Entinostat-exemestane combo yields survival benefit for HR+ advanced BC

In women with hormone-receptor positive advanced breast cancer (HR+ aBC), the addition of the class I selective histone deacetylase (HDAC) inhibitor entinostat to exemestane appeared to be better than treatment with exemestane alone in terms of survival benefit, according to a phase III trial from China.

“[The] disruption of oestrogen-mediated signalling within the breast cancer cell results in acquired resistance to hormone therapy. Entinostat is targeted to re-sensitize these cells to endocrine therapy,” said Dr Binghe Xu from the Cancer Hospital Chinese Academy of Medical Sciences, Beijing, China at SABCS 2021.

A total of 354 pre- or postmenopausal women with aBC (median age 52 years) who have progressed on previous endocrine therapy were included in the analysis. About 70 percent of participants had visceral metastases, ~40 percent had previous chemotherapy, and about a third had primary endocrine resistance. Participants were randomized 2:1 to receive exemestane 25 mg daily, in combination with either oral entinostat 5 mg QW or placebo. Treatment continued until disease progression or intolerable toxicity. [SABCS 2021, abstract GS1-06]

In the full analysis set, progression-free survival (PFS) was significantly better in the entinostat vs the placebo arm (median, 6.32 vs 3.72 months; hazard ratio [HR], 0.74, 95 percent confidence interval [CI], 0.58–0.96; p=0.021).

“Entinostat demonstrated an even better performance in the per protocol set,” noted Xu. This was evident in the median PFS of 7.34 months with entinostat, as opposed to the 3.72 months observed with placebo (HR, 0.70, 95 percent CI, 0.53–0.91; p=0.009).

Entinostat also fared better than placebo in terms of investigator-assessed clinical beneficial rate (45.1 percent vs 31.9 percent; p=0.022), disease control rate (71.9 percent vs 60.5 percent; p=0.040), and duration of response (12.96 vs 5.56 months; p=0.013).

Subgroup* analyses also consistently favoured entinostat over placebo, with HRs ranging between 0.56 and 0.87.

In terms of overall safety, there was a higher incidence of grade 3–5 adverse events (AEs) related to entinostat/exemestane compared with placebo (62 percent vs 13 percent).

The most common grade 3/4 AEs associated with entinostat treatment were haematologic toxicities, such as neutropenia (44 percent), leukopenia (6 percent), and thrombocytopenia (9 percent). “[Nonetheless, these] were mostly asymptomatic and manageable through supportive care,” said Xu. The corresponding rates in the placebo arm were low at 0.8, 0, and 0.8 percent, respectively.

“[Taken together,] this pivotal study proved that [combining] the class I selective oral HDAC inhibitor entinostat with an aromatase inhibitor showed PFS benefit, with manageable adverse effects in HR+ aBC patients who have progressed after prior endocrine therapy,” Xu concluded.