Randomized Phase II Study of Akt Blockade With or Without Ipatasertib in Abiraterone-Treated Patients With Metastatic Prostate Cancer With and Without PTEN Loss

Purpose: PI3K-Akt-mTOR and AR signaling are commonly aberrantly activated in metastatic castration-resistant prostate cancer (mCRPC), with PTEN loss associating with poor prognosis. We therefore conducted a phase 1b/2 study of the combination of ipatasertib, an Akt inhibitor, with the CYP17 inhibitor abiraterone in patients with mCRPC. Experimental Design: Patients were randomized 1:1:1 to ipatasertib 400 mg, ipatasertib 200 mg, or placebo, with abiraterone 1000 mg twice daily orally. Co-primary efficacy endpoints were radiographic progression-free survival (rPFS) in the intent-to-treat population and in patients with PTEN-loss tumors. Results: rPFS was prolonged in the ipatasertib cohort vs placebo, with similar trends in overall survival and time-to-PSA progression. A larger rPFS prolongation for the combination was demonstrated in PTEN-loss tumors vs those without. The combination was well tolerated, with no treatment-related deaths. Conclusion: In mCRPC, combined blockade with abiraterone and ipatasertib showed superior antitumor activity to abiraterone alone, especially in patients with PTEN-loss tumors.

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