ARomatase Inhibition plus/minus Src-inhibitor SaracaTinib (AZD0530) in Advanced breast CAncer Therapy (ARISTACAT): a randomised phase II study

Ailsa Oswald; Stefan N Symeonides; Duncan Wheatley; Stephen Chan; Adrian Murray Brunt; Karen McAdam; Peter Schmid; Simon Waters; Christopher Poole; Chris Twelves; Timothy Perren; John Bartlett; Tammy Piper; Eve Macdonald Chisholm; Michelle Welsh; Robert Hill; Lisa E Hopcroft; Peter Barrett-Lee; David A Cameron

doi:10.1007/s10549-023-06873-8

ARomatase Inhibition plus/minus Src-inhibitor SaracaTinib (AZD0530) in Advanced breast CAncer Therapy (ARISTACAT): a randomised phase II study

Ailsa Oswald^*, Stefan N Symeonides, Duncan Wheatley, Stephen Chan, Adrian Murray Brunt, Karen McAdam, Peter Schmid, Simon Waters, Christopher Poole, Chris Twelves, Timothy Perren, John Bartlett, Tammy Piper, Eve Macdonald Chisholm, Michelle Welsh, Robert Hill, Lisa E Hopcroft, Peter Barrett-Lee, David A Cameron

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

Purpose

The development of oestrogen resistance is a major challenge in managing hormone-sensitive metastatic breast cancer. Saracatinib (AZD0530), an oral Src kinase inhibitor, prevents oestrogen resistance in animal models and reduces osteoclast activity. We aimed to evaluate the efficacy of saracatinib addition to aromatase inhibitors (AI) in patients with hormone receptor-positive metastatic breast cancer.
Methods

This phase II multicentre double-blinded randomised trial allocated post-menopausal women to AI with either saracatinib or placebo (1:1 ratio). Patients were stratified into an “AI-sensitive/naïve” group who received anastrozole and “prior-AI” group who received exemestane. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR) and toxicity.
Results

140 patients were randomised from 20 UK centres to saracatinib/AI (n = 69) or placebo/AI (n = 71). Saracatinib was not associated with an improved PFS (3.7 months v. 5.6 months placebo/AI) and did not reduce likelihood of bony progression. There was no benefit in OS or ORR. Effects were consistent in “AI-sensitive/naive” and “prior-AI” sub-groups. Saracatinib was well tolerated with dose reductions in 16% and the main side effects were gastrointestinal, hypophosphatemia and rash.
Conclusion

Saracatinib did not improve outcomes in post-menopausal women with metastatic breast cancer. There was no observed beneficial effect on bone metastases.

CRUKE/11/023, ISRCTN23804370.

Original language	English
Journal	Breast cancer research and treatment
DOIs	https://doi.org/10.1007/s10549-023-06873-8
Publication status	Published - 2 Mar 2023

Keywords / Materials (for Non-textual outputs)

hormone receptor positive breast cancer
endocrine resistance
SRC
bone metastasis

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s10549-023-06873-8
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Cite this

Oswald, A., Symeonides, S. N., Wheatley, D., Chan, S., Murray Brunt, A., McAdam, K., Schmid, P., Waters, S., Poole, C., Twelves, C., Perren, T., Bartlett, J., Piper, T., Macdonald Chisholm, E., Welsh, M., Hill, R., Hopcroft, L. E., Barrett-Lee, P., & Cameron, D. A. (2023). ARomatase Inhibition plus/minus Src-inhibitor SaracaTinib (AZD0530) in Advanced breast CAncer Therapy (ARISTACAT): a randomised phase II study. Breast cancer research and treatment. https://doi.org/10.1007/s10549-023-06873-8

@article{9d500f76cfbe46d5b5fcdbc14bfd8050,

title = "ARomatase Inhibition plus/minus Src-inhibitor SaracaTinib (AZD0530) in Advanced breast CAncer Therapy (ARISTACAT): a randomised phase II study",

abstract = "PurposeThe development of oestrogen resistance is a major challenge in managing hormone-sensitive metastatic breast cancer. Saracatinib (AZD0530), an oral Src kinase inhibitor, prevents oestrogen resistance in animal models and reduces osteoclast activity. We aimed to evaluate the efficacy of saracatinib addition to aromatase inhibitors (AI) in patients with hormone receptor-positive metastatic breast cancer.MethodsThis phase II multicentre double-blinded randomised trial allocated post-menopausal women to AI with either saracatinib or placebo (1:1 ratio). Patients were stratified into an “AI-sensitive/na{\"i}ve” group who received anastrozole and “prior-AI” group who received exemestane. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR) and toxicity.Results140 patients were randomised from 20 UK centres to saracatinib/AI (n = 69) or placebo/AI (n = 71). Saracatinib was not associated with an improved PFS (3.7 months v. 5.6 months placebo/AI) and did not reduce likelihood of bony progression. There was no benefit in OS or ORR. Effects were consistent in “AI-sensitive/naive” and “prior-AI” sub-groups. Saracatinib was well tolerated with dose reductions in 16% and the main side effects were gastrointestinal, hypophosphatemia and rash.ConclusionSaracatinib did not improve outcomes in post-menopausal women with metastatic breast cancer. There was no observed beneficial effect on bone metastases.CRUKE/11/023, ISRCTN23804370.",

keywords = "hormone receptor positive breast cancer, endocrine resistance, SRC, bone metastasis",

author = "Ailsa Oswald and Symeonides, {Stefan N} and Duncan Wheatley and Stephen Chan and {Murray Brunt}, Adrian and Karen McAdam and Peter Schmid and Simon Waters and Christopher Poole and Chris Twelves and Timothy Perren and John Bartlett and Tammy Piper and {Macdonald Chisholm}, Eve and Michelle Welsh and Robert Hill and Hopcroft, {Lisa E} and Peter Barrett-Lee and Cameron, {David A}",

note = "Funding Information: Primary analysis was planned after 110 PFS events occurred, or a minimum of 6 months of follow-up in all patients. The study was registered (ISRCTN23804370), sponsored by the Common Services Agency for the Scottish Health Service (UK), partially funded by AstraZeneca (UK) with infrastructure support from the R&D departments of the NHS in the 4 UK nations (NIHR, CSO, HCRW, HSC PHA), and endorsed by Cancer Research UK{\textquoteright}s Clinical Trials Awards & Advisory Committee (CTAAC). It was conducted in accordance with ICH Good Clinical Practice and UK National Research Ethics Committee approval was obtained from the West of Scotland Research Ethics Service. Funding Information: Dr Oswald holds a clinical research fellowship at the University of Edinburgh that is supported by funding from AstraZeneca. At the time of the trial, Dr Symeonides held a clinical fellowship with the University of Edinburgh and AstraZeneca. The remaining authors declare no competing interests. AO: AstraZeneca funded clinical research fellowship (University of Edinburgh) from August 2020 to present. SS: AstraZeneca clinical fellowship (University of Edinburgh) from November 2012 to September 2014. DW, SC, AMB, KM, PS, SW, CP, CT, TPe, JB, TPi, EMC, MW, RH, LH and P B-L: No competing interests to disclose. DC: At the time the trial was conducted DC had no competing interests, but now has non-personal potential conflicts with Pfizer, Astra-Zenca, Novartis and Lilly. Funding Information: This study was supported by AstraZeneca UK. The funders did not play a role in study design, analysis or preparation of manuscript. Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = mar,

day = "2",

doi = "10.1007/s10549-023-06873-8",

language = "English",

journal = "Breast cancer research and treatment",

issn = "0167-6806",

publisher = "Springer",

}

Oswald, A, Symeonides, SN, Wheatley, D, Chan, S, Murray Brunt, A, McAdam, K, Schmid, P, Waters, S, Poole, C, Twelves, C, Perren, T, Bartlett, J, Piper, T, Macdonald Chisholm, E, Welsh, M, Hill, R, Hopcroft, LE, Barrett-Lee, P & Cameron, DA 2023, 'ARomatase Inhibition plus/minus Src-inhibitor SaracaTinib (AZD0530) in Advanced breast CAncer Therapy (ARISTACAT): a randomised phase II study', Breast cancer research and treatment. https://doi.org/10.1007/s10549-023-06873-8

TY - JOUR

T1 - ARomatase Inhibition plus/minus Src-inhibitor SaracaTinib (AZD0530) in Advanced breast CAncer Therapy (ARISTACAT): a randomised phase II study

AU - Oswald, Ailsa

AU - Symeonides, Stefan N

AU - Wheatley, Duncan

AU - Chan, Stephen

AU - Murray Brunt, Adrian

AU - McAdam, Karen

AU - Schmid, Peter

AU - Waters, Simon

AU - Poole, Christopher

AU - Twelves, Chris

AU - Perren, Timothy

AU - Bartlett, John

AU - Piper, Tammy

AU - Macdonald Chisholm, Eve

AU - Welsh, Michelle

AU - Hill, Robert

AU - Hopcroft, Lisa E

AU - Barrett-Lee, Peter

AU - Cameron, David A

N1 - Funding Information: Primary analysis was planned after 110 PFS events occurred, or a minimum of 6 months of follow-up in all patients. The study was registered (ISRCTN23804370), sponsored by the Common Services Agency for the Scottish Health Service (UK), partially funded by AstraZeneca (UK) with infrastructure support from the R&D departments of the NHS in the 4 UK nations (NIHR, CSO, HCRW, HSC PHA), and endorsed by Cancer Research UK’s Clinical Trials Awards & Advisory Committee (CTAAC). It was conducted in accordance with ICH Good Clinical Practice and UK National Research Ethics Committee approval was obtained from the West of Scotland Research Ethics Service. Funding Information: Dr Oswald holds a clinical research fellowship at the University of Edinburgh that is supported by funding from AstraZeneca. At the time of the trial, Dr Symeonides held a clinical fellowship with the University of Edinburgh and AstraZeneca. The remaining authors declare no competing interests. AO: AstraZeneca funded clinical research fellowship (University of Edinburgh) from August 2020 to present. SS: AstraZeneca clinical fellowship (University of Edinburgh) from November 2012 to September 2014. DW, SC, AMB, KM, PS, SW, CP, CT, TPe, JB, TPi, EMC, MW, RH, LH and P B-L: No competing interests to disclose. DC: At the time the trial was conducted DC had no competing interests, but now has non-personal potential conflicts with Pfizer, Astra-Zenca, Novartis and Lilly. Funding Information: This study was supported by AstraZeneca UK. The funders did not play a role in study design, analysis or preparation of manuscript. Publisher Copyright: © 2023, The Author(s).

PY - 2023/3/2

Y1 - 2023/3/2

N2 - PurposeThe development of oestrogen resistance is a major challenge in managing hormone-sensitive metastatic breast cancer. Saracatinib (AZD0530), an oral Src kinase inhibitor, prevents oestrogen resistance in animal models and reduces osteoclast activity. We aimed to evaluate the efficacy of saracatinib addition to aromatase inhibitors (AI) in patients with hormone receptor-positive metastatic breast cancer.MethodsThis phase II multicentre double-blinded randomised trial allocated post-menopausal women to AI with either saracatinib or placebo (1:1 ratio). Patients were stratified into an “AI-sensitive/naïve” group who received anastrozole and “prior-AI” group who received exemestane. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR) and toxicity.Results140 patients were randomised from 20 UK centres to saracatinib/AI (n = 69) or placebo/AI (n = 71). Saracatinib was not associated with an improved PFS (3.7 months v. 5.6 months placebo/AI) and did not reduce likelihood of bony progression. There was no benefit in OS or ORR. Effects were consistent in “AI-sensitive/naive” and “prior-AI” sub-groups. Saracatinib was well tolerated with dose reductions in 16% and the main side effects were gastrointestinal, hypophosphatemia and rash.ConclusionSaracatinib did not improve outcomes in post-menopausal women with metastatic breast cancer. There was no observed beneficial effect on bone metastases.CRUKE/11/023, ISRCTN23804370.

AB - PurposeThe development of oestrogen resistance is a major challenge in managing hormone-sensitive metastatic breast cancer. Saracatinib (AZD0530), an oral Src kinase inhibitor, prevents oestrogen resistance in animal models and reduces osteoclast activity. We aimed to evaluate the efficacy of saracatinib addition to aromatase inhibitors (AI) in patients with hormone receptor-positive metastatic breast cancer.MethodsThis phase II multicentre double-blinded randomised trial allocated post-menopausal women to AI with either saracatinib or placebo (1:1 ratio). Patients were stratified into an “AI-sensitive/naïve” group who received anastrozole and “prior-AI” group who received exemestane. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR) and toxicity.Results140 patients were randomised from 20 UK centres to saracatinib/AI (n = 69) or placebo/AI (n = 71). Saracatinib was not associated with an improved PFS (3.7 months v. 5.6 months placebo/AI) and did not reduce likelihood of bony progression. There was no benefit in OS or ORR. Effects were consistent in “AI-sensitive/naive” and “prior-AI” sub-groups. Saracatinib was well tolerated with dose reductions in 16% and the main side effects were gastrointestinal, hypophosphatemia and rash.ConclusionSaracatinib did not improve outcomes in post-menopausal women with metastatic breast cancer. There was no observed beneficial effect on bone metastases.CRUKE/11/023, ISRCTN23804370.

KW - hormone receptor positive breast cancer

KW - endocrine resistance

KW - SRC

KW - bone metastasis

U2 - 10.1007/s10549-023-06873-8

DO - 10.1007/s10549-023-06873-8

M3 - Article

SN - 0167-6806

JO - Breast cancer research and treatment

JF - Breast cancer research and treatment

ER -

ARomatase Inhibition plus/minus Src-inhibitor SaracaTinib (AZD0530) in Advanced breast CAncer Therapy (ARISTACAT): a randomised phase II study

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Keywords / Materials (for Non-textual outputs)

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