Aromatase inhibition plus/minus Src inhibitor saracatinib (AZD0530) in advanced breast cancer therapy (ARISTACAT): a randomised phase II study

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Abstract

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.

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Most cited references 46

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RECIST 1.1-Update and clarification: From the RECIST committee.

Lawrence H. Schwartz, Saskia Litiere, Elisabeth de Vries … (2016)

The Response Evaluation Criteria in Solid Tumours (RECIST) were developed and published in 2000, based on the original World Health Organisation guidelines first published in 1981. In 2009, revisions were made (RECIST 1.1) incorporating major changes, including a reduction in the number of lesions to be assessed, a new measurement method to classify lymph nodes as pathologic or normal, the clarification of the requirement to confirm a complete response or partial response and new methodologies for more appropriate measurement of disease progression. The purpose of this paper was to summarise the questions posed and the clarifications provided as an update to the 2009 publication.

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Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer

Gabriel N Hortobagyi, Salomon Stemmer, Howard Burris … (2016)

Background The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2). Methods In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. We randomly assigned the patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. A preplanned interim analysis was performed on January 29, 2016, after 243 patients had disease progression or died. Prespecified criteria for superiority required a hazard ratio of 0.56 or less with P<1.29×10(-5). Results The duration of progression-free survival was significantly longer in the ribociclib group than in the placebo group (hazard ratio, 0.56; 95% CI, 0.43 to 0.72; P=3.29×10(-6) for superiority). The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63.0% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib group and 42.2% (95% CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively (P<0.001). Common grade 3 or 4 adverse events that were reported in more than 10% of the patients in either group were neutropenia (59.3% in the ribociclib group vs. 0.9% in the placebo group) and leukopenia (21.0% vs. 0.6%); the rates of discontinuation because of adverse events were 7.5% and 2.1%, respectively. Conclusions Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT01958021 .).

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Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial

Massimo Cristofanilli, Nicholas Turner, Igor N. Bondarenko … (2016)

In the PALOMA-3 study, the combination of the CDK4 and CDK6 inhibitor palbociclib and fulvestrant was associated with significant improvements in progression-free survival compared with fulvestrant plus placebo in patients with metastatic breast cancer. Identification of patients most suitable for the addition of palbociclib to endocrine therapy after tumour recurrence is crucial for treatment optimisation in metastatic breast cancer. We aimed to confirm our earlier findings with this extended follow-up and show our results for subgroup and biomarker analyses.

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Author and article information

Contributors

Ailsa J. Oswald:

ORCID: http://orcid.org/0000-0002-0702-3892

ailsa.oswald@ed.ac.uk

Journal

Journal ID (nlm-ta): Breast Cancer Res Treat

Journal ID (iso-abbrev): Breast Cancer Res Treat

Title: Breast Cancer Research and Treatment

Publisher: Springer US (New York )

ISSN (Print): 0167-6806

ISSN (Electronic): 1573-7217

Publication date (Electronic): 2 March 2023

Publication date PMC-release: 2 March 2023

Publication date (Print): 2023

Volume: 199

Issue: 1

Pages: 35-46

Affiliations

[1 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, University of Edinburgh, ; Edinburgh, Scotland, UK

[2 ]GRID grid.416116.5, ISNI 0000 0004 0391 2873, Royal Cornwall Hospital, ; Truro, Cornwall England, UK

[3 ]GRID grid.240404.6, ISNI 0000 0001 0440 1889, Nottingham University Hospitals NHS Trust, ; Nottingham, England, UK

[4 ]GRID grid.439752.e, ISNI 0000 0004 0489 5462, University Hospitals of North Midlands NHS Trust, Stoke-On-Trent & University of Keele, ; Staffordshire, England, UK

[5 ]GRID grid.417250.5, ISNI 0000 0004 0398 9782, Peterborough City Hospital, ; Peterborough, England, UK

[6 ]GRID grid.4868.2, ISNI 0000 0001 2171 1133, Barts Cancer Institute, ; London, England, UK

[7 ]GRID grid.470144.2, ISNI 0000 0004 0466 551X, Velindre Hospital, ; Whitchurch, Cardiff Wales, UK

[8 ]GRID grid.15628.38, ISNI 0000 0004 0393 1193, University Hospitals Coventry & Warwickshire, ; Coventry, England, UK

[9 ]GRID grid.9909.9, ISNI 0000 0004 1936 8403, University of Leeds and St James’ Hospital, ; Leeds, England, UK

[10 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, University of Edinburgh, ; Edinburgh, Scotland, UK

[11 ]Scottish Clinical Trials Research Unit, Edinburgh, Scotland, UK

[12 ]GRID grid.470144.2, ISNI 0000 0004 0466 551X, Velindre Cancer Centre, ; Cardiff, Wales, UK

Author information

Ailsa J. Oswald http://orcid.org/0000-0002-0702-3892

Article

Publisher ID: 6873

DOI: 10.1007/s10549-023-06873-8

PMC ID: 10147753

PubMed ID: 36859649

SO-VID: 58456169-ef8a-4243-bc8b-74db5445615c

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 21 December 2022

Date accepted : 31 January 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100004325, AstraZeneca;

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: hormone receptor-positive breast cancer,endocrine resistance,src,bone metastasis

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: hormone receptor-positive breast cancer, endocrine resistance, src, bone metastasis

Aromatase inhibition plus/minus Src inhibitor saracatinib (AZD0530) in advanced breast cancer therapy (ARISTACAT): a randomised phase II study

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Karger: Oncology

Most cited references 46

RECIST 1.1-Update and clarification: From the RECIST committee.

Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer

Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial

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