Onapristone Extended Release: Safety Evaluation from Phase I–II Studies with an Emphasis on Hepatotoxicity

Abstract

Introduction Antiprogestins have demonstrated promising activity against breast and gynecological cancers, but liver-related safety concerns limited the advancement of this therapeutic class. Onapristone is a full progesterone receptor antagonist originally developed as an oral contraceptive and later evaluated in phase II studies for metastatic breast cancer. Because of liver enzyme elevations identified during clinical studies, further development was halted. Evaluation of antiprogestin pharmacology and pharmacokinetic data suggested that liver enzyme elevations might be related to off-target or metabolic effects associated with clinical drug exposure. Objective We explored whether the use of a pharmaceutic strategy targeting efficacious systemic dose concentrations, but with diminished peak serum concentrations and/or total drug exposure would mitigate hepatotoxicity. Twice-daily dosing of an extended-release formulation of onapristone was developed and clinically evaluated in light of renewed interest in antiprogestin therapy for treating progesterone receptor-positive breast and gynecologic cancers. The hepatotoxic potential of extended-release onapristone was assessed from two phase I–II studies involving patients with breast, ovarian, endometrial, and prostate cancer. Results Among the 88 patients in two phase I–II studies in progesterone receptor-positive malignancies treated with extended-release onapristone, elevated alanine aminotransferase/aspartate aminotransferase levels were found in 20% of patients with liver metastases compared with 6.3% without metastases. Of five patients with grade 3 or higher alanine aminotransferase elevations with or without bilirubin elevations (four with breast cancer and one with endometrial cancer), four were assessed as unrelated to extended-release onapristone by the safety data review committee. Furthermore, while the fifth patient’s liver enzyme elevations were considered possibly drug related by the study investigator, they were adjudicated as unlikely to be related (< 25% likelihood) by a subsequent independent hepatologist. Conclusions These results suggest that the extended-release formulation by reducing drug exposure may be associated with a reduced risk of hepatotoxicity, and supports the continued clinical evaluation of extended-release onapristone for treating progesterone receptor-positive cancers.

Clinical Significance of Transient Asymptomatic Elevations in Aminotransferase (TAEAT) in Oncology

“…For example, despite having no obvious liver involvement in AML, autopsy reports indicated hepatic infiltration in >75% of patients 107. In addition, higher rates of elevated aminotransferases (>5×ULN) were reported in patients treated with onapristone with bone (2.4% to 4.8%) or liver (4.0%to 12.0%) metastases compared with those without these metastases (0.0% to 4.3% and 0.0% to 1.6%, respectively) 108. Similarly, aminotransferases were significantly elevated in patients with solid tumors and liver metastasis versus those without metastases 109–111.…”

“…107 In addition, higher rates of elevated aminotransferases ( > 5×ULN) were reported in patients treated with onapristone with bone (2.4% to 4.8%) or liver (4.0%to 12.0%) metastases compared with those without these metastases (0.0% to 4.3% and 0.0% to 1.6%, respectively). 108 Similarly, aminotransferases were significantly elevated in patients with solid tumors and liver metastasis versus those without metastases. [109][110][111] In contrast, a pooled analysis of 31 phase 2 and 3 oncology trials found that the incidence of ALT and AST elevations was generally similar in patients with or without liver metastases.…”

Drug-Induced Liver Injury: Highlights and Controversies in the Recent Literature

“…However, concerns about DILI related to its use led to its discontinuation from further development by the original sponsor [132]. In a recent study evaluating 88 patients from phase I-II studies who received twice-daily dosing of onapristone, the authors found elevations in AST/ ALT in 20.0% of subjects with known liver metastases, compared with only 6.0% for ALT and 9.5% for AST for patients without known liver metastases [133]. The one patient with a grade 3-4 ALT elevation and three of four patients with grade 3-4 AST elevations had liver metastases were assessed as being more likely related to liver metastases by the data review committee, rather than DILI.…”

“…While the sample size is small, this would suggest that onapristone-related DILI is less common than previously suggested. Therefore, it was concluded that further development and collection of safety data should continue in the planned phase II-III studies of onapristone in order to adequately characterize the hepatic safety profile [133].…”

StackPR is a new computational approach for large-scale identification of progesterone receptor antagonists using the stacking strategy

“…Similarly, concerns regarding hepato-cytotoxicity have limited the advancement of onipristone, a full progesterone antagonist, despite promising activity against breast and gynecological cancers. The clinical trial with onipristone is currently being re-evaluated with a lower drug dosage 32 . In this regard, there appears to be particular promise in developing newer PR antagonists.…”