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

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.

Exploring the benefits of in-diet versus repeated oral dosing of saracatinib (AZD0530) in chronic studies: insights into pharmacokinetics and animal welfare

“…Therefore, characterizing the orally active test drugs in preclinical models has a translational potential. Saracatinib has been tested in various experimental models and its PK and toxicity at high doses are also known from clinical trials (8,37). Our published work has demonstrated the disease-modifying effects of saracatinib in experimental models of epilepsy (3,25).…”

“…Fyn/Src is highly expressed in proliferating cells such as cancerous cells (1,2) neurons and glial cells of the central nervous system in response to brain insults such as exposure to neurotoxins (3) or seizures (4,5) or in chronic neurodegenerative diseases such as Alzheimer's disease (6). Considering the role of Fyn/Src kinases in cell proliferation, saracatinib has been in clinical trials for various types of cancers, such as bone, ovarian, and breast cancer (7)(8)(9). Excessive production of Fyn/Src and its phosphorylation in reactive glial cells or neurons causes hyperexcitability, neuroinflammation, and neurodegeneration (10,11).…”

“…However, long-term treatment with this drug at an optimal dose is required for debilitating and chronic diseases such as cancer and neurodegenerative diseases to achieve beneficial effects with minimum adverse effects. In humans, saracatinib has been tested in clinical trials for some of these conditions for varying periods (8,9). In experimental models of epilepsy, we tested repeated oral dosing of saracatinib for about a week and observed some disease-modifying effects depending on the severity of the disease and the models of epilepsy (3,16).…”

Dual Drug Repurposing: The Example of Saracatinib

“…To the best of our knowledge, the clinical trials of saracatinib for cancer treatment stopped in 2016, with no articles published since then. Nevertheless, in the last year, a randomised phase II clinical trial testing the therapeutic efficacy of an aromatase inhibitor combined with saracatinib in hormone receptor-positive metastatic breast cancer was published after promising results in a phase I trial [39,40]. This study was based on pre-clinical data that showed the efficacy of saracatinib in enhancing the anti-proliferative effects of endocrine agents in breast cancer cell lines [41].…”

“…Moreover, bone is the most common site of metastases in hormone-sensitive breast cancer, and considering the capability of saracatinib to inhibit osteoclast activity, this area was also evaluated in the trial [36]. Unfortunately, the trial revealed that saracatinib was incapable of improving the patients' outcomes under the study conditions, and showed no promising effect on bone metastases either [39]. However, despite this, the article seems to recommend a return to saracatinib for cancer treatment, and a clinical trial was conducted between 2012 and 2015.…”