Messaggi chiave
- È stato condotto uno studio di fase 2, randomizzato, in aperto, a disegno parallelo, volto a valutare attività e sicurezza di enobosarm, un modulatore selettivo del recettore degli androgeni (AR), nel trattamento del carcinoma mammario (BC) ER+/AR+/HER2- localmente avanzato/metastatico già precedentemente trattato.
- Nel periodo settembre 2015 – novembre 2017, 136 pazienti in età post-menopausale sono state randomizzate a enobosarm 9 mg o 18 mg per via orale al giorno. A un follow-up mediano di 7,5 mesi, il tasso di beneficio clinico a 24 settimane è risultato pari al 32 e 29% nei due gruppi, con un tasso di eventi avversi correlati al trattamento di grado 3/4 (soprattutto aumento delle transaminasi, ipercalcemia e fatigue) rispettivamente pari all’8 e 16%.
- Malgrado i limiti legati al disegno dello studio e alle dimensioni del campione, i risultati ottenuti supportano l’ulteriore valutazione di enobosarm e di altre strategie di attivazione selettiva del recettore androgenico per il trattamento del BC avanzato ER+/AR+/HER2-.
Abstract
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.
Note: Funded by GTx; G200802 ClinicalTrials.gov number, NCT02463032