Although endocrine therapies are a cornerstone of many treatments for hormone-dependent cancers, resistance to first-line CDK4/6 inhibitors and endocrine therapies often develop. This leaves only limited treatment options and, as a result, alternatives are much needed
Activation of the AKT pathway is thought to be involved in the development of resistance to endocrine therapy.
AstraZeneca (AZ) is therefore investigating capivasertib, a drug that acts on AKT in a variety of different cancers, which was discovered after a collaboration with Astex Therapeutics.1
These tumours have alterations in the AKT pathway, including PI3K, AKT and PTEN. AZ is also evaluating tumours that require signalling via this pathway for their survival.
The drug is being investigated as a monotherapy and also in combination with numerous other anticancer agents; it’s an adenosine triphosphate competitive inhibitor of all three isoforms of AKT.
In a double-blind, randomised Phase III trial, 708 patients with hormone receptor positive breast cancer that was also low or negative for HER2 — and which had recurred or progressed either during or after aromatase inhibitor therapy — were enrolled.2
Subjects were given 400 mg doses of capivasertib twice a day in combination with the oestrogen antagonist fulvestrant or a “placebo plus fulvestrant” combination.
Early results indicate that there was a 40% reduction in the risk of disease progression or death compared with a regimen of placebo plus fulvestrant. The median progression free survival was 7.3 months in the capivasertib group compared with 3.1 months in the placebo group.
Rash was the most common adverse event. Early data on overall survival were encouraging and the trial continues to assess this as a secondary endpoint.
Other studies that have been done include a Phase I trial in prostate cancer during which it was given in combination with abiraterone — with a third of the subjects having at least a 20% decrease in prostate specific antigen during the study.3
Another trial in prostate cancer involved a combination with docetaxel.4
In this Phase II trial, although a progression-free survival primary endpoint was not extended, the secondary endpoint of overall survival was significantly improved: 25.3 months with the capivasertib combination and 20.3 months with the placebo combination.
It appeared to be particularly beneficial in patients who had previously been given drugs targeted at the androgen receptor.
Combinations with olaparib have also been investigated in endometrial, ovarian and triple negative breast cancers. In a Phase Ib trial in these cancers, six of 32 subjects had a partial response, but the partial response rate was 43% in endometrial cancer.5