AZ has another setback with Truqap after failed TNBC trial

AstraZeneca’s first-in-class pan-AKT inhibitor Truqap was unable to improve overall survival (OS) in a phase 3 trial in triple-negative breast cancer (TNBC), denting the prospects of the new drug.

The CAPItello-290 study is comparing the combination of Truqap (capivasertib) with paclitaxel to paclitaxel and placebo as a first-line therapy for patients with inoperable locally advanced or metastatic inoperable TNBC. The combination was unable to improve OS in both the overall patient population and a subgroup of patients with specific tumour biomarkers, namely PIK3CA, AKT1, or PTEN.

AZ was the first company to bring an AKT inhibitor to market, getting FDA approval last year for Truqap in combination with the company’s oestrogen receptor antagonist Faslodex (fulvestrant) for adults with hormone receptor (HR)-positive and HER2-negative locally advanced or metastatic breast cancer whose disease has progressed after at least one prior endocrine treatment or earlier adjuvant therapy.

However, the US regulator restricted the use of the drug to patients with PIK3CA, AKT1, or PTEN alterations – a narrower label than AZ had been hoping for. In the EU, the EMA’s human medicines committee recommended approval with a similar biomarker-restricted label in April.

Commenting on the new data readout, CAPItello-290 lead investigator Peter Schmid, of the London-based Barts Cancer Institute, said the results “have not shown what we hoped.”

“Despite modest advances, triple-negative breast cancer remains one of the most challenging forms of disease to treat due to the lack of known actionable biomarker targets, and chemotherapy-based regimens continue to be the mainstay of treatment,” he added.

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. That prediction was, however, predicted on a broad label in the HR-positive, HER2-negative breast cancer population, as well as approval in follow-up indications like TNBC.

Mutations in PIK3CA, AKT1, and alterations in PTEN occur frequently, affecting up to 50% of patients with advanced HR-positive breast cancer and more than a third (35%) of TNBC cases, but testing for them isn’t widespread.

AZ still has a few more shots on goal with Truqap, including the CAPItello-292 study looking at the drug as a triplet with Faslodex and investigator’s choice of CDK 4/6 inhibitor in HR-positive, HER2-negative breast cancer, and two studies (CAPItello-280 and CAPItello-281, respectively) in castration-resistant and hormone-sensitive prostate cancer.

Roche abandoned a drug in the same class, called ipatasertib, after reporting disappointing results in castration-resistant prostate cancer last year, which followed earlier failures in TNBC.