Activation of the AKT pathway and outcomes in patients (pts) treated with or without ipatasertib (ipat) in metastatic castration-resistant prostate cancer (mCRPC): Next-generation sequencing (NGS) data from the phase III IPATential150 trial.

5056 Background: Ipat + abiraterone (abi) significantly reduced the risk of radiographic disease progression vs placebo (pbo) + abi in pts with mCRPC and PTEN loss tumors by immunohistochemistry (IHC; HR, 0.77; 95% CI: 0.61, 0.98; P=0.034) but not in ITT pts (HR, 0.84; 95% CI: 0.71, 0.99; P=0.043; Sweeney Lancet 2021). A greater risk reduction was seen in pts with PTEN loss by NGS (HR, 0.65; 95% CI: 0.45, 0.95). We describe the efficacy and safety of pbo + abi vs ipat + abi at the second interim analysis (IA) of overall survival (OS) and explore the impact of AKT pathway alterations. Methods: Pts with mCRPC were randomized 1:1 to ipat (400 mg/d) + abi (1000 mg/d) + prednisone (5 mg bid) or pbo + abi + prednisone. Coprimary endpoints were investigator-assessed radiographic progression-free survival by Prostate Cancer Working Group 3 (PCWG3) criteria in pts with PTEN loss tumors by IHC (PTEN loss in ≥50% of tumor cells) and in ITT pts. Secondary endpoints in both populations included OS, objective response rate (ORR) per RECIST 1.1 and PCWG3 and time to pain progression (TPP). Ad hoc analyses assessed pts with PIK3CA/ AKT1/ PTEN alterations by NGS vs wildtype (WT). Results: Median follow-up was 31 mo (cutoff: 2021 Sept 30). In PTEN loss by IHC pts, median OS was 35.8 mo (n=261) with pbo + abi and 36.8 mo (n=260) with ipat + abi (HR: 0.95; 95% CI: 0.74, 1.21; P=0.665); in ITT pts, median OS was 36.7 mo (n=554) with pbo + abi and 40.3 mo (n=547) with ipat + abi (HR: 0.90; 95% CI: 0.76, 1.07). With longer follow-up, the safety profile was consistent with that of the primary analysis. In the full NGS evaluable population (n=743), ipat + abi was associated with better outcomes in pts with PIK3CA/ AKT1/ PTEN alterations (Table). Among pts with PTEN loss tumors by NGS (205 of the evaluable 518 pts), median OS was 29.8 mo (n=102) with pbo + abi and 35.8 mo (n=103) with ipat + abi (unstratified HR: 0.82; 95% CI: 0.56, 1.19). Conclusions: At the second IA, no significant improvement in OS was observed with ipat + abi in pts with PTEN loss by IHC. Exploratory analyses in pts with PIK3CA/ AKT1/ PTEN alterations by NGS suggest that these patients have poorer prognosis but may derive greater benefit from ipat + abi. Clinical trial information: NCT03072238. [Table: see text]