AZ first to AKT finish line, but FDA clears narrow label

AstraZeneca has claimed FDA approval for its first-in-class pan-AKT inhibitor capivasertib, getting a green light for the drug as a treatment for breast cancer, but with a more restrictive label than it originally hoped for.

Capivasertib has been approved as Truqap for use in combination with AZ’s oestrogen receptor antagonist Faslodex (fulvestrant) for adults with hormone receptor (HR)-positive and HER2-negative locally advanced or metastatic breast cancer, but only if they also have PIK3CA, AKT1, or PTEN mutations.

It can be used in patients whose disease has progressed despite prior endocrine therapy or has recurred within 12 months of adjuvant (post-surgery) treatment.

Capivasertib was billed as one of Clarivate’s drugs to watch for 2023, with the potential to achieve more than $1 billion in sales within five years - assuming, however, that it was approved with a broad label in this patient population, as well as for follow-up indications.

AZ’s success in bringing the AKT inhibitor to regulatory approval comes after rival drugmaker Roche abandoned a drug in the same class – ipatasertib – after disappointing results in castration-resistant prostate cancer (CRPC) earlier this year, which followed earlier fails in triple-negative breast cancer (TNBC).

Truqap’s approval is based on the results of the CAPItello-291 study, which showed that the combination of Truqap and Faslodex reduced the risk of disease progression or death by 50% compared to Faslodex alone in this PI3K/AKT pathway biomarker-altered breast cancer population.

The FDA has cleared the drug only for patients carrying the mutations, even though CAPItello-291 did show a benefit with the drug for an all-comer population, including those without the biomarkers, with a 40% reduction in progression-free survival (PFS) overall. That may be because the non-biomarker group in the study included quite a high proportion of untested patients in whom PIK3CA/AKT1/PTEN status was unknown.

Mutations in PIK3CA, AKT1, and alterations in PTEN occur frequently, affecting up to 50% of patients with advanced HR-positive breast cancer, according to AZ. However, at the moment, testing for those mutations isn’t widespread, so, the first task for AZ will be to encourage screening now that Truqap is available.

The FDA also approved a FoundationOne CDx assay from Foundation Medicine as a companion diagnostic device to identify patients with breast cancer for treatment with the combination.

AZ, meanwhile, is also developing the AKT inhibitor in phase 3 trials in combination with paclitaxel as first-line treatment for locally advanced or metastatic TNBC, and also has late-stage studies on the go in metastatic CRPC in combination with docetaxel.

The company’s head of oncology, Dave Fredrickson, said the approval of Truqap “reinforces the important role of the PI3K/AKT pathway in HR-positive breast cancer and the critical need to test patients at the time of diagnosis.”

Regulatory applications for Truqap in combination with Faslodex are also currently under review in China, the EU, Japan, and several other countries, according to AZ.