Abstract P3-11-09: ARISTACAT - Aromatase inhibition plus minus saracatinib as advanced breast cancer therapy: A randomised phase II study of aromatase inhibition plus/minus the Src-inhibitor AZD0530 in post-menopausal women with advanced breast cancer
Authors: Cameron David , Symeonides Stefan , Brunt Murray , Schmid Peter , Waters Simon , Twelves Christopher , Barrett-Lee Peter , Bartlett John , Piper Tammy , McAdam Karen , Chisholm Eve Macdonald , Welsh Michelle , Hill Robert 
Published: March 2020

Abstract
Background: Src, the first proto-oncogene to be described, is a non-receptor tyrosine kinase interacting with multiple oncogenic pathways, including cell proliferation, survival, angiogenesis and osteoclast activity. Src activation occurs in up to 40% of ER+ breast cancers, is linked with poor prognosis, and pre-clinically has been strongly implicated in endocrine resistance. Saracatinib (AZD0530) is a potent, oral selective Src inhibitor that enhances the anti-proliferative effect of endocrine agents in pre-clinical breast cancer models, preventing the development of endocrine-resistance and restoring endocrine sensitivity. In a murine model of prostate bony metastases saracatinib inhibits osteoclast activity, reducing bone resorption and the development and progression of bone lesions. Clinically, saracatinib is generally well-tolerated with mainly gastro-intestinal adverse events (AEs), clinically meaningful durations of stable disease as monotherapy, and partial responses observed in combination with other therapies.
Methods: Multi-centre, placebo-controlled, double-blind, randomised phase II trial. Post-menopausal women with advanced/metastatic breast cancer suitable for 1st or 2nd second line hormonal treatment, were randomised to receive an aromatase inhibitor (AI) plus saracatinib 175mg mg/day or placebo. Patients were stratified as either (i) “AI-sensitive/naïve”, who received anastrazole 1mg daily ± saracatinib, or (ii) “prior-AI”, if they had progressed on a non-steroidal AI but were considered likely to retain some endocrine sensitivity, who received exemestane 25mg daily ± saracatinib. Other stratification factors were bone metastases, bisphosphonate use, performance status, and treatment centre. Treatment was until progression, intolerable toxicity or at the patient’s request. The primary endpoint was PFS; secondary endpoints were toxicity, ORR & OS; exploratory endpoints explored molecular correlates in on-treatment samples (including optional biopsies).
Results: 140 patients were enrolled from 22 UK sites between August 2012 and April 2015 of whom 69 were in the “AI-sensitive/naïve” group and 71 in the “prior-AI” group; 134 patients were eligible for efficacy evaluation and 136 for safety. Interim safety data analyses by an IDMC identified no new safety signals. Treatment emergent AEs were generally low grade, the most frequent being fatigue (70%) and nausea (49%); AEs occurring significantly (p&lt;0.05) more often with saracatinib were hypophosphataemia (40% vs 6%), rash (34% vs 12%), anorexia (43% vs 19%), vomiting (33% vs 15%) and diarrhoea (31% vs 16%). More patients receiving saracatinib had a dose reduction or stopped treatment due to toxicity (16% vs 10% and 5% vs 3%, respectively; n.s.). There was no indication of greater efficacy from the addition of saracatinib with respect to PFS (3.7 v 5.6 months; n.s.) or OS (24 vs 23 months; n.s.). ORR appeared lower with saracatinib (11% vs 31%) even when excluding non-evaluable patients. Effects were consistent in the “AI-sensitive/naïve” and “prior-AI” groups. Patients receiving saracatinib were no less likely to progress with bone metastases, while bisphosphonate use was associated with an increased PFS and OS across the trial population. Translational work underway includes assessing Src pathway suppression.
Conclusions: Saractinib did not improve outcomes in post-menopausal women with advanced breast cancer treated with exemestane with numerically inferior p response rate and PFS, and no apparent beneficial effect on bone metastases. These data do not support further evaluation of saracatinib in combination with AIs.
ARISTACAT - Abstract - San Antonio 2019
Citation Format: David Cameron, Stefan Symeonides, Murray Brunt, Peter Schmid, Simon Waters, Christopher Twelves, Peter Barrett-Lee, John Bartlett, Tammy Piper, Karen McAdam, Eve Macdonald Chisholm, Michelle Welsh, Robert Hill. ARISTACAT - Aromatase inhibition plus minus saracatinib as advanced breast cancer therapy: A randomised phase II study of aromatase inhibition plus/minus the Src-inhibitor AZD0530 in post-menopausal women with advanced breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-09.