For decades, hormonal treatment of breast cancer has had one aim – blocking oestrogen, but now a global study has discovered there may be another less toxic way to defeat the most common form of breast cancer, offering hope to millions of women in the future.
The study found the drug enobosarm stimulates the androgen receptor (AR), making it effective against oestrogen receptor-positive (ER+) breast cancer, which constitutes up to 80% of all breast cancer cases.
“The effectiveness of enobosarm lies in its ability to activate the AR and trigger a natural defence mechanism in breast tissue, thereby slowing the growth of ER+ breast cancer, which relies on oestrogen to grow and spread,” said senior co-author Professor Wayne Tilley, director of the Dame Roma Mitchell Cancer Research Laboratories at the University of Adelaide.
Newswise reports that the clinical study is supported by the institution’s pre-clinical research, which had established that the AR is a tumour suppressor in both normal breast tissue and ER+ breast cancer.
Along with investigators from the University of Adelaide and Dana-Farber Cancer Institute (DFCI) in Boston, USA, the international study also included researchers from the University of Liverpool in the UK and other experts around the world, reports Newswise.
The team assessed enobosarm’s efficacy and safety in 136 post-menopausal women with advanced or metastatic ER-positive, HER2-negative breast cancer.
Enobosarm showed significant anti-tumour activity and was well-tolerated by patients, without adversely affecting their quality of life or causing masculinising symptoms.
This discovery represents the first advancement in hormonal treatment of ER+ breast cancer in decades and offers a promising new oral treatment strategy for the most prevalent form of breast cancer.
The new hormonal strategy, published in The Lancet Oncology, differs from the existing standard-of-care hormonal treatments, which have been around for decades and involve suppressing oestrogen activity in the body or inhibiting the ER.
Although successful initially, treatments targeting ER can cause severe side effects and treatment-resistant progression of the disease is common.
“Our findings are very promising. They demonstrate that stimulating the androgen receptor pathway with enobosarm can be beneficial,” said senior co-author and study principal investigator Dr Beth Overmoyer from DFCI.
“This is the first time a non-oestrogen receptor hormonal treatment approach has been shown to be clinically advantageous in ER+ breast cancer. The study supports further investigation of enobosarm in earlier stages of breast cancer as well as in combination with targeted therapies, such as ribociclib, a CDK 4/6 inhibitor.”
More than 2.3m cases of breast cancer are identified globally each year.
Study details
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
Carlo Palmieri, Hannah Linden, Lee Schwartzberg, et al.
Published in The Lancet Oncology on 8 February 2024
Summary
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 post-menopausal (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).
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.
The Lancet Oncology article – Activity and safety of enobosarm (Open access)
Newswise article – Strongest contender in decades in fight against breast cancer (Open access)
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