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A Randomized, Open-label, Presurgical, 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

A Randomized, Open-label, Presurgical, 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 Thumbnail


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

©2020 American Association for Cancer Research. 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 limitations. Pharmacodynamic data suggest complete ER degradation is not achieved at fulvestrant's clinically feasible dose. This presurgical study (NCT03236974) compared the pharmacodynamic effects of fulvestrant with AZD9496, a novel, orally bioavailable, nonsteroidal, potent SERD, in treatment-naïve patients with ER+ HER2- primary breast cancer awaiting curative intent surgery. PATIENTS AND METHODS: Patients were randomized 1:1 to receive AZD9496 250 mg twice daily from day 1 for 5-14 days, or fulvestrant 500 mg on day 1. On-treatment imaging-guided core tumor biopsies were taken between day 5 and 14 and compared with pretreatment 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 pharmacokinetic/pharmacodynamic 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. CONCLUSIONS: This was the first presurgical study to demonstrate that an oral SERD affects 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, Presurgical, 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), 4242-4249. 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 Aug 15, 2020
Deposit Date Apr 6, 2020
Publicly Available Date Mar 28, 2024
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Print ISSN 1078-0432
Electronic ISSN 1557-3265
Publisher American Association for Cancer Research
Peer Reviewed Peer Reviewed
Volume 26
Issue 16
Pages 4242-4249
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

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