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.

Pharmacokinetically, Onapristone is characterized by high plasma protein binding (99.5%) and metabolism primarily via cytochrome P450 3A4 (CYP3A4), an enzyme it also inactivates, creating a high potential for drug-drug interactions. As of April 2023, the most recent developer, Context Therapeutics, ceased internal development of ONA-XR and is exploring strategic options, effectively halting its progression. Onapristone remains an unmarketed investigational agent. Its history serves as a compelling case study on the ability of formulation science to overcome critical safety issues, but also underscores the formidable challenge of demonstrating compelling clinical efficacy in the modern oncology landscape, even with a mechanistically sound and safer compound.

Introduction and Developmental History: A Cycle of Promise and Setback

The trajectory of Onapristone's development is a multi-decade narrative characterized by initial scientific promise, a critical safety failure, and a subsequent, scientifically driven revival that ultimately faced new challenges. This history provides crucial context for its current status and future potential.

Initial Development and Discontinuation

Onapristone was first developed by Schering and described in the scientific literature in 1984.[1] As a potent and highly selective antiprogestin, it was initially investigated for clinical use in hormone-sensitive conditions, most notably for the treatment of breast cancer and as a potential endometrial contraceptive.[1] Early clinical studies with an immediate-release (IR) formulation were encouraging, demonstrating clear anti-tumor activity and establishing proof-of-concept in breast cancer patients.[2]

However, the program was abruptly terminated during Phase III clinical trials in 1995. This decision was precipitated by the discovery that a majority of patients treated with the IR formulation developed significant liver function abnormalities.[1] The hepatotoxicity was considered severe enough to render the risk-benefit profile unacceptable, leading to the cessation of all development activities and shelving of the compound for over a decade.

Rationale for Redevelopment: The Extended-Release Formulation

Years after its discontinuation, a re-evaluation of Onapristone's pharmacology and pharmacokinetic (PK) data led to a new hypothesis regarding the cause of the observed hepatotoxicity. The prevailing theory was that the liver injury was not an intrinsic property of the molecule itself but rather an off-target effect related to the very high peak plasma concentrations ($C_{max}$) achieved with the IR formulation.[2] This hypothesis provided a clear scientific rationale for reviving the drug: if the $C_{max}$ could be reduced while maintaining a therapeutically effective total drug exposure (Area Under the Curve, or AUC), the drug's therapeutic index might be dramatically improved.

This led to a deliberate pharmaceutical reformulation program. The result was the creation of an extended-release (ER) oral tablet, known as ONA-XR, designed specifically to slow the rate of drug absorption. The intended PK profile of ONA-XR was a blunted $C_{max}$ and a more sustained plasma concentration over a longer period, allowing for effective twice-daily (BID) dosing and continuous suppression of the progesterone receptor while avoiding the sharp peaks associated with the original IR formulation.[6]

Recent Development and Current Status

With the new ER formulation in hand, Onapristone re-emerged in the clinical landscape under the stewardship of companies including Arno Therapeutics and, more recently, Context Therapeutics.[12] A new wave of clinical trials was initiated to evaluate ONA-XR in a variety of progesterone receptor-positive (PR+) cancers, including prostate, endometrial, breast, and ovarian cancers.[1]

This modern development phase successfully validated the core hypothesis of the reformulation strategy, demonstrating a significantly improved safety profile, particularly with respect to hepatotoxicity. However, the clinical efficacy results were mixed, and the program encountered challenges with slow patient accrual in some trials.[15] In a decisive turn of events, Context Therapeutics announced in April 2023 that it was ceasing internal development of ONA-XR and was "exploring strategic options" for the asset.[15] This decision, coupled with the termination of associated clinical trials, has effectively archived the program, leaving Onapristone as an unmarketed investigational agent with an uncertain future. The drug's history illustrates a key principle in modern drug development: mitigating a critical safety flaw, while a significant scientific achievement, does not guarantee clinical or commercial success if the efficacy profile is not sufficiently compelling to compete in a crowded and demanding therapeutic landscape.

Physicochemical Profile and Formulations

Onapristone is a synthetic, steroidal small molecule whose chemical structure and properties are fundamental to its biological activity and pharmacokinetic behavior.

Chemical Identity and Structure

Onapristone is unambiguously identified by a standardized set of chemical and regulatory codes. Its IUPAC name is (8S,11R,13R,14S,17S)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxypropyl)-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one.[14] Over its long development history, it has been referred to by numerous synonyms and developmental codes, including ZK-98299, ZK-299, IVV-1001, AR-18, and, for its extended-release formulation, ONA-XR and Apristor.[1] Key identifiers are consolidated in Table 1.

Physicochemical Properties

Onapristone's chemical formula is $C_{29}H_{39}NO_{3}$, corresponding to a molecular weight of approximately 449.6 g/mol.[1] It belongs to the class of organic compounds known as oxosteroids, which are steroid derivatives containing a carbonyl group.[18] Its steroidal backbone provides a rigid scaffold for interaction with nuclear hormone receptors.

Key properties influencing its absorption, distribution, metabolism, and excretion (ADME) profile include its very low aqueous solubility (0.00759 mg/mL) and high lipophilicity, as indicated by a logP value between 3.96 and 4.63.[18] Despite its low solubility, predictive models suggest it has a high bioavailability of 1, indicating efficient absorption from the gastrointestinal tract.[18] The molecule contains two hydrogen bond donors and four hydrogen bond acceptors, contributing to its receptor-binding interactions.[17]

Formulations: Immediate-Release (IR) vs. Extended-Release (ER)

The distinction between Onapristone's two primary oral formulations is central to its developmental story.

• Immediate-Release (IR) Formulation: This was the original formulation used in the clinical trials of the 1980s and 1990s. It was designed for rapid dissolution and absorption, which led to high peak plasma concentrations ($C_{max}$) and was ultimately linked to the dose-limiting hepatotoxicity that halted its development.[8]
• Extended-Release (ER) Formulation (ONA-XR): Developed decades later, this formulation incorporates excipients designed to delay the release of the active ingredient in the gastrointestinal tract. The explicit goal of this formulation is to slow the rate of absorption, thereby lowering the $C_{max}$ and providing a more sustained plasma concentration profile suitable for twice-daily (BID) dosing. This was the core pharmaceutical strategy employed to improve the drug's safety and therapeutic index.[6]

Table 1: Key Identifiers and Physicochemical Properties of Onapristone

Parameter	Value	Source(s)
DrugBank ID	DB12637	16
CAS Number	96346-61-1	1
UNII	H6H7G23O3N	16
Molecular Formula	$C_{29}H_{39}NO_{3}$	1
Molecular Weight	449.635 g/mol (Average)	1
IUPAC Name	(8S,11R,13R,14S,17S)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxypropyl)-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one	14
InChIKey	IEXUMDBQLIVNHZ-YOUGDJEHSA-N	14
Water Solubility	0.00759 mg/mL	18
logP	3.96 - 4.63	18
Chemical Class	Steroid; Oxosteroid	1

Nonclinical Pharmacology and Mechanism of Action (MoA)

Onapristone's therapeutic rationale is rooted in its specific and potent mechanism as a progesterone receptor antagonist. Its pharmacological profile distinguishes it from other agents in its class and has been validated in numerous preclinical cancer models.

Primary Mechanism: A Pure Progesterone Receptor Antagonist

Onapristone is a Type I, or "pure," competitive antagonist of the progesterone receptor (PR).[1] This classification as a "silent" antagonist means that it binds to the PR but is incapable of activating transcription, thereby fully antagonizing the functions of progesterone.[22]

At the molecular level, its mechanism of action is multifaceted. Upon binding to the PR, Onapristone induces a conformational change that prevents the formation of functional PRA and PRB dimers. This action inhibits both ligand-dependent (progesterone-induced) and ligand-independent (e.g., growth factor-induced) phosphorylation of the receptor, a key step in its activation. A specific site of action is the inhibition of phosphorylation at serine 294 (PR-S294) and the prevention of the nuclear translocation of this activated form of the receptor.[14] By blocking these critical activation steps, Onapristone prevents the PR from associating with its co-activators and, crucially, from binding to progesterone response elements on DNA. This complete blockade of PR-mediated gene transcription is the foundation of its potential antineoplastic activity in hormone-driven cancers that overexpress the PR.[8]

Pharmacological Profile and Selectivity

Onapristone demonstrates high-affinity binding to the progesterone receptor, with reported dissociation constants ($K_d$) of 1.6 nM and 11.9 nM for human endometrium and myometrium PR, respectively, confirming its high potency.[25] While its primary target is the PR, it also possesses some additional, weaker hormonal activities. It exhibits reduced antiglucocorticoid activity and minimal antiandrogenic activity, making it more selective for the PR compared to other antiprogestins.[1]

Comparison with Mifepristone

A comparison with the archetypal antiprogestin, mifepristone (RU486), highlights Onapristone's distinct pharmacological profile. The most significant difference lies in their interaction with the PR. While Onapristone is a pure or silent antagonist, mifepristone is a weak partial agonist.[1] This means that while mifepristone generally blocks progesterone action, in certain cellular contexts it can weakly activate the receptor, potentially leading to mixed or unpredictable effects. Onapristone's pure antagonist nature was theorized to provide a more complete and reliable blockade of PR signaling. Furthermore, Onapristone is estimated to be 10- to 30-fold more potent as an antiprogestogen than mifepristone and has a more favorable selectivity profile with its reduced off-target antiglucocorticoid activity.[1] This theoretically superior mechanism formed the core scientific rationale for its development as a next-generation antiprogestin. However, the modest clinical efficacy observed in later trials raises important questions about whether this "cleaner" mechanism translates to superior clinical outcomes, or if this mode of PR antagonism is simply insufficient to drive deep responses in advanced cancers.

Table 2: Pharmacological Comparison of Onapristone and Mifepristone

Feature	Onapristone	Mifepristone (RU486)	Source(s)
Mechanism on PR	Pure ("Silent") Antagonist	Partial Agonist / Antagonist	1
Antiprogestogen Potency	10- to 30-fold higher	Baseline	1
Antiglucocorticoid Activity	Reduced	Significant	1
Antiandrogenic Activity	Little / Minimal	Present	1
Clinical Status	Never Marketed	Approved for medical termination of pregnancy	1

Preclinical Efficacy in Cancer Models

Extensive preclinical research has validated Onapristone's anti-cancer activity and supported its clinical development. Studies have consistently shown that it is active in multiple preclinical models of hormone-dependent cancers.[27] It has demonstrated tumor-inhibitory effects in animal models, including rat and mouse mammary tumors, with efficacy comparable to that of tamoxifen or oophorectomy.[21] In vitro studies on breast cancer cell lines have confirmed its ability to reduce cell viability and induce apoptosis.[25]

More recent preclinical work has focused on its potential in combination therapies. In patient-derived xenograft (PDX) models of ER+/PR+ breast cancer, combining Onapristone with standard-of-care agents such as the selective estrogen receptor degrader (SERD) fulvestrant, the CDK4/6 inhibitor palbociclib, or the PI3K inhibitor alpelisib resulted in significantly increased anti-tumor activity compared to monotherapy. A triple-therapy combination led to tumor regression in a majority of the xenografts, providing a strong rationale for clinical trials evaluating these combinations.[30] Other preclinical studies have suggested that progesterone can promote tumor growth by decreasing immune cell infiltration, providing a basis for investigating antiprogestins like Onapristone to promote an anti-tumor immune response.[30]

Clinical Pharmacokinetics and Metabolism (ADME)

The absorption, distribution, metabolism, and excretion (ADME) profile of Onapristone is critical to understanding its efficacy, safety, and potential for drug-drug interactions. Its high lipophilicity, extensive metabolism, and very high protein binding are defining features.

Absorption

Onapristone is orally bioavailable and well-absorbed from the gastrointestinal tract.[16] The formulation significantly impacts its absorption kinetics. A clinical study of the 10 mg IR formulation in healthy female subjects found that administration with a high-fat, high-calorie meal delayed the time to maximum plasma concentration ($T_{max}$) from 1 hour in the fasted state to 4 hours in the fed state. This was accompanied by a statistically significant decrease in $C_{max}$ of approximately 18% and a small increase in total exposure ($AUC_{0-\infty}$) of approximately 13%.[32] As these changes were within acceptable regulatory limits, it was concluded that Onapristone could be administered without regard to food.[32] The ER formulation was specifically engineered to have a reduced rate of absorption compared to the IR form, resulting in a delayed $T_{max}$ (2.5 hours for ER vs. 1 hour for IR) and a significantly lower day 1 $C_{max}$.[34]

Distribution

Following absorption, Onapristone undergoes extensive distribution into tissues. A key characteristic of its distribution is its exceptionally high binding to plasma proteins, reported to be 99.5% in human plasma.[31] This high degree of protein binding means that only a very small fraction (0.5%) of the drug in circulation is unbound, or "free," to exert its pharmacological effect, be metabolized, or be excreted. This property makes the drug highly susceptible to displacement interactions. If a co-administered drug displaces even a small amount of Onapristone from its binding proteins, it can cause a disproportionately large, and potentially toxic, increase in the free drug concentration. For example, a shift in binding from 99.5% to 99.0% would double the free concentration from 0.5% to 1.0%, a 100% increase in the active fraction. This mechanism may have been an underappreciated contributor to the unpredictable toxicity observed in early trials.

Metabolism

Onapristone is primarily metabolized in the liver. In vitro studies using human liver microsomes have conclusively identified cytochrome P450 3A4 (CYP3A4) as the principal enzyme responsible for its N-demethylation, a primary metabolic pathway.[35] The main metabolite produced is N-mono-desmethyl onapristone, also known as M1.[32]

Complicating its metabolic profile, Onapristone is not only a substrate of CYP3A4 but also a mechanism-based, time-dependent inactivator of the enzyme.[36] This dual role means that Onapristone can inhibit its own metabolism over time and has a high potential to interfere with the metabolism of a wide range of other drugs that are also CYP3A4 substrates. This complex interaction with a major drug-metabolizing enzyme is a critical consideration for potential drug-drug interactions.

Excretion

Detailed human mass balance studies quantifying the routes and proportions of Onapristone excretion are not available in the provided materials. One secondary source indicates that the drug and its metabolites are excreted via both urine and feces, which is typical for lipophilic, hepatically metabolized compounds.[37] The inclusion of renal function criteria (e.g., creatinine clearance < 40-60 mL/min) as an exclusion criterion in multiple clinical trial protocols suggests that renal clearance plays a role in the elimination of Onapristone or its metabolites, and that impairment could lead to drug accumulation.[8]

Pharmacokinetic Profile and Half-Life

The pharmacokinetic profile of Onapristone is heavily dependent on the formulation and dosing regimen.

• IR Formulation: After a single oral dose of the IR formulation, the plasma half-life ($t_{1/2}$) is relatively short, reported to be between 2 and 4.4 hours.[32]
• ER Formulation: After repeated dosing with the ER formulation, the terminal half-life is substantially longer, in the range of 8 to 12 hours. This longer half-life, combined with the slower absorption, contributes to less fluctuation in plasma concentrations between doses. Steady-state concentrations are reached after approximately 200 hours of continuous BID dosing.[7]

Across the tested dose range of the ER formulation (10 mg to 50 mg BID), both the AUC and $C_{max}$ have been shown to be dose-proportional, indicating predictable pharmacokinetics within this therapeutic window.[7]

Table 3: Summary of Key Pharmacokinetic Parameters (IR vs. ER Formulations)

Parameter	100 mg IR QD	50 mg ER BID	Source(s)
$T_{max}$ (Day 1)	~1 hour	~2.5 hours	32
$C_{max}$ (Day 1)	Significantly higher	>2-fold lower than IR	34
Half-life ($t_{1/2}$)	~2-4 hours (single dose)	8-12 hours (repeated dosing)	7
Time to Steady State	Not reported	~200 hours	7

Clinical Efficacy and Development Program

Onapristone has been evaluated in a range of clinical trials across several PR-positive cancer types. Its clinical journey reflects a transition from promising monotherapy in early studies to a more nuanced role in combination therapies and biomarker-selected populations in its recent development phase.

Overview of Clinical Investigations

Clinical development has focused on malignancies where the progesterone receptor is believed to be a driver of tumor growth, including breast, endometrial, ovarian, and prostate cancers.[14] The program's evolution saw a shift from the original IR formulation to the current ER formulation, with trials spanning Phase 0 to Phase II.

Breast Cancer

• Early Trials (IR formulation): Initial Phase II studies from the 1990s established Onapristone's clinical activity. In hormone therapy-naïve patients with locally advanced or metastatic breast cancer, the IR formulation achieved an overall response rate (ORR) of 56% and a clinical benefit rate (CBR) of 67%.[2] In a more challenging population of patients with tamoxifen-resistant metastatic disease, it still produced a 10% ORR and a 49% CBR.[2] These promising results were overshadowed by the hepatotoxicity that led to the program's halt.
• ONAWA Trial (NCT04142892): This recent Phase 0 "window of opportunity" trial provided valuable biological insights into the ER formulation. Postmenopausal women with early-stage, operable ER+/PR+/HER2- breast cancer received Onapristone ER for three weeks prior to surgery. The trial successfully met its primary endpoint, demonstrating a significant antiproliferative effect, as measured by a reduction in the Ki67 proliferation index.[4] This confirmed that the drug was engaging its target and exerting a biological effect in tumor tissue.
• SMILE Trial (NCT04738292): In contrast to the ONAWA results, the Phase II SMILE trial highlighted the challenges of treating advanced disease. This study evaluated Onapristone ER in combination with the SERD fulvestrant in patients with ER+/HER2- metastatic breast cancer that had progressed after prior endocrine therapy and a CDK4/6 inhibitor. In a preliminary analysis of the first 11 patients, the combination was well-tolerated but yielded no objective responses according to RECIST 1.1 criteria. The median time to progression was a short 63 days, although a few patients did achieve stable disease.[41] This outcome suggests that while Onapristone can slow proliferation (a cytostatic effect, as seen in ONAWA), it may lack the potency to induce tumor regression (a cytotoxic effect) in heavily pre-treated, resistant metastatic disease.

Endometrial and Ovarian Cancer

• Phase I/II Basket Trial (NCT02052128): This was a key study for the redevelopment of ONA-XR. It was a dose-escalation trial that included 52 heavily pre-treated patients with various PR-expressing cancers, including endometrial, ovarian, and breast cancer. The study established the recommended Phase II dose (RP2D) of 50 mg ER BID and demonstrated an acceptable safety profile. Clinical benefit, defined as stable disease or response for $\ge$24 weeks, was observed in 9 of the 52 patients, including those with endometrial and ovarian cancer.[8]
• OATH Trial (NCT04719273): This Phase II trial has provided the most promising recent data for Onapristone. It evaluated the combination of ONA-XR with the aromatase inhibitor anastrozole in heavily pre-treated patients with hormone receptor-positive endometrial cancer. Preliminary results from the first 14 patients were encouraging: the 4-month progression-free survival (PFS) rate was 63.5%, and the best overall response included one complete response (CR) and one partial response (PR), for an ORR of 15.4%. An additional nine patients had stable disease (SD), leading to a high disease control rate (DCR) of 84.4%. The combination was also well-tolerated.[44] This supports the hypothesis that Onapristone may be most effective as part of a dual hormonal blockade strategy.
• Phase II Basket Trial (NCT03909152): This study evaluated ONA-XR monotherapy in patients with recurrent PR-positive gynecologic cancers, including a cohort of patients with adult-type granulosa cell tumors (aGCT), a rare type of ovarian cancer. While the drug was well-tolerated, no objective responses were observed. However, it did show signs of clinical activity, with a CBR of 35.7% and a 12-month PFS rate of 20.1% in the GCT cohort, with some patients remaining on treatment for over 18 months.[46]

Prostate Cancer

Onapristone has also been investigated in various stages of prostate cancer, including androgen-independent, recurrent, and metastatic disease, based on the expression of PR in these tumors.[16] As of 2016, prostate cancer was a primary focus for its redevelopment.[1] However, specific efficacy data from these clinical trials are not detailed in the available documentation.

Table 4: Overview of Major Clinical Trials for Onapristone ER

Trial ID (Name)	Phase	Indication	Treatment Arm(s)	Key Outcomes	Source(s)
NCT04142892 (ONAWA)	0	Early-stage HR+/HER2- Breast Cancer	Onapristone ER (neoadjuvant)	Met primary endpoint: significant antiproliferative effect (Ki67 reduction).	40
NCT04738292 (SMILE)	II	Metastatic ER+/HER2- Breast Cancer (post-CDK4/6i)	Onapristone ER + Fulvestrant	Did not meet primary endpoint: 0% ORR in first 11 patients. Median TTP of 63 days.	42
NCT02052128	I/II	PR-expressing solid tumors (Breast, Endometrial, Ovarian)	Onapristone ER (dose escalation)	Established RP2D of 50 mg BID. Clinical benefit in 9/52 patients. Good tolerability.	19
NCT04719273 (OATH)	II	Refractory HR+ Endometrial Cancer	Onapristone ER + Anastrozole	Promising preliminary data: 15.4% ORR, 63.5% 4-month PFS rate, 84.4% DCR.	44
NCT03909152	II	Recurrent PR+ Gynecologic Cancers (inc. GCT)	Onapristone ER	No objective responses. In GCT cohort: 35.7% CBR, 20.1% 12-month PFS rate.	46

Safety, Tolerability, and Risk Profile

The safety profile of Onapristone is defined by the historical hepatotoxicity of its IR formulation and the subsequent mitigation of this risk with the ER formulation. The overall safety database for ONA-XR suggests it is a generally well-tolerated agent.

Hepatotoxicity: The Defining Safety Concern

The development of the original IR formulation of Onapristone was halted in 1995 due to an unacceptable rate of liver function test (LFT) abnormalities.[1] The primary goal of the ER formulation was to address this liability.

Clinical data from the modern development program strongly suggest this goal was achieved. A pooled safety analysis of 88 patients from two Phase I-II trials of ONA-XR found that while elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) occurred, their incidence was strongly associated with the presence of liver metastases (20% in patients with liver metastases vs. 6.3% in those without).[2] Of five patients who experienced Grade 3 or higher ALT elevations, four were assessed as unrelated to ONA-XR by a safety data review committee. The fifth case was ultimately adjudicated by an independent hepatologist as unlikely to be drug-related.[48] Critically, across the entire ONA-XR clinical program, there have been no reported cases of drug-induced liver injury meeting Hy's Law criteria (a standard indicator of severe, potentially fatal hepatotoxicity).[5] This indicates that the reformulation strategy was successful in mitigating the primary safety concern.

Other Adverse Events

The overall safety profile of ONA-XR is generally favorable. In a Phase I study, the most common treatment-related adverse events (AEs) were asthenia (21%), increased AST/ALT (17%), and increased gamma-glutamyl transferase (GGT) (10%).[7] Most Grade 3 or higher AEs, particularly LFT elevations, were associated with patients who had progressive disease in the liver.[7] In the OATH trial of ONA-XR plus anastrozole, the most common AEs were mainly Grade 1 or 2 and included hot flashes (36%), increased ALT/AST (29%), nausea (29%), and diarrhea (21%).[44] Across multiple trials, ONA-XR has been described as well-tolerated, with no treatment-related deaths reported.[20]

Table 5: Summary of Common Adverse Events Reported in Onapristone ER Clinical Trials

Adverse Event	Frequency (%)	Grade	Relevant Trial(s)	Source(s)
Asthenia	21%	Any	Phase I/II (NCT02052128)	7
AST/ALT Increased	17-29%	Any	Phase I/II, OATH	7
GGT Increased	10%	Grade $\ge$3	Phase I/II (NCT02052128)	7
Hot Flashes	36%	Any	OATH (NCT04719273)	44
Nausea	29%	Any	OATH (NCT04719273)	44
Diarrhea	21%	Any	OATH (NCT04719273)	44
Abdominal Pain	N/A	Grade 3	Phase II (NCT03909152)	47

Contraindications and Precautions

Based on its mechanism of action and data from clinical trial protocols, several contraindications and precautions are warranted for Onapristone:

• Reproductive Toxicity: Onapristone is classified under the Globally Harmonized System (GHS) with the hazard statement H360: "May damage fertility or the unborn child".[16] Consequently, it is contraindicated in patients who are pregnant or breastfeeding. Women of childbearing potential must use highly effective non-hormonal contraception during treatment.[50]
• Hepatic Impairment: Patients with pre-existing significant liver dysfunction, active viral hepatitis (Hepatitis B or C), or baseline LFTs above specified limits were excluded from clinical trials.[19]
• Cardiac Conditions: Patients with a history of clinically significant heart disease, uncontrolled hypertension, cardiac arrhythmias, or a baseline corrected QT (QTc) interval > 480 msec have been consistently excluded from studies.[19]
• Gastrointestinal Conditions: Conditions that could preclude adequate drug absorption, such as malabsorption syndromes or refractory nausea and vomiting, are contraindications.[50]

Risk of Methemoglobinemia and Thrombosis

Drug interaction databases have identified specific pharmacodynamic risks associated with Onapristone. There is a potential for an increased risk of methemoglobinemia when Onapristone is combined with a wide range of local anesthetics (e.g., benzocaine, lidocaine, procaine) and other compounds like capsaicin and diphenhydramine.[18] Additionally, there is a potential for an increased risk of thrombosis when it is co-administered with erythropoiesis-stimulating agents such as darbepoetin alfa and erythropoietin.[18] These risks warrant careful consideration of concomitant medications.

Drug-Drug Interactions (DDIs)

Onapristone's metabolic profile and high plasma protein binding create a significant potential for clinically relevant drug-drug interactions (DDIs). These interactions can be pharmacokinetic, affecting drug exposure, or pharmacodynamic, altering drug effects.

Pharmacokinetic DDIs (CYP3A4-Mediated)

Onapristone's relationship with the cytochrome P450 3A4 (CYP3A4) enzyme is complex and represents the primary source of pharmacokinetic DDIs. CYP3A4 is responsible for metabolizing approximately half of all drugs on the market, making interactions involving this enzyme particularly common and important.[54]

• Onapristone as a CYP3A4 Substrate: The N-demethylation of Onapristone is principally mediated by CYP3A4.[35] This means that its plasma concentrations are susceptible to modulation by other drugs:
• CYP3A4 Inhibitors: Co-administration with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir) would be expected to decrease Onapristone's metabolism, leading to increased plasma levels and a heightened risk of toxicity.
• CYP3A4 Inducers: Conversely, co-administration with strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John's Wort) would be expected to accelerate Onapristone's metabolism, leading to lower plasma levels and a potential loss of efficacy. Recognizing this risk, recent clinical trial protocols have explicitly excluded patients receiving strong inhibitors or inducers of CYP3A4.50
• Onapristone as a CYP3A4 Inactivator: In addition to being a substrate, Onapristone has been shown to be a time-dependent, mechanism-based inactivator of CYP3A4.[36] This means that upon its own metabolism, it can form a reactive intermediate that irreversibly binds to and inactivates the enzyme. This can decrease the clearance of other co-administered drugs that are also CYP3A4 substrates, potentially increasing their exposure and toxicity. This creates a complex DDI profile where Onapristone can be both the "victim" and the "perpetrator" of metabolic interactions.

Pharmacodynamic DDIs

Pharmacodynamic interactions occur when drugs have additive or antagonistic effects at the receptor or system level. For Onapristone, two key risks have been identified:

• Methemoglobinemia: The risk or severity of this condition, where hemoglobin is unable to effectively release oxygen to body tissues, can be increased when Onapristone is combined with numerous local anesthetics (e.g., benzocaine, lidocaine, bupivacaine, tetracaine) and other agents such as capsaicin and diphenhydramine.[18]
• Thrombosis: The risk or severity of thrombosis can be increased when Onapristone is used concomitantly with erythropoiesis-stimulating agents like darbepoetin alfa, erythropoietin, and peginesatide.[18]

Protein-Binding DDIs

Onapristone's very high plasma protein binding of 99.5% presents a significant theoretical risk for displacement interactions.[31] When two highly protein-bound drugs are co-administered, they can compete for binding sites on plasma proteins like albumin. If a second drug displaces Onapristone from these sites, the concentration of the pharmacologically active "free" fraction of Onapristone can increase dramatically, even if the total plasma concentration remains unchanged. This could lead to unexpected toxicity. Caution would be required when co-administering Onapristone with other highly bound drugs, such as warfarin, phenytoin, or certain nonsteroidal anti-inflammatory drugs (NSAIDs).

Regulatory and Commercial Status

Despite a long and complex development history spanning several decades and multiple pharmaceutical companies, Onapristone remains an investigational agent that has not achieved regulatory approval in any market.

Global Regulatory Standing

Onapristone has never been marketed for any clinical indication. It has not received approval from major global regulatory agencies, including the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the Australian Therapeutic Goods Administration (TGA).[1] Records indicate no planned submission for FDA approval, and there is no evidence of a formal review process ever being completed by the EMA or TGA.[12] The drug's development was initially halted in 1995, prior to the EMA's formal establishment, and its subsequent redevelopment has not progressed to the point of a marketing authorization application in any major jurisdiction.

Investigational Status and Recent Discontinuation

Onapristone is classified as an investigational small molecule.[18] Its most recent chapter of development concluded in April 2023, when Context Therapeutics, the company leading its clinical evaluation, announced the cessation of internal development for the ONA-XR program. The company stated it would be "exploring strategic options" for the asset, a decision often indicative of deprioritization or out-licensing attempts.[15] This halt was attributed to factors including slow patient accrual in key clinical trials, which made it highly unlikely that the program could support a regulatory filing within a viable timeframe.[15] The subsequent termination and withdrawal of related clinical trials, such as the ELONA study (NCT05618613), further confirmed the discontinuation of active development.[12] Consequently, Onapristone is currently an inactive, late-stage clinical asset without a clear path forward to commercialization.

Expert Analysis and Future Perspectives

The comprehensive review of Onapristone reveals a drug with a compelling scientific rationale but a challenging and ultimately unsuccessful clinical development path. Its story offers valuable lessons on the interplay between pharmacology, pharmaceutical science, clinical efficacy, and commercial viability in modern oncology.

Synthesis of the Onapristone Narrative

Onapristone's journey is a cautionary tale. It began as a promising, mechanistically elegant compound—a pure PR antagonist theoretically superior to its predecessors. This promise was cut short by a severe safety signal (hepatotoxicity) that was, at the time, insurmountable. The drug's revival represents a triumph of pharmaceutical science, where a rational, hypothesis-driven reformulation successfully mitigated the primary toxicity, allowing for re-entry into the clinic. However, this second chapter concluded not with a safety failure, but with the inability to demonstrate a sufficiently compelling efficacy profile to justify continued investment in a highly competitive therapeutic area. This arc highlights that while safety is a prerequisite, it does not guarantee success.

The Success and Limits of Reformulation

The development of ONA-XR stands as a model case for applying pharmacokinetic principles to solve a clinical problem. By identifying high $C_{max}$ as the likely driver of toxicity and engineering a formulation to specifically address it, the developers successfully improved the drug's therapeutic index. The clinical data for ONA-XR clearly show a vastly improved hepatic safety profile compared to the historical data for the IR formulation. This achievement was necessary for the drug to have any chance of progression. However, it was not sufficient. The modest efficacy results, particularly the lack of objective responses in the SMILE trial for metastatic breast cancer, suggest that the level of clinical activity, even with a safer formulation, fell short of the high bar required for new oncology agents, especially in heavily pre-treated patient populations.

Future Viability and Potential Niches

Given the recent halt in development, the future of Onapristone is highly uncertain and contingent on a new sponsor acquiring the asset with a clear and focused strategy. Based on the available data, several potential niches could be explored to maximize its chances of success:

• Combination Therapy: The most promising clinical signal for ONA-XR has come from the OATH trial, where it was combined with anastrozole in endometrial cancer. Preclinical data also strongly support synergy with agents like SERDs and CDK4/6 inhibitors. The future of Onapristone, if one exists, almost certainly lies in combination regimens where it can complement or enhance the activity of other hormonal or targeted agents, rather than as a monotherapy.
• Biomarker-Driven Approaches: The concept of using transcriptionally-activated PR (APR) as a predictive biomarker was explored in the Phase I/II basket trial. A renewed development program would need to rigorously pursue a biomarker strategy to identify a patient subpopulation with a high likelihood of response. In an era of precision oncology, demonstrating efficacy in a targeted, biomarker-defined group is a more viable path to approval than seeking modest activity in a broad population.
• Earlier Lines of Therapy: The disconnect between the positive biological activity in the neoadjuvant ONAWA trial (antiproliferation) and the lack of tumor shrinkage in the late-stage SMILE trial suggests Onapristone's primary effect may be cytostatic. Therefore, its greatest potential may not be in treating advanced, bulky metastatic disease, but rather in earlier settings. A role in the adjuvant or neoadjuvant setting to prevent recurrence or reduce tumor burden before surgery, respectively, could be a more suitable clinical application for a drug with a strong antiproliferative but weak cytotoxic effect.

Final Verdict

Onapristone is a pharmacologically sophisticated molecule and a testament to the power of formulation science to rescue a promising compound from a critical safety flaw. However, its journey also serves as a stark reminder that in the landscape of modern oncology, a sound mechanism of action and an acceptable safety profile are necessary but not sufficient conditions for success. The inability to translate its biological activity into compelling clinical responses in advanced disease has, for a second time, halted its path to the clinic. Without a new champion and a refined clinical strategy focused on rational combinations, biomarker selection, and appropriate disease settings, Onapristone is likely to remain a well-documented but unfulfilled chapter in the history of endocrine cancer therapy.

Works cited

1. Onapristone - Wikipedia, accessed October 29, 2025, https://en.wikipedia.org/wiki/Onapristone
2. Onapristone Extended Release: Safety Evaluation from Phase I–II Studies with an Emphasis on Hepatotoxicity - PMC - NIH, accessed October 29, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7497701/
3. Onapristone, a progesterone receptor antagonist, as first-line therapy in primary breast cancer - PubMed, accessed October 29, 2025, https://pubmed.ncbi.nlm.nih.gov/10448262/
4. Abstract P1-07-02: Primary results of ONAWA (SOLTI-1802) trial: A window of opportunity trial of onapristone in postmenopausal women with progesterone receptor-positive/HER2-negative early breast cancer (EBC) - AACR Journals, accessed October 29, 2025, https://aacrjournals.org/cancerres/article/82/4_Supplement/P1-07-02/680460/Abstract-P1-07-02-Primary-results-of-ONAWA-SOLTI
5. Context Therapeutics Announces Publication of Onapristone Extended Release Safety Review Results - FirstWord Pharma, accessed October 29, 2025, https://firstwordpharma.com/story/5051153
6. Context Therapeutics Announces Publication of Onapristone Extended Release Safety Review Results - BioSpace, accessed October 29, 2025, https://www.biospace.com/context-therapeutics-announces-publication-of-onapristone-extended-release-safety-review-results
7. Safety and pharmacokinetic (PK) results from phase 1 of an ongoing ..., accessed October 29, 2025, https://ascopubs.org/doi/10.1200/jco.2015.33.15_suppl.e16517
8. Phase I study of onapristone, a type I antiprogestin, in female patients with previously treated recurrent or metastatic progesterone receptor-expressing cancers | PLOS One, accessed October 29, 2025, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0204973
9. Definition of extended-release onapristone - NCI Drug Dictionary, accessed October 29, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/extended-release-onapristone
10. KR20170084086A - Onapristone extended-release compositions and methods - Google Patents, accessed October 29, 2025, https://patents.google.com/patent/KR20170084086A/en
11. A randomized, parallel-dose phase 1 study of onapristone (ONA) in patients (pts) with progesterone receptor (PR)-expressing cancers. - ASCO Publications, accessed October 29, 2025, https://ascopubs.org/doi/10.1200/jco.2014.32.15_suppl.tps2643
12. Onapristone - Context Therapeutics - AdisInsight, accessed October 29, 2025, https://adisinsight.springer.com/drugs/800000877
13. Onapristone - Drug Targets, Indications, Patents - Patsnap Synapse, accessed October 29, 2025, https://synapse.patsnap.com/drug/a635cb68b2cf445a93509317a1717b16
14. Buy Onapristone (EVT-277402) | 96346-61-1 - EvitaChem, accessed October 29, 2025, https://www.evitachem.com/product/evt-277402
15. Onapristone extended release (ONA-XR) to treat progesterone receptor–positive recurrent granulosa cell ovarian cancer - Horizon Scanning Database - PCORI, accessed October 29, 2025, https://horizonscandb.pcori.org/report/topics/238
16. Onapristone | C29H39NO3 | CID 5311505 - PubChem - NIH, accessed October 29, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Onapristone
17. onapristone | Ligand page | IUPHAR/BPS Guide to PHARMACOLOGY, accessed October 29, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2882
18. Onapristone: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed October 29, 2025, https://go.drugbank.com/drugs/DB12637
19. Phase 1-2 Study of Onapristone in Patients With Progesterone ..., accessed October 29, 2025, https://www.cancer.gov/clinicaltrials/NCI-2016-00136
20. Phase I study of onapristone, a type I antiprogestin, in female ..., accessed October 29, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6179222/
21. Onapristone – Knowledge and References - Taylor & Francis, accessed October 29, 2025, https://taylorandfrancis.com/knowledge/Medicine_and_healthcare/Pharmaceutical_medicine/Onapristone/
22. Inhibiting Nuclear Phospho-Progesterone Receptor Enhances Antitumor Activity of Onapristone in Uterine Cancer - AACR Journals, accessed October 29, 2025, https://aacrjournals.org/mct/article-pdf/doi/10.1158/1535-7163.MCT-17-0006/1915382/1535-7163_mct-17-0006v2.pdf
23. pubchem.ncbi.nlm.nih.gov, accessed October 29, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Onapristone#:~:text=Upon%20oral%20administration%2C%20onapristone%20binds,in%20cancer%20cells%20overexpressing%20PR.
24. Definition of onapristone - NCI Drug Dictionary - National Cancer Institute, accessed October 29, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/onapristone
25. Onapristone (ZK 98299) | Progesterone Receptor Antagonist - MedchemExpress.com, accessed October 29, 2025, https://www.medchemexpress.com/Onapristone.html
26. Questions and Answers on Mifepristone for Medical Termination of Pregnancy Through Ten Weeks Gestation | FDA, accessed October 29, 2025, https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/questions-and-answers-mifepristone-medical-termination-pregnancy-through-ten-weeks-gestation
27. (PDF) Phase I study of onapristone, a type I antiprogestin, in female patients with previously treated recurrent or metastatic progesterone receptor-expressing cancers - ResearchGate, accessed October 29, 2025, https://www.researchgate.net/publication/328207707_Phase_I_study_of_onapristone_a_type_I_antiprogestin_in_female_patients_with_previously_treated_recurrent_or_metastatic_progesterone_receptor-expressing_cancers
28. Phase I study of onapristone, a type I antiprogestin, in female patients with previously treated recurrent or metastatic progesterone receptor-expressing cancers - PubMed, accessed October 29, 2025, https://pubmed.ncbi.nlm.nih.gov/30304013/
29. The clinical efficacy of progesterone antagonists in breast cancer - Context Therapeutics, accessed October 29, 2025, http://www.contexttherapeutics.com/s/ONAPRISTONE_Schering-2L-mBCa_Jonat-ms3d.pdf
30. Context Therapeutics® Announces Encouraging Preclinical Data ..., accessed October 29, 2025, https://ir.contexttherapeutics.com/node/7011/pdf
31. A single dose PK study of onapristone including the ... - ResearchGate, accessed October 29, 2025, https://www.researchgate.net/profile/Alain-Patat/publication/277252493_A_single-dose_PK_study_of_onapristone_including_the_effect_of_food_on_absorption/links/6568ccb33fa26f66f43b2c24/A-single-dose-PK-study-of-onapristone-including-the-effect-of-food-on-absorption.pdf?origin=scientificContributions
32. A single-dose PK study of onapristone including the effect of food on absorption - PubMed, accessed October 29, 2025, https://pubmed.ncbi.nlm.nih.gov/26006702/
33. Abstract 4636: Pharmacokinetic (PK) food effect study of immediate-release onapristone and its primary metabolite (M1) in healthy female subjects: implications for design of a new formulation | Cancer Research - AACR Journals, accessed October 29, 2025, https://aacrjournals.org/cancerres/article/74/19_Supplement/4636/596937/Abstract-4636-Pharmacokinetic-PK-food-effect-study
34. Onapristone Extended Release: Safety Evaluation from Phase I–II Studies with an Emphasis on Hepatotoxicity - ResearchGate, accessed October 29, 2025, https://www.researchgate.net/publication/342502717_Onapristone_Extended_Release_Safety_Evaluation_from_Phase_I-II_Studies_with_an_Emphasis_on_Hepatotoxicity
35. Cytochrome P4503A4-mediated N-demethylation of the antiprogestins lilopristone and onapristone - PubMed, accessed October 29, 2025, https://pubmed.ncbi.nlm.nih.gov/9321513/
36. Antiprogestin-mediated inactivation of cytochrome P450 3A4 - PubMed, accessed October 29, 2025, https://pubmed.ncbi.nlm.nih.gov/9532615/
37. PHARMACOLOGY OF Onapristone ; Overview, Mechanism of action, Pharmacokinetics, Uses, Effects - YouTube, accessed October 29, 2025, https://www.youtube.com/watch?v=040wpp8VyKA
38. Safety and pharmacokinetic (PK) results from phase 1 of an ongoing phase 1-2 study of onapristone (ONA) in patients (pts) with progesterone receptor (PR)-expressing cancers. - ASCO, accessed October 29, 2025, https://www.asco.org/abstracts-presentations/ABSTRACT150771
39. Onapristone Completed Phase 0 Trials for Breast Cancer Treatment | DrugBank Online, accessed October 29, 2025, https://go.drugbank.com/drugs/DB12637/clinical_trials?conditions=DBCOND0028036&phase=0&purpose=treatment&status=completed
40. Study Details | NCT04142892 | Onapristone as Preoperative Treatment for Postmenopausal Women With Hormone Receptor + and HER2- Breast Cancer | ClinicalTrials.gov, accessed October 29, 2025, https://www.clinicaltrials.gov/study/NCT04142892
41. Onapristone and Fulvestrant for Patients with ER-Positive, HER2 ..., accessed October 29, 2025, https://www.cancer.gov/clinicaltrials/NCI-2021-00371
42. A Phase II Trial of Onapristone and Fulvestrant for Patients With ER+ and HER2- Metastatic Breast Cancer - PubMed, accessed October 29, 2025, https://pubmed.ncbi.nlm.nih.gov/39824712/
43. Study Details | NCT04738292 | Onapristone and Fulvestrant for ER+ ..., accessed October 29, 2025, https://www.clinicaltrials.gov/study/NCT04738292
44. OATH trial: A phase II clinical trial evaluating the combination of onapristone with anastrozole for women with hormone receptor positive endometrial cancer—Preliminary results. - ASCO Publications, accessed October 29, 2025, https://ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.5601
45. Context Therapeutics Highlights Clinical Responses from the Phase 2 OATH Clinical Trial Evaluating ONA-XR for the Treatment of Endometrial Cancer, accessed October 29, 2025, https://ir.contexttherapeutics.com/news-releases/news-release-details/context-therapeutics-highlights-clinical-responses-phase-2-oath/
46. Basket study of oral progesterone antagonist onapristone extended release in progesterone receptor-positive recurrent granulosa cell, low-grade serous ovarian cancer, or endometrioid endometrial cancer - PMC - NIH, accessed October 29, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11867184/
47. Basket study of oral progesterone antagonist onapristone extended release (ONA-XR) in progesterone receptor positive (PR+) recur, accessed October 29, 2025, https://ascopubs.org/doi/pdf/10.1200/JCO.2022.40.16_suppl.5521
48. Onapristone Extended Release: Safety Evaluation from Phase I-II Studies with an Emphasis on Hepatotoxicity - PubMed, accessed October 29, 2025, https://pubmed.ncbi.nlm.nih.gov/32594454/
49. Pooled analysis of onapristone extended release (ONA ER) in metastatic cancer patients (pts): A review of liver safety. - ASCO Publications, accessed October 29, 2025, https://ascopubs.org/doi/10.1200/JCO.2019.37.15_suppl.e14647
50. NCT04872608 | A Study of Letrozole, Palbociclib, and Onapristone ER in People With Metastatic Breast Cancer | ClinicalTrials.gov, accessed October 29, 2025, https://www.clinicaltrials.gov/study/NCT04872608
51. Study Details | NCT06938711 | A Rollover Protocol of Elacestrant, in ..., accessed October 29, 2025, https://www.clinicaltrials.gov/study/NCT06938711
52. Onapristone Extended-Release, Letrozole, and Palbociclib for the Treatment of Unresectable or Metastatic Estrogen Receptor Positive, Progesterone Receptor Positive, HER2 Negative Breast Cancer, accessed October 29, 2025, https://www.cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2021-09840
53. go.drugbank.com, accessed October 29, 2025, https://go.drugbank.com/drugs/DB12637#:~:text=Cocaine-,The%20risk%20or%20severity%20of%20methemoglobinemia%20can%20be,Onapristone%20is%20combined%20with%20Cocaine.&text=The%20risk%20or%20severity%20of%20Thrombosis%20can%20be%20increased,alfa%20is%20combined%20with%20Onapristone.&text=Diphenhydramine-,The%20risk%20or%20severity%20of%20methemoglobinemia%20can%20be,Onapristone%20is%20combined%20with%20Diphenhydramine.
54. Drug Interactions with CYP3A4: An Update - Pharmacy Times, accessed October 29, 2025, https://www.pharmacytimes.com/view/drug-interactions-with-cyp3a4-an-update
55. Onapristone and Anastrozole for the Treatment of Refractory Hormone Receptor Positive Endometrial Cancer | Clinical Research Trial Listing - CenterWatch, accessed October 29, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT04719273/onapristone-and-anastrozole-for-the-treatment-of-refractory-hormone-receptor-positive-endometrial-cancer
56. AusPAR Ulipristal acetate - Therapeutic Goods Administration (TGA), accessed October 29, 2025, https://www.tga.gov.au/sites/default/files/auspar-ulipristal-acetate-161019.docx
57. OncLive's August EMA Regulatory Recap: Key EU Approvals in Oncology, accessed October 29, 2025, https://www.onclive.com/view/onclive-s-august-ema-regulatory-recap-key-eu-approvals-in-oncology
58. Mifepristone Linepharma - European Medicines Agency, accessed October 29, 2025, https://www.ema.europa.eu/en/documents/referral/questions-and-answers-mifepristone-linepharma-and-associated-names-mifepristone-200-mg-tablet_en.pdf