Add-On HDAC Inhibitor No Help in Breast Cancer
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Survival in advanced hormone receptor (HR)-positive breast cancer did not improve with the addition of a histone deacetylase (HDAC) inhibitor to standard endocrine therapy, according to a randomized trial.

Median progression-free survival (PFS) improved from 3.1 to 3.3 months and median overall survival (OS) from 21.7 to 23.4 months among patients who received entinostat plus the aromatase inhibitor (AI) exemestane. Neither difference reached statistical significance, despite a significant increase in lysine acetylation, which correlated in improved PFS in an earlier trial of the HDAC inhibitor.

“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,” reported Roisin M. Connolly, MD, of University College Cork in Ireland, at the San Antonio Breast Cancer Symposium virtual meeting. “Pharmacogenomic analysis confirmed target inhibition in entinostat-treated patients.”

“Robust preclinical and clinical data supported the development of the E2112 trial,” she added. “The results highlight the importance of phase III confirmation of promising phase II data.”

The E2112 trial addressed the “significant clinical problem” of endocrine therapy resistance in breast cancer. In a preclinical model, entinostat overcame letrozole resistance.

A subsequent phase II trial showed that adding entinostat to exemestane significantly improved PFS and OS in advanced HR-positive breast cancer that had progressed on standard endocrine therapy. Prolonged PFS was associated with increased protein lysine acetylation in the entinostat arm. Additionally, a phase III trial conducted in China showed a significant increase in median PFS when the HDAC inhibitor tucidinostat was paired with exemestane.

Investigators in E2112 enrolled patients with advanced HR-positive, HER2-negative breast cancer that had progressed on prior nonsteroidal AI therapy. Pre- and postmenopausal women could participate, as could men. Patients were randomized to exemestane plus entinostat or placebo, and treatment continued until disease progression. Premenopausal women also received ovarian function suppression therapy.

The primary endpoints were PFS (by central assessment) and OS, and secondary endpoints included safety, objective response rate (ORR), and the prognostic value of lysine acetylation. Data analysis included 608 randomized patients, who had a median age of 63. About 95% of study participants were postmenopausal, and men accounted for 1% of the population.

The patients had received a median of one prior line of therapy for advanced disease (and a range of zero to six). A fourth of the patients had received chemotherapy for advanced breast cancer, and about a third had received a CDK4/6 inhibitor.

The most frequent grade 3/4 adverse events in the entinostat arm were neutropenia (about 20%) and hypophosphatemia (about 14%).

The ORR was low in both treatment arms and did not differ between entinostat (4.6%) and placebo (4.3%). Analysis of PFS yielded a 0.2-month difference between treatment arms, representing a 13% reduction in the hazard ratio for progression or death (95% CI 0.67-1.13). The 1.7-month difference in OS translated into an HR of 0.99 (95% CI 0.82-1.21).

Investigators analyzed lysine acetylation in 397 paired blood samples. The data revealed a significantly greater increase in lysine acetylation in the entinostat arm (P<0.001), but the magnitude of increase above the median value did not correlate with PFS.

Responding to a question from the virtual audience, Connolly said, “The results speak for themselves. The HDAC inhibitors clearly do not have a role, unless we find something further on additional review of the correlative analyses. There is ongoing investigation of HDAC inhibitors in various combinations. They’ve been combined with chemotherapies and other targeted therapies over the years, but unfortunately have not broke into the solid tumor space. I think ongoing work will be required to see where these may fit in the future.”

Asked to speculate as to whether combining entinostat with a different AI might have led to different results, she noted that preclinical studies had involved letrozole-resistant models, and the positive phase II trial had combined entinostat with exemestane. “It’s possible that we may have seen different results with a different AI, but I think it’s unlikely.”

  • Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007. Follow

Disclosures

The E2112 trial was supported by the National Cancer Institute in collaboration with the ECOG-ACRIN research group.

Connolly disclosed relevant relationships with Genentech, Merck, Novartis, Macrogenics, Puma Biotechnology, and Pfizer.

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