Fulvestrant (FUL) plus enzastaurin (ENZA) vs FUL plus placebo (PBO) in aromatase inhibitor (AI)-resistant metastatic breast cancer (MBC): a randomized, double-blind, phase 2 trial

AIs are used as first-line treatment for postmenopausal women with hormone-receptor-positive MBC. Overexpression of PKC α has been linked to AI resistance in several studies. We examined whether Enza, a serine/threonine kinase inhibitor that targets PKC, could improve the effect of Ful in pts who progressed following first-line AI treatment for MBC. Postmenopausal pts with hormone-receptor-positive, HER2-negative, locally advanced or MBC who progressed on prior AI received a loading dose of Ful 500 mg IM on Day (D) 1 and 250 mg on D 15 of Cycle (C) 1 and D 1 of each cycle thereafter. Enza 500 mg or PBO was administered orally once daily (QD) or 250 mg twice daily (BID). Primary endpoint was the clinical benefit rate (CBR). Secondary endpoints were response rate (RR), duration of CB, progression-free survival (PFS) and safety. A total of 156 pts was randomly assigned to therapy; 152 received at least 1 dose of study drug (39 BID; 55 QD; 58 PBO). Baseline disease characteristics were balanced across arms. There was no statistically significant difference in CBR between pts in Ful + Enza vs Ful + PBO. There was no statistically significant difference in CBRs, RRs and PFS between pts on QD and BID dosing schedules. Pts on BID dosing had numerically more TEAEs vs those on QD and PBO (61.5%, 43.6%, and 46.6%, respectively) and numerically more Grade 3/4 TEAEs vs QD and PBO (17.9%, 9.1%, and 5.2%, respectively). Most frequent Grade 3/4 TEAEs in the BID arm were fatigue (n [%]) (4 [10.3%]), dyspnea (2 [5.1%]) and nausea (2 [5.1%]). 8 pts died; 5 due to disease, 3 due to AEs: 1 drug-related hepatic dysfunction (Enza QD arm), 1 non-drug-related myocardial infarction and 1 non-drug-related respiratory failure (both in the Enza BID arm). Addition of Enza to Ful does not improve disease outcome in pts with locally advanced or MBC after progression on AI.