325PD - Phase I/II trial of abiraterone acetate (AA) in estrogen receptor (ERα) or androgen receptor (AR) positive metastatic breast cancer (mBC)
|Date||01 October 2012|
|Event||ESMO Congress 2012|
|Session||Breast cancer, locally advanced and metastatic|
|Topics|| Breast Cancer, Metastatic
C.H.M. Ng1, I. Macpherson2, D. Rea3, J. Spicer4, A. Bowman5, A. Jones6, M. Dowsett7, S.R.D. Johnston8, N. Dobbs9, J.S. De Bono10
Abiraterone irreversibly inhibits 17-hydroxylase/c-17-20 lyase (CYP17), reducing androgen and estrogen levels and improves overall survival from castration resistant prostate cancer. We hypothesized that: A) Postmenopausal ERα+ MBC continue to be ERα + /AR driven; and, B) Postmenopausal ERα- AR+ MBC can be driven by AR.Methods
This Phase I/II trial of AA with hydrocortisone evaluated tolerability, pharmacokinetic (PK)-pharmacodynamic (PD) profile and anti-tumor activity. Two parallel but non-randomized Phase II arms utilized a Gehan design (95% probability of detecting a 24wk clinical benefit rate (CBR, partial response [PR] + stable disease) of > 20%; 14 patients [pts] in the first stage; 11 in the second stage for each arm). Prior therapy with ≥ 2 lines of endocrine therapy (for ERα+ arm); ≥ 1 line of chemo (for AR + ERα- arm); and prior trastuzumab if HER2-positive was required. ERα and AR positivity was defined as immunoreactivity in ≥ 1% cells.Results
In the phase I study, daily dosing of AA was well tolerated with variable PK at all dose levels. PD studies of CYP17 blockade demonstrated suppression of circulating estradiol and androgen levels below the limit of assay detection with 1000mg and 250-2000mg AA respectively; 1000mg was selected for Phase II evaluation. In the ERα+ arm, 6 pts (Phase I) and 25pts (Phase II) received 1000mg AA, of whom 4 were HER2-positive. The median age (range) was 60 (46-80), prior lines of hormonal and chemotherapy were 3 (2-4) and 2 (0-5) respectively. There was 1 partial response (PR) lasting 14m in a pt who had received 4 and 5 lines of hormonal and chemotherapy respectively. Median progression-free survival was 11wk. CBR at 24wk was 21%. In the AR + ERα- arm, recruitment is ongoing. Hypokalaemia easily managed by hydrocortisone administration, was the commonest drug related adverse event (AE).Conclusion
AA was well tolerated and merits further evaluation in MBC. Cancer Research UK (Drug Development Office) Sponsored and funded the trial. Johnson & Johnson provided AA.Disclosure
M. Dowsett: The Institute of Cancer Research has a commercial interest in Abiraterone. Mitch Dowsett is an employee of the Institute of Cancer Research, which has a ‘Rewards to Inventors’ scheme and is a recipient of the scheme.
J.S. de Bono: The Institute of Cancer Research has a commercial interest in Abiraterone. Prof de Bono is an employee of the Institute of Cancer Research, and recipient of a ‘Rewards to Inventors’ scheme. He is also a consultant for Johnson and Johnson.
All other authors have declared no conflicts of interest.