Background: mCRPC commonly has hyperactivated PI3K/Akt signaling, usually via PTEN loss; androgen receptor (AR) blockade activates Akt, supporting mCRPC cell survival. We hypothesized that co-inhibition of Akt with Ipatasertib (Ipat), a potent novel oral ATP-competitive inhibitor of Akt, and of AR by Abi would improve outcome in mCRPC. Methods: Patients (pts) with mCRPC, previously treated with docetaxel, were double-blinded randomized 1:1:1 to three arms: Ipat-400, Ipat-200, or placebo (pbo), all in combination with Abi 1000 mg and prednisone 10 mg, daily (NCT01485861). Pts were stratified by prior enzalutamide (yes or no), number of chemotherapies (one vs more), and progression by PSA only vs other. Primary endpoint was radiographic progression-free survival (rPFS), with key secondary endpoint of overall survival (OS). Exploratory endpoints included assessment of the effect of PI3K/Akt pathway alterations in archival tumor tissue on rPFS. Results: 253 patients (pts) were randomized with 173 rPFS events (68%) at the primary analysis. Compared to pbo, Ipat-400 showed increased rPFS (median 8.2 vs 6.4 m; HR = 0.75; p= 0.17) with consistent trends in subgroup analyses. At 41% OS events, analysis showed an increased OS for Ipat-400 vs pbo (median 18.9m vs 15.6m; HR = 0.72; p= 0.22). Results for the Ipat-200 vs pbo showed less robust HR (rPFS HR = 0.94, p= 0.75; OS HR = 0.96, p= 0.87) - a potential dose effect for this combination. mCRPC with PTEN loss had superior rPFS benefit from Ipat-400 over pbo. AEs more common with Ipat were generally consistent with PI3K/Akt pathway inhibitor class and included diarrhea, nausea, vomiting, asthenia, rash, decreased appetite, and hyperglycemia. These AEs were dose-dependent, manageable, and reversible with Abi dose intensity maintained. Conclusions: This study provides evidence that Ipat in combination with Abi may improve rPFS and OS in pts with mCRPC post docetaxel, with potentially increased benefit in patients with decreased PTEN expression. Clinical trial information: NCT01485861