A Comprehensive Monograph on Onapristone (DB12637): An Investigational Progesterone Receptor Antagonist

Executive Summary

Onapristone (DrugBank ID: DB12637) is an investigational, orally bioavailable, synthetic steroidal small molecule classified as a Type I, or "pure," competitive antagonist of the progesterone receptor (PR). First described in 1984, its initial development for breast cancer and as an endometrial contraceptive showed significant promise. However, this was abruptly halted during Phase III trials in 1995 due to an unacceptable incidence of severe hepatotoxicity associated with the immediate-release (IR) formulation.

The compound was later revived based on the pharmacokinetic hypothesis that the liver toxicity was driven by high peak plasma concentrations ($C_{max}$). This led to the development of an extended-release (ER) formulation, ONA-XR, designed to lower $C_{max}$ while maintaining therapeutic drug exposure. Recent clinical investigations with ONA-XR have successfully demonstrated a markedly improved safety profile, with no definitive cases of drug-induced liver injury meeting Hy's Law criteria.

Despite this pharmaceutical success, the clinical efficacy of ONA-XR has been modest. While a Phase 0 study in early breast cancer (ONAWA) confirmed its antiproliferative biological activity, a Phase II trial in heavily pre-treated metastatic breast cancer (SMILE) failed to demonstrate any objective responses. More promising signals have emerged from combination therapy, particularly in the Phase II OATH trial, where Onapristone plus anastrozole showed encouraging activity in heavily pre-treated endometrial cancer.