Activity and safety of enobosarm, a novel, oral, selective androgen receptor modulator, in androgen receptor-positive, oestrogen receptor-positive, and HER2-negative advanced breast cancer (Study G200802): a randomised, open-label, multicentre, multinational, parallel design, phase 2 trial.

Autor:	Palmieri C; The Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, UK; Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular, and Integrative Biology, The University of Liverpool, Liverpool, UK. Electronic address: c.palmieri@liverpool.ac.uk., Linden H; Division of Hematology and Oncology, Fred Hutchinson Cancer Center/University of Washington, Seattle, WA, USA., Birrell SN; Wellend Health/Burnside War Memorial Hospital, Toorak Gardens, SA, Australia; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia., Wheelwright S; Sussex Health Outcomes Research & Education in Cancer (SHORE-C), University of Sussex, Falmer, Brighton, UK., Lim E; The Kinghorn Cancer Centre and Cancer Research Theme, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia., Schwartzberg LS; Renown Health-Pennington Cancer Institute, Reno, NV, USA., Dwyer AR; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia., Hickey TE; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia., Rugo HS; Department of Medicine, University of California San Francisco Comprehensive Cancer Center, San Francisco, CA, USA., Cobb P; Cancer Centers of Montana, Billings, MT, USA., O'Shaughnessy JA; Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, TX, USA., Johnston S; The Breast Unit, The Royal Marsden NHS Foundation Trust, London, UK., Brufsky A; Division of Hematology/Oncology, Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA, USA., Tilley WD; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia., Overmoyer B; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Jazyk:	angličtina
Zdroj:	The Lancet. Oncology [Lancet Oncol] 2024 Mar; Vol. 25 (3), pp. 317-325. Date of Electronic Publication: 2024 Feb 08.
DOI:	10.1016/S1470-2045(24)00004-4
Abstrakt:	Background: The androgen receptor is a tumour suppressor in oestrogen receptor-positive breast cancer. The activity and safety of enobosarm, an oral selective androgen receptor modulator, was evaluated in women with oestrogen receptor (ER)-positive, HER2-negative, and androgen receptor (AR)-positive disease. Methods: Women who were postmenopausal (aged ≥18 years) with previously treated ER-positive, HER2-negative, locally advanced or metastatic breast cancer with an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled in a randomised, open-label, multicentre, multinational, parallel design, phase 2 trial done at 35 cancer treatment centres in nine countries. Participants were stratified on the setting of immediately preceding endocrine therapy and the presence of bone-only metastasis and randomly assigned (1:1) to 9 mg or 18 mg oral enobosarm daily using an interactive web response system. The primary endpoint was clinical benefit rate at 24 weeks in those with centrally confirmed AR-positive disease (ie, the evaluable population). This trial is registered with ClinicalTrials.gov (NCT02463032). Findings: Between Sept 10, 2015, and Nov 28, 2017, 136 (79%) of 172 patients deemed eligible were randomly assigned to 9 mg (n=72) or 18 mg (n=64) oral enobosarm daily. Of these 136 patients, 102 (75%) patients formed the evaluable population (9 mg, n=50; 18 mg, n=52). The median age was 60·5 years (IQR 52·3-69·3) in the 9 mg group and 62·5 years (54·0-69·3) in the 18 mg group. The median follow-up was 7·5 months (IQR 2·9-14·1). At 24 weeks, 16 (32%, 95% CI 20-47) of 50 in the 9 mg group and 15 (29%, 17-43) of 52 in the 18 mg group had clinical benefit. Six (8%) of 75 patients who received 9 mg and ten (16%) of 61 patients who received 18 mg had grade 3 or grade 4 drug-related adverse events, most frequently increased hepatic transaminases (three [4%] of 75 in the 9 mg group and two [3%] of 61 in the 18 mg group), hypercalcaemia (two [3%] and two [3%]), and fatigue (one [1%] and two [3%]). Four deaths (one in the 9 mg group and three in the 18 mg group) were deemed unrelated to the study drug. Interpretation: Enobosarm has anti-tumour activity in patients with ER-positive, HER2-negative advanced breast cancer, showing that AR activation can result in clinical benefit, supporting further clinical investigation of selective AR activation strategies for the treatment of AR-positive, ER-positive, HER2-negative advanced breast cancer. Funding: GTx. Competing Interests: Declaration of interests CP reports grants or contracts from Seagen, Daiichi-Sankyo, Pfizer, and Exact Science (outside of this work); consulting for Seagen, Daiichi-Sankyo, Exact Science, MEDAC, Gilead, and Pfizer; honoraria from Pfizer, Seagen, AstraZeneca, Roche, Eisai, and Novartis; travel support from Roche and Novartis; leadership role in Advise Make 2nd Count (unpaid); and stock in Digistain. HL reports grants or contracts from Sanofi, Zionexa, Tolmar, Pfizer, Zeno Pharmaceutical, Zymeworks, and Veru (outside of this work); consulting for Sanofi, GE Healthcare, Lilly, Novartis, and Gilead; and honoraria from Sanofi, GE Healthcare, Lilly, Novartis, and Gilead. EL reports research funding from Pfizer and Ellipses Pharma (outside of this work); honoraria for Ellipses Pharma, Pfizer, AstraZeneca, Gilead, MSD, and Lilly; patents planned, issued, or pending with Walter & Eliza Hall Institute; advisory board with Ellipses Pharma, Novartis, Pfizer, AstraZeneca, Gilead, MSD, Lilly (all paid to institution); and leadership in Breast Cancer Trials Australia, American Society of Clinical Oncology Research Committee. TEH reports grant funding from Australian National Health and Medical Research Council and National Breast Cancer Foundation (Australia). ARD reports grant funding from Australian National Health and Medical Research Council and National Breast Cancer Foundation (Australia); research support from Ellipses Pharma (outside of this work); and travel support from Fusion Conferences. HSR reports grants from Astellas Pharma, AstraZeneca, Daiichi Sankyo, F. Hoffmann-La Roche AG/Genentech, Gilead Sciences, GlaxoSmithKline, Lilly, Merck, Novartis Pharmaceutical Corporation, Pfizer, Fionyr Immunotherapeutics, Sermonix Pharmaceuticals, Taiho Oncology, and Veru; and honoraria from Daiichi Sankyo, Mylan, NAPO, and Puma Biotechnology. PC reports research support from GTx. JAO reports consulting for AbbVie, Agendia, Amgen Biotechnology, Aptitude Health, AstraZeneca, Bayer, Bristol-Myers Squibb, Carrick Therapeutics, GlaxoSmithKline, Genentech, Genzyme, Gilead Sciences, Immunomedics, Incyte Corporation, Lilly, Merck, Novartis, Ontada, Pfizer, Pharmacyclics, Pierre Fabre Pharmaceuticals, Puma Biotechnology, Prime Oncology, Roche, Samsung Bioepis, Sanofi, Seagen, Stemline Therapeutics, Theralink, Synthon and Veru; and honoraria from AbbVie, Agendia, Amgen Biotechnology, Aptitude Health, AstraZeneca, Bayer, Bristol-Myers Squibb, Carrick Therapeutics, GlaxoSmithKline, Genentech, Genzyme, Gilead Sciences, Immunomedics, Incyte Corporation, Lilly, Merck, Novartis, Ontada, Pfizer, Pharmacyclics, Pierre Fabre Pharmaceuticals, Puma Biotechnology, Prime Oncology, Roche, Samsung Bioepis, Sanofi, Seagen, Stemline Therapeutics, Theralink, Synthon and Veru. SJ reports research funding from Pfizer, Puma Biotechnology, Lilly, AstraZeneca, Novartis, Roche/Genentech (outside of this work); consulting or advisory role for Lilly, AstraZeneca, Puma Biotechnology, Pfizer, Novartis, and Sanofi Genzyme; and honoraria from Pfizer, Eisai, AstraZeneca, and Roche/Genentech. WDT reports grant funding from Australian National Health and Medical Research Council; research support from Ellipses Pharma (outside of this work); and consulting for HavaH. AB reports consulting for AstraZeneca, Pfizer, Novartis, Lilly, Genentech/Roche, SeaGen, Daiichi Sankyo, Merck, Agendia, Sanofi, Puma Biotechnology, Myriad, and Gilead. BO reports funding from GTx; research support from Eisai and Incyte (outside of this work); and Chief Medical Advisory role for the Milburn Foundation (unpaid). (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
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