Apatorsen

Bellmunt J, et al. Annals of Oncology, 2017, 28(10), 2481-2488.

Apatorsen, an inhibitor of heat shock protein 27 (Hsp27), represents an innovative approach to overcoming chemoresistance in advanced urothelial carcinoma. Hsp27, a molecular chaperone, is implicated in tumor survival pathways, including apoptosis inhibition and resistance to stress-induced damage. By suppressing Hsp27, apatorsen aims to enhance the efficacy of standard chemotherapeutic regimens.
In a phase II, placebo-controlled trial involving 183 patients with inoperable urothelial carcinoma, apatorsen was evaluated in combination with gemcitabine and cisplatin (GC). Participants received GC alongside either placebo, 600 mg, or 1000 mg of apatorsen, followed by maintenance monotherapy for responders. The primary endpoint was overall survival (OS).
The study found no significant OS improvement in the overall apatorsen-treated population compared to placebo (hazard ratios of 0.86 and 0.90 for 600 mg and 1000 mg doses, respectively). However, exploratory analyses indicated a potential benefit in patients with poor prognostic features, with a 28% reduction in mortality risk observed in the 600 mg apatorsen group (HR = 0.72). Additionally, lower serum Hsp27 (sHsp27) levels correlated with improved outcomes, suggesting its utility as a biomarker. Patients achieving reduced sHsp27 levels in both treatment arms exhibited hazard ratios of 0.45 and 0.62, respectively.