BACKGROUND The current single‐arm, open‐label trial was designed to evaluate the activity of apitolisib (GDC‐0980), a dual phosphoinositide 3‐kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor, in patients with advanced endometrial cancer (EC). METHODS Patients with recurrent or persistent EC who were treated with 1 to 2 prior lines of chemotherapy but no prior PI3K/mTOR inhibitor received oral apitolisib at a dose of 40 mg daily during 28‐day cycles until disease progression or intolerable toxicity occurred. Patients with type I/II diabetes who required insulin were excluded. The primary endpoints were progression‐free survival (PFS) at 6 months and objective response rate. RESULTS A total of 56 women were enrolled, including 13 (23%) with well‐controlled diabetes. Reasons for discontinuation were disease progression (24 patients; 43%), adverse events (13 patients; 23%), and withdrawal by subject (12 patients; 21%). Grade 3/4 apitolisib‐related adverse events were hyperglycemia (46%), rash (30%), colitis (5%), and pneumonitis (4%) (toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0). The PFS rate at 6 months was 20% (Kaplan‐Meier estimate; 95% confidence interval 95% CI, 7%‐33%). The objective response rate was 6% (confirmed). The median PFS was 3.5 months (95% CI, 2.7‐3.7 months) and the median overall survival was 15.7 months (95% CI, 9.2‐17.0 months). Nineteen patients discontinued the study before the first tumor assessment. Dose reductions were required for 4 diabetic (31%) and 18 nondiabetic (42%) patients. Comprehensive molecular profiling of 46 evaluable archival tumor samples demonstrated that 57% of patients had at least 1 alteration in phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha (PIK3CA), phosphatase and tensin homolog (PTEN), or AKT1. All 3 patients with a confirmed response had at least 1 alteration in a PI3K pathway gene. CONCLUSIONS The antitumor activity noted with the use of a dose of 40 mg of apitolisib daily was limited by tolerability, especially in diabetic patients. Patients with PI3K pathway mutations may have derived enhanced benefit from apitolisib. Cancer 2016;122:3519–28. © 2016 American Cancer Society. Patients with endometrial cancer with ≥1 alteration in phosphoinositide 3‐kinase (PI3K) signaling components may potentially benefit from a single‐agent dual PI3K/mammalian target of rapamycin (mTOR) inhibitor, apitolisib, if sufficient drug exposure is received. Apitolisib has a relatively narrow therapeutic index, with poor tolerability and limited efficacy. Selective inhibitors of PI3K/mTOR signaling may benefit from patient enrichment via biomarker data. See also pages 3428–9.