Pooled analysis of onapristone extended release (ONA ER) in metastatic cancer patients (pts): A review of liver safety.

Abstract

e14647 Background: ONA, a type I progesterone receptor (PR) antagonist, prevents PR activation by disrupting PR dimerization and DNA binding, and inhibits tumor progression. ONA (immediate release) has efficacy comparable to other endocrine therapies in pts with metastatic breast cancer (BC). The only notable toxicity was transient elevation in liver chemistries in some pts. In 2 clinical trials, ONA ER was given to 88 cancer pts who underwent frequent liver chemistry monitoring. Methods: We pooled and reviewed all liver safety data from 2 trials. A hepatologist (PBW) reviewed all pts with either a hepatobiliary SOC AE or who experienced an elevation > ULN of any liver-related laboratory test. Results: Of 88 pts who received ONA ER for a median 8 weeks (3-51), 59% were female, median age 68 (36-89), 99% Caucasian, 28% had liver metastases (mets), 48% bone mets and 17% also took abiraterone (ABI), which has liver toxicity. 54 pts (61%) experienced any ONA ER-related AE. More AEs were seen in ABI pts (67%), those with liver mets (72%) and BC (76%).. In terms of liver-related TEAEs, overall 10% of pts had ALT and 13% AST elevations, while 20% pts with liver mets had raised ALT/AST and 29% of BC pts. Overall 15% pts had G3 TEAEs, compared to 28% pts with liver mets, mostly due to increased GGT (24%), which has unclear clinical impact. There were no discontinuations for LFT elevations. A relationship between the liver events and ONA ER was judged to be unlikely in each subject, except one. This event was detected at day 29 of treatment and consisted of a marked rise in serum GGT and alkaline phosphatase with only a moderate rise in serum ALT (peak – 262). These abnormalities improved quickly after stopping ONA but recurred on reintroduction: these events are not serious by international criteria and the pt was able to continue ONA at a lower dose for 40 weeks without recurrence Conclusions: The safety experience for ONA ER has been reassuring but must continue to be characterized. For new ONA ER studies, weekly liver chemistry monitoring is planned for the first 4 weeks with Q2W monitoring thereafter. The occasional G3 elevations in serum AST, ALT or bilirubin will prompt interruption, but re-starting treatment at a lower dose should be possible for most pts. Clinical trial information: NCT02052128 and NCT02049190.