PI3K/AKT pathway biomarkers analysis from the phase III IPATential150 trial of ipatasertib plus abiraterone in metastatic castration-resistant prostate cancer.
Johann S. de Bono, Christopher J. Sweeney, Sergio Bracarda, Cora N. Sternberg, Kim N., David Olmos, Shahneen Sandhu, Christophe Massard, Nobuaki Matsubara, Josep Garcia, Małgorzata Nowicka, Matthew Wongchenko, Zhen Shi
Abstract
13 Background: In IPATential150 (NCT03072238), ipatasertib (ipat) + abiraterone (abi) as first-line treatment for metastatic castration-resistant prostate cancer (mCRPC) significantly reduced the risk for disease worsening or death vs placebo (pbo) + abi in patients (pts) with tumors with PTEN loss by immunohistochemistry (IHC; HR, 0.77 [95% CI: 0.61, 0.98]; P = 0.0335) but not in the intention-to-treat population (de Bono, ESMO 2020). In patients with PTEN loss tumors by IHC, median radiographic progression-free survival (rPFS) was 16.5 mo (95% CI: 13.9, 17.0) with pbo + abi and 18.5 mo (95% CI: 16.3, 22.1) with ipat + abi. Here, we present exploratory analyses evaluating putative biomarker associations with rPFS. Methods: Before randomization, tumor samples ( > 90% archival) were tested for PTEN loss by VENTANA PTEN (SP218) IHC assay (N = 1101). PTEN loss was pre-defined as ≥ 50% of tumor cells with no specific cytoplasmic IHC staining. Exploratory analysis evaluated different IHC staining cutoffs. Tumor genomic alterations were profiled with next-generation sequencing (NGS) using the Foundation Medicine FoundationOne CDx NGS assay (Shi, ASGO-GU 2020; n = 743 evaluable by NGS, of which n = 518 were PTEN evaluable). rPFS was determined by the investigator. Results: Consistent benefit with the combination arm vs pbo + abi was observed when PTEN loss by IHC was defined more stringently (rPFS at ≥ 60% tumor cells with PTEN loss: HR, 0.72 [95% CI, 0.56, 0.92]; ≥ 70%: HR, 0.72 [95% CI, 0.56, 0.93]; ≥ 80%: HR, 0.71 [95% CI, 0.54, 0.92]; ≥ 90%: HR, 0.72 [95% CI, 0.53, 0.97]; 100%: HR, 0.65 [95% CI, 0.39, 1.08]). In contrast, ipat + abi was not associated with improved rPFS in pts with PTEN intact by IHC tumors ( < 50% no staining; stratified HR, 0.91 [95% CI: 0.72, 1.16]); the median rPFS was 19.1 mo (95% CI: 16.4, 21.9) with pbo + abi and 19.7 mo (95% CI: 16.4, 26.3) with ipat + abi. By NGS assessment, pts with tumors with PTEN loss and with genomic alterations in PIK3CA/AKT1/PTEN had a larger magnitude of rPFS benefit with ipat + abi than pts with no detectable alterations (Table). Conclusions: Analyses of more-stringent biomarkers associated with activation of the PI3K/AKT pathway further support ipat + abi as a treatment option for first-line mCRPC with PI3K/AKT pathway alterations, a mCRPC subtype with a worse prognosis. Clinical trial information: NCT03072238. [Table: see text]