Tucidinostat plus exemestane for advanced, HR+ breast cancer aces phase III trial
The histone deacetylase (HDAC) inhibitor tucidinostat, when used in combination with exemestane for treating patients with advanced, HR-positive, HER2-negative breast cancer, prolongs progression-free survival (PFS) and substantially increases overall response and clinical benefit, while having a manageable safety profile, as shown in the results of the phase III ACE trial.
“Primary and secondary drug resistance to endocrine therapy remains a major challenge in the treatment of hormone receptor-positive breast cancer. Epigenetic modulation plus endocrine blockade with tucidinostat and exemestane is a feasible and adequately tolerated strategy against drug resistance and relapse in advanced breast cancer,” according to the investigators.
ACE randomly assigned 365 patients (median age, 55 years) who had relapsed or progressed after at least one endocrine therapy (either in advanced or metastatic or adjuvant setting) to treatment with either 30-mg oral tucidinostat (n=244) or placebo (n=121) twice weekly in addition to 25-mg oral exemestane daily. Endocrine therapy was not necessarily the most recent therapy before randomization, but all patients experienced recurrence or progression after their most recent therapy.
During a median follow-up of 13.9 months, treatment with tucidinostat yielded a substantial improvement in the primary endpoint of investigator-assessed PFS compared with placebo (median, 13.9 vs 7.4 months). On Cox proportional hazards analysis, the active drug cut the risk of death or progression by 25 percent (hazard ratio, 0.75, 95 percent CI, 0.58–0.98; p=0.033). [Lancet Oncol 2019;20:806-815]
Furthermore, significantly more patients in the tucidinostat vs placebo arm showed an objective response (18 percent vs 9 percent; p=0;026) and experienced clinical benefit (47 percent vs 36 percent; p=0.034). Results for overall survival were not mature at the data cutoff date.
In terms of safety, the most common grade 3 or 4 adverse events (AEs) included neutropoenia (51 percent with tucidinostat vs 2 percent with placebo), thrombocytopaenia (27 percent vs 2 percent) and leukopaenia (19 percent vs 2 percent). Serious AEs also occurred more frequently with the HDAC inhibitor (21 percent vs 6 percent). There were no treatment-related deaths recorded.
The present data suggest that the tucidinostat–exemestane combination could be a new treatment option for postmenopausal women with advanced HR-positive, HER2-negative breast cancer that has progressed after previous endocrine therapy, the investigators said.
In a linked editorial, Dr Aditya Bardia and colleagues from the Massachusetts General Hospital agreed that HDAC inhibitors could emerge as a new therapeutic tool in the rapidly evolving landscape of targeted therapies for the said population. [Lancet Oncol 2019;20:746-748]
“Overall, the results of the ACE trial represent an important step forward in the development of epigenetic therapy for endocrine-resistant breast cancer [and] provide important insight into the potential of epigenetic targeting to overcome antioestrogen resistance,” Bardia and colleagues wrote.
Nevertheless, additional studies have to be conducted before HDAC inhibitors can be incorporated into routine clinical practice, they added.