Background:PIK3CA mutations frequently occur in breast cancer (BC), being present in ∼40% of estrogen receptor (ER)-positive, HER2-negative breast tumors. PIK3CA mutations promote growth and proliferation of tumors and mediate resistance to endocrine therapies in BC. Taselisib is a potent and selective PI3-kinase (PI3K) inhibitor that displays greater selectivity for mutant PI3Kα than wild-type PI3Kα through a unique mechanism. In cell studies, taselisib preferentially degraded mutant compared with wild-type PI3Kα, which was not seen with alpelisib and pictilisib. Taselisib has enhanced activity against PIK3CA-mutant BC cell lines, and clinical data include confirmed partial responses in patients with PIK3CA-mutant BC treated with taselisib either as a single agent or in combination with fulvestrant.

Trial design: SANDPIPER is a double-blinded, placebo-controlled, randomized, phase III study, designed to evaluate efficacy and safety of taselisib plus fulvestrant in patients with ER-positive, HER2-negative locally advanced or metastatic BC. Patients will be randomized 2:1 to receive either taselisib (4 mg daily) or placebo plus fulvestrant (500 mg intramuscular on Days 1 and 15 of Cycle 1, and on Day 1 of each subsequent 28-day cycle). Randomization will be stratified by visceral disease, endocrine sensitivity, and geographic region. The study enriches for patients with PIK3CA-mutant tumors who will be randomized separately from those with non-mutant tumors.

Eligibility: Postmenopausal women with ER-positive, HER2-negative, locally advanced or metastatic BC are eligible if they have disease recurrence or progression during or after aromatase inhibitor treatment. A valid cobas® PIK3CA Mutation Test result via central assessment is required prior to enrollment.

Aims: The primary efficacy endpoint is investigator-assessed progression-free survival (PFS) in patients with PIK3CA-mutant tumors. Additional endpoints include overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), duration of objective response, safety, pharmacokinetics, and patient-reported outcomes.

Statistical methods: The primary efficacy analysis population will include all randomized patients with PIK3CA-mutant tumors. Patients will be grouped according to randomized treatment arm. Median PFS and OS will be estimated using Kaplan–Meier methodology. Cox proportional-hazards models, stratified by the stratification factors, will be used to estimate the hazard ratio with 95% confidence intervals (CIs). ORR, CBR, and their 95% CIs will be estimated. Duration of objective response will be estimated using Kaplan–Meier methodology. Quality of life will be analyzed and summarized. Safety will be analyzed for all treated patients according to actual treatment received.

Accrual: Target enrollment is 600 patients. The study is open for enrollment and, as at April 2016, over 200 patients have been enrolled. Clinicaltrials.gov ID: NCT02340221.

Contact information: For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only).

Citation Format: Baselga J, Cortés J, De Laurentiis M, Dent S, Diéras V, Harbeck N, Hsu J, Jin H, Schimmoller F, Wilson TR, Im Y-H, Jacot W, Krop IE, Verma S. SANDPIPER: Phase III study of the PI3-kinase inhibitor taselisib (GDC-0032) plus fulvestrant in patients with estrogen receptor-positive, HER2-negative locally advanced or metastatic breast cancer enriched for patients with PIK3CA-mutant tumors [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-01.