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Bone Health Outcomes from the International, Multicenter, Randomized, Phase 3, Placebo-Controlled D-CARE Study Assessing Adjuvant Denosumab in Early Breast Cancer
Introduction D-CARE, an international, phase 3, randomized, double-blind, placebo-controlled study in women with early-stage breast cancer at high risk of disease recurrence, failed to meet its primary endpoint—improvement in bone metastasis-free survival (BMFS) with adjuvant denosumab vs placebo in...
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| Published in: | Advances in therapy 2021-08, Vol.38 (8), p.4569-4580 |
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| creator | Coleman, Robert Zhou, Ying Jandial, Danielle Cadieux, Benoit Chan, Arlene |
| description | Introduction
D-CARE, an international, phase 3, randomized, double-blind, placebo-controlled study in women with early-stage breast cancer at high risk of disease recurrence, failed to meet its primary endpoint—improvement in bone metastasis-free survival (BMFS) with adjuvant denosumab vs placebo injections. As a result of the limitations of assessing BMFS, which includes relapse in bone with and without extraskeletal recurrences and deaths from any cause, the prespecified exploratory bone endpoints’ analysis may provide a more clinically meaningful effect of denosumab in this disease setting.
Methods
The study enrolled women (aged ≥ 18 years) with histologically confirmed stage II/III breast cancer. Patients treated with adjuvant/neoadjuvant chemotherapy meeting inclusion criteria were randomly assigned 1:1 to receive either denosumab (120 mg) or placebo subcutaneously every 3–4 weeks for about 6 months and then every 3 months for a total treatment duration of 5 years. Five prespecified exploratory bone endpoints and post hoc subgroup analysis based on age ( |
| doi_str_mv | 10.1007/s12325-021-01812-9 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8342342</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2546601171</sourcerecordid><originalsourceid>FETCH-LOGICAL-c446t-72bcc90e9a85c2756c803618169c652f60965994f88cabf0d2fb48632d52ac43</originalsourceid><addsrcrecordid>eNp9kcFuEzEQhi0EoiHwAhyQjxxisL27Xu8FKU0DrVRUVHrgZnm9s8lGXrvY3krhaZB4E54Mh5QKLki2bM3883s8H0IvGX3DKK3fRsYLXhHKGaFMMk6aR2jGpKhI3vwxmtG6ZIQX8ssJehbjjlJO60o-RSdFyWTFq2aGfpx6B_gctE1bfDUl40eIuA9-xGkL-MIlCE6nwTttF_jjZNNg4BBc4GvtOj8O36Bb4E9bHeHn9yLfrDbQerLyLgVvLXT4jKyW12v8OU3dHi9jhBgHt8HLbjfdaZfwGTgfp1G3eHB4rYPd49MAOia80s5AeI6e9NpGeHF_ztHN-_XN6pxcXn24WC0viSlLkUjNW2MaCo2WleF1JYykhciDEY3J8-gFbUTVNGUvpdFtTzvet6UUBe8qrk1ZzNG7o-3t1I7QHb4ZtFW3YRh12CuvB_Vvxg1btfF3ShYlP6w5en1vEPzXCWJS4xANWKsd-CkqXpVCUMZqlqX8KDXBxxigf3iGUXWAq45wVYarfsNVTS569XeDDyV_aGZBcRTEnHIbCGrnp4zPxv_Z_gJ7RrKE</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2546601171</pqid></control><display><type>article</type><title>Bone Health Outcomes from the International, Multicenter, Randomized, Phase 3, Placebo-Controlled D-CARE Study Assessing Adjuvant Denosumab in Early Breast Cancer</title><source>Springer Link</source><source>Alma/SFX Local Collection</source><creator>Coleman, Robert ; Zhou, Ying ; Jandial, Danielle ; Cadieux, Benoit ; Chan, Arlene</creator><creatorcontrib>Coleman, Robert ; Zhou, Ying ; Jandial, Danielle ; Cadieux, Benoit ; Chan, Arlene</creatorcontrib><description>Introduction
D-CARE, an international, phase 3, randomized, double-blind, placebo-controlled study in women with early-stage breast cancer at high risk of disease recurrence, failed to meet its primary endpoint—improvement in bone metastasis-free survival (BMFS) with adjuvant denosumab vs placebo injections. As a result of the limitations of assessing BMFS, which includes relapse in bone with and without extraskeletal recurrences and deaths from any cause, the prespecified exploratory bone endpoints’ analysis may provide a more clinically meaningful effect of denosumab in this disease setting.
Methods
The study enrolled women (aged ≥ 18 years) with histologically confirmed stage II/III breast cancer. Patients treated with adjuvant/neoadjuvant chemotherapy meeting inclusion criteria were randomly assigned 1:1 to receive either denosumab (120 mg) or placebo subcutaneously every 3–4 weeks for about 6 months and then every 3 months for a total treatment duration of 5 years. Five prespecified exploratory bone endpoints and post hoc subgroup analysis based on age (< 50 and ≥ 50 years) and menopause status (premenopausal and postmenopausal) were evaluated.
Results
Overall, 4509 women with early-stage breast cancer were assigned to receive denosumab (
N
= 2256) or placebo (
N
= 2253). The baseline demographics and clinical characteristics were comparable between the two arms. The hazard ratio (HR) for time to first bone metastasis was 0.82 (95% CI 0.66–1.02;
p
= 0.068), with HRs of 0.70 (95% CI 0.52–0.94;
p
= 0.018) for patients < 50 years old and 0.74 (95% CI 0.55–0.98;
p
= 0.038) for premenopausal patients, favoring the denosumab group. The HRs for time to first on-study fracture and time to first on-study skeletal-related event were 0.76 (95% CI 0.63–0.92;
p
= 0.004) and 0.52 (95% CI 0.35–0.78;
p
= 0.001), respectively, again favoring the denosumab group.
Conclusion
The exploratory bone endpoints indicate the benefits of denosumab treatment in patients with high-risk early breast cancer, supporting the expected bone health benefits contributed by denosumab.
Trial Registration Number
NCT01077154</description><identifier>ISSN: 0741-238X</identifier><identifier>EISSN: 1865-8652</identifier><identifier>DOI: 10.1007/s12325-021-01812-9</identifier><identifier>PMID: 34185259</identifier><language>eng</language><publisher>Cheshire: Springer Healthcare</publisher><subject>Bone Neoplasms - drug therapy ; Breast Neoplasms - drug therapy ; Brief Report ; Cardiology ; Denosumab - therapeutic use ; Double-Blind Method ; Endocrinology ; Female ; Humans ; Internal Medicine ; Medicine ; Medicine & Public Health ; Middle Aged ; NCT ; NCT01077154 ; Neoplasm Recurrence, Local ; Oncology ; Outcome Assessment, Health Care ; Pharmacology/Toxicology ; Rheumatology</subject><ispartof>Advances in therapy, 2021-08, Vol.38 (8), p.4569-4580</ispartof><rights>The Author(s) 2021</rights><rights>2021. The Author(s).</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c446t-72bcc90e9a85c2756c803618169c652f60965994f88cabf0d2fb48632d52ac43</citedby><cites>FETCH-LOGICAL-c446t-72bcc90e9a85c2756c803618169c652f60965994f88cabf0d2fb48632d52ac43</cites><orcidid>0000-0003-2135-2286</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34185259$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Coleman, Robert</creatorcontrib><creatorcontrib>Zhou, Ying</creatorcontrib><creatorcontrib>Jandial, Danielle</creatorcontrib><creatorcontrib>Cadieux, Benoit</creatorcontrib><creatorcontrib>Chan, Arlene</creatorcontrib><title>Bone Health Outcomes from the International, Multicenter, Randomized, Phase 3, Placebo-Controlled D-CARE Study Assessing Adjuvant Denosumab in Early Breast Cancer</title><title>Advances in therapy</title><addtitle>Adv Ther</addtitle><addtitle>Adv Ther</addtitle><description>Introduction
D-CARE, an international, phase 3, randomized, double-blind, placebo-controlled study in women with early-stage breast cancer at high risk of disease recurrence, failed to meet its primary endpoint—improvement in bone metastasis-free survival (BMFS) with adjuvant denosumab vs placebo injections. As a result of the limitations of assessing BMFS, which includes relapse in bone with and without extraskeletal recurrences and deaths from any cause, the prespecified exploratory bone endpoints’ analysis may provide a more clinically meaningful effect of denosumab in this disease setting.
Methods
The study enrolled women (aged ≥ 18 years) with histologically confirmed stage II/III breast cancer. Patients treated with adjuvant/neoadjuvant chemotherapy meeting inclusion criteria were randomly assigned 1:1 to receive either denosumab (120 mg) or placebo subcutaneously every 3–4 weeks for about 6 months and then every 3 months for a total treatment duration of 5 years. Five prespecified exploratory bone endpoints and post hoc subgroup analysis based on age (< 50 and ≥ 50 years) and menopause status (premenopausal and postmenopausal) were evaluated.
Results
Overall, 4509 women with early-stage breast cancer were assigned to receive denosumab (
N
= 2256) or placebo (
N
= 2253). The baseline demographics and clinical characteristics were comparable between the two arms. The hazard ratio (HR) for time to first bone metastasis was 0.82 (95% CI 0.66–1.02;
p
= 0.068), with HRs of 0.70 (95% CI 0.52–0.94;
p
= 0.018) for patients < 50 years old and 0.74 (95% CI 0.55–0.98;
p
= 0.038) for premenopausal patients, favoring the denosumab group. The HRs for time to first on-study fracture and time to first on-study skeletal-related event were 0.76 (95% CI 0.63–0.92;
p
= 0.004) and 0.52 (95% CI 0.35–0.78;
p
= 0.001), respectively, again favoring the denosumab group.
Conclusion
The exploratory bone endpoints indicate the benefits of denosumab treatment in patients with high-risk early breast cancer, supporting the expected bone health benefits contributed by denosumab.
Trial Registration Number
NCT01077154</description><subject>Bone Neoplasms - drug therapy</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Brief Report</subject><subject>Cardiology</subject><subject>Denosumab - therapeutic use</subject><subject>Double-Blind Method</subject><subject>Endocrinology</subject><subject>Female</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Middle Aged</subject><subject>NCT</subject><subject>NCT01077154</subject><subject>Neoplasm Recurrence, Local</subject><subject>Oncology</subject><subject>Outcome Assessment, Health Care</subject><subject>Pharmacology/Toxicology</subject><subject>Rheumatology</subject><issn>0741-238X</issn><issn>1865-8652</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kcFuEzEQhi0EoiHwAhyQjxxisL27Xu8FKU0DrVRUVHrgZnm9s8lGXrvY3krhaZB4E54Mh5QKLki2bM3883s8H0IvGX3DKK3fRsYLXhHKGaFMMk6aR2jGpKhI3vwxmtG6ZIQX8ssJehbjjlJO60o-RSdFyWTFq2aGfpx6B_gctE1bfDUl40eIuA9-xGkL-MIlCE6nwTttF_jjZNNg4BBc4GvtOj8O36Bb4E9bHeHn9yLfrDbQerLyLgVvLXT4jKyW12v8OU3dHi9jhBgHt8HLbjfdaZfwGTgfp1G3eHB4rYPd49MAOia80s5AeI6e9NpGeHF_ztHN-_XN6pxcXn24WC0viSlLkUjNW2MaCo2WleF1JYykhciDEY3J8-gFbUTVNGUvpdFtTzvet6UUBe8qrk1ZzNG7o-3t1I7QHb4ZtFW3YRh12CuvB_Vvxg1btfF3ShYlP6w5en1vEPzXCWJS4xANWKsd-CkqXpVCUMZqlqX8KDXBxxigf3iGUXWAq45wVYarfsNVTS569XeDDyV_aGZBcRTEnHIbCGrnp4zPxv_Z_gJ7RrKE</recordid><startdate>20210801</startdate><enddate>20210801</enddate><creator>Coleman, Robert</creator><creator>Zhou, Ying</creator><creator>Jandial, Danielle</creator><creator>Cadieux, Benoit</creator><creator>Chan, Arlene</creator><general>Springer Healthcare</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-2135-2286</orcidid></search><sort><creationdate>20210801</creationdate><title>Bone Health Outcomes from the International, Multicenter, Randomized, Phase 3, Placebo-Controlled D-CARE Study Assessing Adjuvant Denosumab in Early Breast Cancer</title><author>Coleman, Robert ; Zhou, Ying ; Jandial, Danielle ; Cadieux, Benoit ; Chan, Arlene</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c446t-72bcc90e9a85c2756c803618169c652f60965994f88cabf0d2fb48632d52ac43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Bone Neoplasms - drug therapy</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Brief Report</topic><topic>Cardiology</topic><topic>Denosumab - therapeutic use</topic><topic>Double-Blind Method</topic><topic>Endocrinology</topic><topic>Female</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Middle Aged</topic><topic>NCT</topic><topic>NCT01077154</topic><topic>Neoplasm Recurrence, Local</topic><topic>Oncology</topic><topic>Outcome Assessment, Health Care</topic><topic>Pharmacology/Toxicology</topic><topic>Rheumatology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Coleman, Robert</creatorcontrib><creatorcontrib>Zhou, Ying</creatorcontrib><creatorcontrib>Jandial, Danielle</creatorcontrib><creatorcontrib>Cadieux, Benoit</creatorcontrib><creatorcontrib>Chan, Arlene</creatorcontrib><collection>SpringerOpen</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Advances in therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Coleman, Robert</au><au>Zhou, Ying</au><au>Jandial, Danielle</au><au>Cadieux, Benoit</au><au>Chan, Arlene</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bone Health Outcomes from the International, Multicenter, Randomized, Phase 3, Placebo-Controlled D-CARE Study Assessing Adjuvant Denosumab in Early Breast Cancer</atitle><jtitle>Advances in therapy</jtitle><stitle>Adv Ther</stitle><addtitle>Adv Ther</addtitle><date>2021-08-01</date><risdate>2021</risdate><volume>38</volume><issue>8</issue><spage>4569</spage><epage>4580</epage><pages>4569-4580</pages><issn>0741-238X</issn><eissn>1865-8652</eissn><abstract>Introduction
D-CARE, an international, phase 3, randomized, double-blind, placebo-controlled study in women with early-stage breast cancer at high risk of disease recurrence, failed to meet its primary endpoint—improvement in bone metastasis-free survival (BMFS) with adjuvant denosumab vs placebo injections. As a result of the limitations of assessing BMFS, which includes relapse in bone with and without extraskeletal recurrences and deaths from any cause, the prespecified exploratory bone endpoints’ analysis may provide a more clinically meaningful effect of denosumab in this disease setting.
Methods
The study enrolled women (aged ≥ 18 years) with histologically confirmed stage II/III breast cancer. Patients treated with adjuvant/neoadjuvant chemotherapy meeting inclusion criteria were randomly assigned 1:1 to receive either denosumab (120 mg) or placebo subcutaneously every 3–4 weeks for about 6 months and then every 3 months for a total treatment duration of 5 years. Five prespecified exploratory bone endpoints and post hoc subgroup analysis based on age (< 50 and ≥ 50 years) and menopause status (premenopausal and postmenopausal) were evaluated.
Results
Overall, 4509 women with early-stage breast cancer were assigned to receive denosumab (
N
= 2256) or placebo (
N
= 2253). The baseline demographics and clinical characteristics were comparable between the two arms. The hazard ratio (HR) for time to first bone metastasis was 0.82 (95% CI 0.66–1.02;
p
= 0.068), with HRs of 0.70 (95% CI 0.52–0.94;
p
= 0.018) for patients < 50 years old and 0.74 (95% CI 0.55–0.98;
p
= 0.038) for premenopausal patients, favoring the denosumab group. The HRs for time to first on-study fracture and time to first on-study skeletal-related event were 0.76 (95% CI 0.63–0.92;
p
= 0.004) and 0.52 (95% CI 0.35–0.78;
p
= 0.001), respectively, again favoring the denosumab group.
Conclusion
The exploratory bone endpoints indicate the benefits of denosumab treatment in patients with high-risk early breast cancer, supporting the expected bone health benefits contributed by denosumab.
Trial Registration Number
NCT01077154</abstract><cop>Cheshire</cop><pub>Springer Healthcare</pub><pmid>34185259</pmid><doi>10.1007/s12325-021-01812-9</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-2135-2286</orcidid><oa>free_for_read</oa></addata></record> |
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| source | Springer Link; Alma/SFX Local Collection |
| subjects | Bone Neoplasms - drug therapy Breast Neoplasms - drug therapy Brief Report Cardiology Denosumab - therapeutic use Double-Blind Method Endocrinology Female Humans Internal Medicine Medicine Medicine & Public Health Middle Aged NCT NCT01077154 Neoplasm Recurrence, Local Oncology Outcome Assessment, Health Care Pharmacology/Toxicology Rheumatology |
| title | Bone Health Outcomes from the International, Multicenter, Randomized, Phase 3, Placebo-Controlled D-CARE Study Assessing Adjuvant Denosumab in Early Breast Cancer |
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