients in the denosumab arms, compared with 10 (29%) of 35 patients in the IV BP arm (P <.001). The proportion of patients with uNTx lower than 50 was maintained at week 25 (64% denosumab arms; 37% IV BP arm; P =.01). The incidence of SREs was six (8%) of 73 and six (17%) of 35 in the denosumab group and IV BP group, respectively. Rates of adverse events were similar between treatment groups. Conclusion Among patients with elevated uNTx despite ongoing IV BP therapy, denosumab normalized uNTx levels more frequently than the continuation of IV BP. Fewer patients receiving denosumab experienced on-study SREs than those receiving IV BPs.

AB - Purpose Patients with bone metastases and elevated urinary N-telopeptide (uNTx), representing excessive bone resorption, are at increased risk for skeletal-related events (SREs), cancer progression, and death. Osteoclast-mediated bone resorption is regulated by RANKL. We evaluated the effect of denosumab, a fully human monoclonal antibody against RANKL, in patients with bone metastases and elevated uNTx levels despite ongoing intravenous (IV) bisphosphonate (BP) therapy. Patients and Methods Eligible patients had histologically confirmed malignancy, ≥ 1 bone metastases, and uNTx levels higher than 50 nmol/L bone collagen equivalents (BCE)/mM creatinine despite IV BPs. They were stratified by tumor type and screening uNTx levels (50 to 100 or > 100 nmol/L BCE/mM creatinine), and randomly assigned to continue IV BPs every 4 weeks or receive subcutaneous denosumab 180 mg every 4 weeks or every 12 weeks. Results Among 111 patients accrued, the primary end point of uNTx levels lower than 50 nmol/L BCE/mM creatinine (uNTx < 50) at week 13 was achieved by 49 (71%) of 69 patients in the denosumab arms, compared with 10 (29%) of 35 patients in the IV BP arm (P <.001). The proportion of patients with uNTx lower than 50 was maintained at week 25 (64% denosumab arms; 37% IV BP arm; P =.01). The incidence of SREs was six (8%) of 73 and six (17%) of 35 in the denosumab group and IV BP group, respectively. Rates of adverse events were similar between treatment groups. Conclusion Among patients with elevated uNTx despite ongoing IV BP therapy, denosumab normalized uNTx levels more frequently than the continuation of IV BP. Fewer patients receiving denosumab experienced on-study SREs than those receiving IV BPs.

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