Pre-clinical models of estrogen receptor (ER) positive breast cancer have established that the androgen receptor (AR) functions as a tumour suppressor (Hickey et al, Nature Medicine 2021). Agonist activation of the AR strongly suppresses the growth of ER and AR positive breast cancer, both in the context of disease sensitive to and resistant to endocrine therapy, with or without inhibition of cyclin-dependent kinase (CDK) 4/6.
Historically, androgen therapies such as testosterone propionate or fluoxymesterone produced disease regression in up to 30% of patients with advanced breast cancer. Despite the therapeutic benefits of androgen therapy for breast cancer, this strategy was supplanted due to the virilising side-effects of such androgen formulations and the advent of ER-directed strategies.
Preclinical and mechanistic insights as well as the availability of selective AR modulators (SARMs) have provided both the rationale and ability to revisit AR agonism in ER positive breast cancer. SARMs have a high specificity for binding to ARs, act in a tissue-selective manner, and do not cause virilising effects in women.
Enobosarm (GTx-024) is an oral aryl-propinamide non-steroidal SARM that durably inhibits in-vivo growth of ER positive breast cancer and inhibits tumour growth in models of endocrine resistance. We recently reported (Palmieri et al, Lancet Oncology 2024) that enobosarm has anti-tumour activity in patients with ER-positive, HER- negative advanced breast cancer, indicating that AR activation can result in clinical benefit, and supporting further clinical investigation of selective AR activation strategies.
Prof Wayne Tilley is internationally-recognised for research on the role of sex hormones (estrogens, progestogens and androgens) in hormone-dependent cancers, in particular breast and prostate cancer. He is a former President of the Australian Society for Medical Research and was Chair of the National Breast Cancer Foundation (NBCF) Research Advisory Committee and a member of the Board of the NBCF between 2003 and 2012. He convenes the International PacRim Breast and Prostate Cancer Meeting Series (2003-current).
In recognition of research excellence in the field of hormone-dependent cancers, he received the 2016 Endocrine Society of Australia Senior Plenary Award for outstanding research in the field of endocrinology. He was also awarded the 2023 Rob Sutherland Translational Award by Breast Cancer Trials Australia, in recognition of excellence in scientific and translational research and achievements and contributions to improved patient outcomes.
