Roche finally drops curtain on AKT drug ipatasertib


In amongst a clutch of discontinued phase 3 programmes in Roche's fourth-quarter results update was the news that it has stopped a study of AKT inhibitor ipatasertib as a treatment for first-line castration-resistant prostate cancer (CRPC).

Moreover, the drug no longer appears in its development pipeline at all, suggesting the drug has finally come to the end of the line more than two years after it generated mixed results in an earlier readout.

The IPATential150 study tested ipatasertib in combination with Janssen's Zytiga (abiraterone) and prednisone/prednisolone in mCRPC patients whose tumours had phosphatase and tensin homologue (PTEN) loss.

It generated mixed results in 2020 with an improvement seen in radiographic progression-free survival (rPFS) for a subgroup of patients, but not the whole population. At the time, Roche said the study was continuing to see if the ipatasertib combination was able to muster any improvement in overall survival.

The demise of the CRPC study comes after ipatasertib also generated disappointing results in earlier studies in breast cancer, including the IPATunity-170 trial in triple-negative breast cancer and IPATunity-130 in hormone receptor-positive, HER2-negative, and PTEN-mutated breast cancer.

So far, no AKT inhibitors have been brought to market, but several remain in clinical development.

Roche's decision to drop the programme comes after AstraZeneca's rival AKT inhibitor capivasertib improved PFS when added to Faslodex (fulvestrant) as a second-line therapy for HR-positive, HER2-negative advanced breast cancer.

The trial met both primary endpoints, improving PFS in the overall patient population and in a prespecified biomarker subgroup of patients whose tumours had qualifying alterations in the PIK3CA, AKT1, or PTEN genes.

AZ has a pair of phase 3 trials of capivasertib due to report this year, namely CAPItello-290 in TNBC and CAPItello-291 in HR-positive, HER2-negative breast cancer, as well as the late-stage CAPItello-281 trial on the go in hormone-sensitive prostate cancer. The drug has been listed among Clarivate's drugs to watch in 2023.

Ipatasertib was initially discovered by Roche subsidiary Genentech in collaboration with Array BioPharma.

Also listed among discontinued trials in Roche's update is its Alzheimer's drug gantenerumab – as previously announced – along with a phase 3 study of idiopathic pulmonary fibrosis (IPF) candidate zinpentraxin alfa (PRM-151) and a phase 1 study of efmarodocokin alfa in acute graft versus host disease (GVHD).