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A randomized, open-label, pre-surgical, window of opportunity study comparing the pharmacodynamic effects of the novel oral SERD AZD9496 with fulvestrant in patients with newly diagnosed ER+ HER2- primary breast cancer

Robertson, John F.R.; Evans, Abigail; Henschen, Stephan; Kirwan, Cliona C.; Jahan, Ali; Kenny, Laura M.; Dixon, J. Michael; Schmid, Peter; Kothari, Ashutosh; Mohamed, Omar; Fasching, Peter A.; Cheung, Kwok-Leung; Wuerstlein, Rachel; Carroll, Danielle; Klinowska, Teresa; Lindemann, Justin P.O.; MacDonald, Alexander; Mather, Richard; Maudsley, Rhiannon; Moschetta, Michele; Nikolaou, Myria; Roudier, Martine P.; Sarvotham, Tinnu; Schiavon, Gaia; Zhou, Diansong; Zhou, Li; Harbeck, Nadia

Authors

Abigail Evans

Stephan Henschen

Cliona C. Kirwan

Ali Jahan

Laura M. Kenny

J. Michael Dixon

Peter Schmid

Ashutosh Kothari

Omar Mohamed

Peter A. Fasching

Rachel Wuerstlein

Danielle Carroll

Teresa Klinowska

Justin P.O. Lindemann

Alexander MacDonald

Richard Mather

Rhiannon Maudsley

Michele Moschetta

Myria Nikolaou

Martine P. Roudier

Tinnu Sarvotham

Gaia Schiavon

Diansong Zhou

Li Zhou

Nadia Harbeck



Abstract

Purpose: Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ER+ breast cancer, but it has administration and pharmacokinetic (PK) limitations. Pharmacodynamic (PD) data suggests complete ER degradation is not achieved at fulvestrant’s clinically feasible dose. This pre-surgical study (NCT03236974) compared the PD effects of fulvestrant with AZD9496, a novel, orally bioavailable, non steroidal, potent SERD, in treatment naive patients with ER+ human epidermal growth factor receptor 2 negative primary breast cancer awaiting curative intent surgery.

Methods: Patients were randomized 1:1 to receive AZD9496 250 mg twice daily from Day (D) 1 for 5–14 days, or fulvestrant 500 mg on D 1. On-treatment imaging guided core tumor biopsies were taken between D 5–14 and compared with pre treatment diagnostic biopsies. The primary objective was to compare the effects of AZD9496 and fulvestrant on ER expression. Secondary objectives included changes in progesterone receptor (PR) and Ki-67 PK/PD relationships and safety.

Results: Forty-six women received treatment (AZD9496 n=22; fulvestrant n=24); 35 paired biopsies were evaluable (AZD9496 n=15; fulvestrant n=20). The least square mean estimate for ER H-score reduction was 24% after AZD9496 versus 36% after fulvestrant treatment (p=0.86). AZD9496 also reduced PR H-scores (-33.3%) and Ki 67 levels (-39.9%) from baseline, but was also not superior to fulvestrant (PR: -68.7%, p=0.97; Ki 67: 75.4%, p=0.98). No new safety findings were identified.

Conclusion: This was the first pre surgical study to demonstrate that an oral SERD impacts its key biological targets. However, AZD9496 was not superior to fulvestrant at the dose tested.

Citation

Robertson, J. F., Evans, A., Henschen, S., Kirwan, C. C., Jahan, A., Kenny, L. M., …Harbeck, N. (2020). A randomized, open-label, pre-surgical, window of opportunity study comparing the pharmacodynamic effects of the novel oral SERD AZD9496 with fulvestrant in patients with newly diagnosed ER+ HER2- primary breast cancer. Clinical Cancer Research, 26(16), https://doi.org/10.1158/1078-0432.ccr-19-3387

Journal Article Type Article
Acceptance Date Mar 26, 2020
Online Publication Date Mar 31, 2020
Publication Date 2020-08
Deposit Date Apr 6, 2020
Publicly Available Date Apr 1, 2021
Journal Clinical Cancer Research
Print ISSN 1078-0432
Electronic ISSN 1557-3265
Publisher American Association for Cancer Research
Peer Reviewed Peer Reviewed
Volume 26
Issue 16
Article Number 4242
DOI https://doi.org/10.1158/1078-0432.ccr-19-3387
Keywords Cancer Research; Oncology
Public URL https://nottingham-repository.worktribe.com/output/4248891
Publisher URL https://clincancerres.aacrjournals.org/content/early/2020/03/31/1078-0432.CCR-19-3387