Purpose Irosustat is a first-generation, orally active, irreversible
steroid sulfatase inhibitor. We performed a multicentre,
open label phase II trial of the addition of Irosustat
to a first-line aromatase inhibitor (AI) in patients with
advanced BC to evaluate the safety of the combination and
to test the hypothesis that the addition of Irosustat to AI
may further suppress estradiol levels and result in clinical
benefit.
Experimental design Postmenopausal women with ERpositive
locally advanced or metastatic breast cancer who
had derived clinical benefit from a first-line AI and who
subsequently progressed were enrolled. The first-line AI
was continued and Irosustat (40 mg orally daily) added.
The primary endpoint was clinical benefit rate (CBR).
Secondary endpoints included safety, tolerability, and
pharmacodynamic end points.
Results Twenty-seven women were recruited, four discontinued
treatment without response assessment. Based
on local reporting, the CBR was 18.5% (95% CI
6.3–38.1%) on an intent to treat basis, increasing to 21.7%
(95% CI 7.4–43.7%) by per-protocol analysis. In those
patients that achieved clinical benefit (n = 5), the median
(interquartile range) duration was 9.4 months (8.1–11.3)
months. The median progression-free survival time was
2.7 months (95% CI 2.5–4.6) in both the ITT and perprotocol
analyses. The most frequently reported grade 3/4
toxicities were dry skin (28%), nausea (13%), fatigue
(13%), diarrhoea (8%), headache (7%), anorexia (7%) and
lethargy (7%).
Conclusions The addition of Irosustat to aromatase inhibitor
therapy resulted in clinical benefit with an acceptable
safety profile. The study met its pre-defined success
criterion by both local and central radiological assessments.