PD01-04: Entinostat, a Novel Histone Deacetylase Inhibitor, Added to Exemestane Improves PFS in Advanced Breast Cancer in a Randomized, Phase II, Double-Blind Study.

Abstract

Abstract Background: Entinostat is a novel, oral, class I-selective histone deacetylase inhibitor (HDACi) that has been shown pre-clinically to inhibit mechanisms of aromatase inhibitor (AI) resistance through epigenetically driven down-regulation of activated growth factor signaling pathways and normalization of estrogen receptor levels. This provided a strong rationale for the entinostat breast cancer (BC) program, which was designed to evaluate entinostat's ability to increase and/or restore sensitivity to treatment with an AI. Methods: Postmenopausal women with ER+ advanced BC who had ≤ 1 prior chemotherapy and had progressed on a non-steroidal AI were randomized 1:1 to exemestane 25 mg daily + entinostat 5 mg or placebo weekly. Progression free survival (PFS) was the primary endpoint; objective response rate and clinical benefit rate were secondary endpoints and overall survival (OS) was an exploratory endpoint. Prospectively defined subsets of interest included patients with “AI-sensitive and AI-resistant disease”. AI-sensitive was defined as having had a PR, CR or SD for ≥6 months (mos) in the metastatic setting or having completed and remained disease free for ≥12 months post adjuvant therapy. All others were considered AI-resistant. Treatment continued until disease progression or unacceptable toxicity. Response assessments were performed every 8 weeks. Results: 130 women were enrolled (64 exemestane+entinostat [E+E]; 66 exemestane+placebo [E+P]. All but 1 patient had Stage IV disease. 82% had measurable disease, of which 60% had visceral involvement. 42% had 1 prior line of hormonal therapy; 58% had >1. Analysis of the intent-to-treat (ITT) population showed significantly (defined prospectively as p<0.10) longer PFS with E+E than with E+P (median 4.28 vs 2.27 mos, respectively; hazard ratio [HR] = 0.73; p=0.06) (CI 0.49, 1.09). While not powered, results for pre-defined subsets were consistent with improved PFS in the E+E arm. Interestingly, the subset of patients identified as AI-resistant, demonstrated a HR of 0.61 (CI 0.30, 1.25) (median 3.72 vs. 1.78 mos). While OS is still early, at 18 mos median follow-up at time of abstract submission, the E+E arm demonstrated a median OS of 26.94 mos compared to the E+P arm of 20.33 mos (HR = 0.56) (CI 0.31, 1.02). Entinostat combined with exemestane was well tolerated. The most frequent adverse events (AEs) were fatigue, gastrointestinal disturbances, and hematologic abnormalities. AEs with a ≥ 20% higher incidence with E+E than E+P were fatigue (46% vs 26%) and uncomplicated neutropenia (25% vs 0%). Serious AE rate was similar for both arms (13% vs 12%). Conclusions: Adding entinostat to exemestane resulted in improved PFS, the study's primary endpoint. At a median follow-up of 18 mos, the exploratory endpoint of OS was also increased in the E+E arm. Importantly for a phase II study, the PFS benefit in all subsets evaluated was consistent with the overall improvement seen in the ITT. These data demonstrate that the addition of entinostat to AI therapy may prolong the duration of AI therapy, thereby delaying the initiation of subsequent therapies such as chemotherapy, a goal for many breast cancer patients. A phase III study is planned. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD01-04.