Author: By Lynda Williams, Senior medwireNews Reporter
medwireNews: The addition of entinostat to exemestane therapy for hormone receptor (HR)-positive advanced breast cancer after progression on a nonsteroidal aromatase inhibitor (AI) in the E2112 study did not significantly improve patient survival.
Roisin Connolly, from University College Cork in Ireland, reported the phase III trial results during the 2020 San Antonio Breast Cancer Symposium.
Noting that the findings do not bear out the results of the phase II ENCORE301 study of the selective oral class I histone deacetylase (HDAC) inhibitor, the presenter commented that the E2112 results “highlight the importance of phase III confirmation of promising phase II data.”
The E2112 findings also “differ from those of the multicentre ACE trial where a modest PFS [progression-free survival] advantage was observed with the addition of the HDAC inhibitor chidamide […] to exemestane in a Chinese population”, she added.
The study included patients who had received no more than one line of chemotherapy for metastatic HR-positive, HER2-negative breast cancer and had progressed while using a nonsteroidal AI in the adjuvant or advanced setting, and around a third of patients had previously received a CDK4/6 inhibitor.
The patients were aged a median of 63 years, the majority were White, female and postmenopausal, and all had an ECOG performance status of 0 or 1.
The co-primary endpoint of median PFS, determined after 247 events had occurred in 360 patients, was a comparable 3.3 months for the 180 patients who were randomly assigned to receive entinostat 5 mg/week alongside exemestane 25 mg/day and 3.1 months for the 180 patients instead given placebo with exemestane.
The overall response rate in the two groups was also similar in the entinostat and placebo arms, at 4.6% versus 4.3%, as was the co-primary endpoint of overall survival, at a median of 23.4 versus 21.7 months.
“The short median progression-free survival and low overall response rate observed with an endocrine therapy backbone suggests that improved decision-making tools are required to help determine who may need chemotherapy versus alternative strategies in this setting”, commented Roisin Connolly.
The patients given entinostat had a significantly greater increase in lysine acetylation by day 15 of their first cycle of treatment than their placebo-treated counterparts, “confirming target inhibition”, the investigator said, but this increase did not translate to a significant increase in median PFS.
She added that the patients in both arms received a median three cycles of treatment and that dose reduction was required by 30% of entinostat-treated patients versus 3% of controls. Entinostat was also associated with a higher grade 3 incidence of neutropenia (19 vs <1%) and hypophosphatemia (13 vs 1%) than placebo.
Roisin Connolly concluded that additional correlative and patient-reported outcome data analyses are now ongoing.
Abstract GS4-02. Connolly RM, Zhao F, Miller KD, et al. E2112: Randomized phase 3 trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer. A trial of the ECOG-ACRIN cancer research group. 2020 San Antonio Breast Cancer Symposium; 8–11 December.
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