PTEN loss, which leads to elevated PI3K/Akt pathway activation, is one of the most common changes in mCRPC and is associated with a worse prognosis. Ipatasertib (Ipat) is a potent, novel oral ATP-competitive inhibitor of Akt. When combined with abiraterone acetate (Abi), Ipat improved radiographic progression-free survival (rPFS) and overall survival in unselected patients (pts) with mCRPC (de Bono et al, ASCO 2016). In this analysis, rPFS in pts with PTEN loss was assessed, and the relationship between PTEN expression by immunohistochemistry (IHC) and genomic loss of PTEN was further explored.
Pts with mCRPC, previously treated with docetaxel, were randomized 1:1:1 (double blinded) to 3 arms: Ipat-400 mg, Ipat-200 mg or placebo (Pbo) in combination with Abi 1000 mg and prednisone 10 mg daily. PTEN expression was assessed by IHC in archival or fresh tumor samples, with prospectively defined criteria for PTEN loss. PTEN genomic loss was detected by fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS).
253 pts were randomized and 173 rPFS events (68%) were observed at the primary analysis. PTEN status was IHC evaluable in 165 cases, with PTEN loss reported in 71 cases (43%). PTEN loss was associated with a worse rPFS outcome in the Pbo arm, while Ipat improved rPFS compared with Pbo at both doses, with a greater treatment effect at 400 mg and in PTEN-loss cancers (Table). There was high concordance for PTEN loss between FISH, NGS and IHC.
|PTEN Loss||Non-PTEN Loss|
|Ipat-400 + Abi (n = 25)||Ipat-200 + Abi (n =25)||Pbo + Abi (n =21)||Ipat-400 + Abi (n = 32)||Ipat-200 + Abi (n = 27)||Pbo + Abi (n = 35)|
|rPFS events, n %||15 (60)||16 (64)||18 (86)||20 (63)||20 (74)||26 (74)|
This study indicates that combining Akt inhibition with improved AR pathway blockade in mCRPC may provide pt benefit and is the first clinical demonstration supporting PTEN loss as a predictive response biomarker for mCRPC. These findings warrant the co-development of Ipat with a companion diagnostic assay to select mCRPC pts with PTEN loss and improve outcomes. NCT01485861.
Clinical trial identification
Legal entity responsible for the study
F. Hoffmann La-Roche
F. Hoffmann La-Roche
J.S. de Bono: Genentech Advisory Board meetings as a paid consultant. C. Massard: Genentech, Astellas, Medimmune, Ipsen, Jansen, Novartis, Pfizer, Roche, Sanofi, Orion, New Oncology.
S. Bracarda: Advisory Board Member for: Bayer, Pfizer, Astellas, BMS, Novartis, Exelixis, Roche. Honoraria: Pfizer, Novartis, Astellas, Bayer, BMS. W. Yu, W. Chan, S. Gendreau, L. Zhang, M.J. Wongchenko, D. Maslyar: Employee and shareholder of Genentech/Roche.
All other authors have declared no conflicts of interest.