The first response to Zytiga in treating advanced breast cancer has been reported in an ongoing clinical trial to evaluate its efficacy. The candidates for this trial had been heavily pretreated with chemotherapy and hormonal therapy. Any response in the category is deemed remarkable. 6 patients were enrolled into the Phase I part of the study. Of these patients there has been one response to Zytiga with an overall survival of 14 months. This is an important result and shows that Zytiga can continue to work when other therapies such as chemotherapy have failed. Zytiga is a rational approach to the treatment of breast cancer since it blocks the production of all androgenic and estrogenic hormones including estradiol. The level of these hormones falls to undetectable levels following Zytiga treatment. This starves the breast cancer of estrogens and they cannot grow any further halting tumour development. This response to Zytiga and the low toxicity profile in combination with hydrocortisone means that Zytiga would work as a safer option to chemotherapy and warrants further investigation in the pre chemotherapy setting for the earlier treatment of breast cancer especially if it is hormone dependent breast cancer.
Zytiga for Breast Cancer
PHASE I/II TRIAL OF ZYTIGA (ABIRATERONE ACETATE, AA) IN ESTROGEN RECEPTOR (ER) OR ANDROGEN RECEPTOR (AR) POSITIVE METASTATIC BREAST CANCER
Background
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.
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
Zytiga was well tolerated and merits further evaluation in Metastatic Breast Cancer.
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