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SAN ANTONIO -- Adding a histone deacetylase (HDAC) inhibitor to standard endocrine therapy led to a modest but statistically significant improvement in progression-free survival (PFS) in advanced hormone receptor-positive breast cancer, a randomized trial showed.

Median PFS increased from 3.72 months with exemestane and placebo to 6.32 months with the addition of entinostat. A preliminary analysis of overall survival (OS) showed a trend in favor of adding the HDAC inhibitor, but median survival had yet to be reached in either arm of the study.

The add-on therapy added to toxicity, including a five-fold higher incidence of grade ≥3 treatment-related adverse events, reported Binghe Xu, MD, of the Cancer Hospital of the Chinese Academy of Medical Sciences in Beijing, at the San Antonio Breast Cancer Symposium (SABCS).

"As a class I selective oral HDAC inhibitor, entinostat proved in this pivotal study that combination with aromatase inhibitor showed a PFS benefit with manageable adverse effects in HR [hormone receptor]-positive advanced breast cancer patients who have progressed after prior endocrine therapy," Xu said in conclusion.

The results contrasted with those of a negative study with a similar design reported a year ago at SABCS. That multinational trial showed virtually no improvement in PFS with the addition of entinostat to exemestane and a nonsignificant 2-month improvement in median OS.

Fielding virtually submitted questions following his presentation, Xu noted that few Chinese patients receive CDK4/6 inhibitors for advanced HR-positive breast cancer, whereas CDK4/6 inhibitors have become standard treatment in the United States and most Western nations. That disparity might have contributed to the different outcomes of the two entinostat trials, he explained.

The study populations also differed in several responses, Xu continued. For example, the U.S. study enrolled mostly patients who had aromatase inhibitor failure, whereas the Chinese patient population was more heterogeneous. The U.S. trial required endpoint assessments every 3 months as compared with every 8 weeks in the Chinese study, a difference that could have influenced PFS.

"These are two different studies and it is difficult to compare them head to head," said Xu.

The findings came from a randomized, placebo-controlled, phase III trial to evaluate the nonsteroidal aromatase inhibitor exemestane with or without entinostat in pre- or post-menopausal patients with advanced HR-positive/HER2-negative breast cancer that had progressed on prior endocrine therapy. All patients received exemestane and were randomized 2:1 to the HDAC inhibitor or matching placebo. Treatment continued until disease progression or intolerable toxicity, and the primary endpoint was PFS as assessed by independent review.

Data analysis included 354 randomized patients. The study population had a median age of about 52. Almost 70% had visceral metastases, and 60% had received one or two prior treatments for advanced disease. About a third of the patients had primary endocrine resistance, 6-7% had received a CDK4/6 inhibitor, and a fourth of the patients had prior exposure to fulvestrant.

The primary analysis showed that the addition of entinostat led to a 26% reduction in the hazard for disease progression or death (95% CI 0.58-0.96, P=0.021). A prespecified per-protocol analysis (N=331) showed a median PFS of 7.34 months with entinostat versus 3.72 months with placebo (HR 0.70, 95% CI 0.53-0.91, P=0.009). The early analysis of OS yielded a nonsignificant hazard ratio of 0.75 favoring entinostat (95% CI 0.49-1.15).

The objective response rates were 15.7% with entinostat and 10.1% with placebo, and clinical benefit rates were 37.4% and 32.8%, respectively, with neither outcome achieving statistical significance. Unplanned analyses of disease control rate (DCR) and duration of response (DOR) also favored the addition of entinostat. DCR by independent review was 70.2% with entinostat versus 55.5% with placebo (P=0.007). Median DOR had yet to be reached in the entinostat arm versus 7.47 months with placebo. Investigator-assessed DOR suggested superiority for entinostat (12.96 vs 5.56 months, P=0.013).

Entinostat was associated with increased toxicity, particularly hematologic toxicity. All-grade neutropenia occurred in 73.2% of entinostat-treated patients, leukopenia in 63.8%, thrombocytopenia in 66.8%, and anemia in 21.3%. Grade 3/4 rates of the same hematologic parameters were 43%, 6.4%, 8.5%, and 3.4%. Only grade 3/4 neutropenia occurred substantially more often with entinostat than with placebo (0.8%).

The treatment landscape for advanced HR-positive/HER2-negative breast cancer differs substantially between China and the United States, limiting the applicability of the study findings outside of China, said Neelima Vidula, MD, of Massachusetts General Cancer Center in Boston.

"For hormone receptor-positive breast cancer, we have a number of targeted agents, some of which have very compelling survival data, such as CDK4/6 inhibitors and PIK3C inhibitors," she told 口袋女优. "This agent [entinostat] had a very modest improvement in PFS and no survival benefit. I could see it potentially being used as another option to delay the onset of chemotherapy, but that's really all."

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