Opevesostat (MK-5684/ODM-208): A Comprehensive Clinical and Scientific Review of a First-in-Class CYP11A1 Inhibitor for Hormone-Dependent Cancers

1.0 Introduction to Opevesostat

Opevesostat is an investigational, orally bioavailable, non-steroidal new drug representing a first-in-class therapeutic agent designed as a selective inhibitor of the cytochrome P450 11A1 (CYP11A1) enzyme.[1] Also known as the cholesterol side-chain cleavage enzyme, CYP11A1 is the critical gatekeeper for the entire steroid biosynthesis pathway. By targeting this initial, rate-limiting step, opevesostat offers a novel and potentially more profound mechanism for suppressing the production of all steroid hormones and their precursors.[2]

The primary therapeutic rationale for opevesostat is centered on the treatment of hormone-dependent malignancies, with the most advanced clinical program focused on metastatic castration-resistant prostate cancer (mCRPC).[1] In mCRPC, the androgen receptor (AR) signaling pathway remains a fundamental driver of tumor progression, even in the castrate setting where testicular androgen production is suppressed.[4] Resistance to standard-of-care androgen receptor pathway inhibitors (ARPIs) often involves mechanisms that reactivate AR signaling, such as mutations in the AR ligand-binding domain (AR-LBD) that allow activation by alternative steroid ligands.[4] Opevesostat's mechanism of action is hypothesized to overcome this resistance by eliminating the entire pool of potential steroid ligands—both androgens and their precursors—that could promiscuously activate wild-type or mutated ARs.[4]

The drug was discovered by scientists at Orion Corporation and has progressed through early-phase clinical development under a collaborative agreement with Merck & Co., Inc. (known as MSD outside the United States and Canada).[1] Following promising results from the Phase 1/2 CYPIDES trial, the collaboration has evolved, with Merck now holding exclusive global rights to advance the comprehensive late-stage clinical development and potential commercialization of opevesostat.[7] As of 2024, the agent is being evaluated in a robust pivotal Phase 3 program for mCRPC, and its potential is also being explored in other hormone-sensitive cancers, including breast, endometrial, and ovarian cancers.[1]

2.0 Molecular Profile and Physicochemical Properties

A comprehensive understanding of opevesostat begins with its fundamental molecular identity and physicochemical characteristics. As a new molecular entity, its precise chemical structure and properties are foundational to its pharmacological behavior.[10] Opevesostat is a small molecule classified chemically as an antineoplastic agent belonging to several classes, including ethers, isoindoles, piperidines, pyrones, and sulfones.[10] Its detailed chemical and physical data have been cataloged across multiple chemical and drug databases, providing a consistent and verifiable molecular profile.

The formal International Union of Pure and Applied Chemistry (IUPAC) name for the compound is 2-(1,3-dihydroisoindol-2-ylmethyl)-5-[(1-methylsulfonylpiperidin-4-yl)methoxy]pyran-4-one.[1] It is most commonly referred to by its nonproprietary name, opevesostat, or its development code names, MK-5684 and ODM-208.[1] The molecular formula is , corresponding to a molar mass of approximately 418.51 .[1] A complete list of its identifiers and key properties is consolidated in Table 1, which serves as a definitive reference for the compound. These identifiers are crucial for cross-referencing information across scientific literature, clinical trial registries, and regulatory filings.

Property	Value	Source(s)
IUPAC Name	2-(1,3-dihydroisoindol-2-ylmethyl)-5-[(1-methylsulfonylpiperidin-4-yl)methoxy]pyran-4-one	1
Other Names / Synonyms	Opevesostat (USAN/INN), MK-5684, ODM-208, ODM208	1
Molecular Formula		1
Molar Mass	418.51	1
CAS Number	2231294-96-3	1
PubChem CID	135151902	1
DrugBank ID	DB18818	2
UNII	1Z7MAV4KQC	1
KEGG ID	D13110	1
ChEMBL ID	CHEMBL5314533	1
SMILES	CS(=O)(=O)N1CCC(CC1)COC2=COC(=CC2=O)CN3CC4=CC=CC=C4C3	1
InChIKey	LHVKCOBGLZGRQZ-UHFFFAOYSA-N	1
Table 1: Summary of Opevesostat Identifiers and Physicochemical Properties.

3.0 Mechanism of Action: Upstream Inhibition of Steroidogenesis

The therapeutic novelty of opevesostat lies in its unique and highly specific mechanism of action, which targets the very origin of steroid hormone production. This "upstream" approach distinguishes it fundamentally from all currently approved hormonal therapies for prostate cancer and forms the scientific basis for its development.

3.1 Targeting CYP11A1: The Gatekeeper of Steroid Biosynthesis

Opevesostat is a potent and selective inhibitor of the mitochondrial enzyme cytochrome P450 11A1 (CYP11A1), also known as the cholesterol side-chain cleavage enzyme.[1] This enzyme serves as the gatekeeper for the entire steroidogenesis pathway. It catalyzes the conversion of cholesterol to pregnenolone, which is the universal precursor for all subsequent steroid hormones.[2] This reaction is not only the first step but also the rate-limiting step in the biosynthesis of androgens, glucocorticoids, and mineralocorticoids.[2] By targeting this initial enzymatic reaction, opevesostat effectively shuts down the production of all steroidogenic lineages at their source.[3] It is important to note that some non-specialist literature has incorrectly identified the target of opevesostat as glutamine-fructose-6-phosphate transaminase 1 (GFPT1).[12] This is inconsistent with the overwhelming body of evidence from peer-reviewed studies, clinical trial protocols, and developer communications, which uniformly and authoritatively confirm CYP11A1 as the molecular target.[1]

3.2 Pharmacodynamic Effects: Achieving Comprehensive Suppression of Steroid Hormones and Precursors

The direct pharmacodynamic consequence of CYP11A1 inhibition is a profound and comprehensive suppression of all steroid hormones and their precursors.[6] Clinical data from early-phase trials have unequivocally confirmed this potent on-target effect. In patients with mCRPC treated with opevesostat, median circulating testosterone levels declined to undetectable levels, typically within the first week of initiating therapy.[13] This suppression goes far beyond testosterone; potent inhibition of other key steroid metabolites, including dehydroepiandrosterone (DHEA) sulfate, androstenedione, and pregnenolone itself, has also been demonstrated, validating the drug's mechanism of achieving a near-complete blockade of the steroidogenic cascade.[15]

This comprehensive blockade carries an inevitable and predictable on-target consequence: iatrogenic adrenal insufficiency.[13] Because the production of essential glucocorticoids (like cortisol) and mineralocorticoids (like aldosterone) is also dependent on CYP11A1, its inhibition necessitates hormone replacement therapy.[5] The occurrence of adrenal insufficiency is therefore not an off-target side effect but rather a clinical confirmation of the drug's potent and intended mechanism of action. It serves as a pharmacodynamic proof-of-concept, demonstrating that the drug is successfully engaging its target and achieving the desired comprehensive steroid suppression. The central clinical challenge, therefore, is not to avoid this effect but to manage it proactively and effectively with concomitant glucocorticoid and mineralocorticoid replacement, typically dexamethasone and fludrocortisone.[13]

3.3 Rationale and Differentiation from Existing Androgen Receptor Pathway Inhibitors (ARPIs)

The strategic rationale for developing a CYP11A1 inhibitor is best understood by contrasting its mechanism with existing standards of care for mCRPC, namely CYP17 inhibitors and direct AR antagonists.

Differentiation from Abiraterone Acetate (CYP17 Inhibitor): Abiraterone acetate, a prodrug of abiraterone, inhibits CYP17, an enzyme complex that functions further downstream in the steroidogenesis pathway.[5] While abiraterone is effective at blocking the synthesis of testosterone in the testes, adrenal glands, and tumor tissue, its inhibition of CYP17 leads to a compensatory accumulation of upstream steroid precursors.[5] These precursors, which are not formed when CYP11A1 is inhibited, can themselves bind to and activate the androgen receptor, particularly mutated forms of the AR that are common in advanced disease. This phenomenon is a well-recognized mechanism of resistance to abiraterone. Opevesostat's "upstream" blockade of CYP11A1 prevents the formation of this entire pool of precursors, thereby offering a more complete and potentially more durable suppression of ligands that can drive AR signaling.[5]

Differentiation from Enzalutamide (AR Antagonist): Enzalutamide is a potent AR antagonist that works at the final step of the pathway by directly binding to the AR, preventing its nuclear translocation and binding to DNA.[21] A primary mechanism of resistance to enzalutamide and other AR antagonists involves the emergence of mutations in the AR ligand-binding domain (AR-LBD).[4] These mutations can render the receptor "promiscuous," allowing it to be activated by non-canonical ligands, including adrenal steroid precursors, or can lead to constitutive, ligand-independent activation.[4] The therapeutic hypothesis for opevesostat is that by eliminating the entire spectrum of potential steroid ligands, it can effectively "starve" these mutated, promiscuous ARs, thereby overcoming this critical mode of resistance.[4] This provides a strong scientific rationale for the efficacy of opevesostat in patients whose tumors have developed AR-LBD mutations and progressed on prior AR-targeted therapies.

4.0 Clinical Pharmacology Profile

The clinical pharmacology of opevesostat has been characterized in dedicated studies to understand its absorption, metabolism, and potential for interactions with other medications. These data are crucial for establishing a safe and effective dosing regimen.

4.1 Pharmacokinetics (PK): Absorption, Metabolism, and Excretion

Opevesostat is formulated as an orally bioavailable small molecule, allowing for convenient administration.[2] Pharmacokinetic analyses from clinical trials have demonstrated consistent and predictable plasma concentration-time profiles.[24] Specific studies, such as one designed for Chinese patients with mCRPC, aim to fully characterize its PK parameters, including maximum plasma concentration (), time to maximum plasma concentration (), area under the curve (), apparent volume of distribution (), oral clearance (), and half-life ().[25] Additionally, a dedicated study was conducted to assess the drug's pharmacokinetics in participants with moderate hepatic impairment, a common comorbidity in this patient population.[13]

4.2 Drug-Drug Interaction (DDI) Potential and CYP Enzyme Effects

Given that patients with mCRPC are often elderly and receive multiple concurrent medications, understanding the potential for drug-drug interactions is a critical aspect of clinical development. Initial in vitro studies indicated that an active metabolite of opevesostat, known as M1, exhibited time-dependent inhibition of cytochrome P450 3A4 (CYP3A4), a major enzyme responsible for the metabolism of a vast number of drugs.[24] This finding necessitated a formal clinical DDI study to assess its real-world relevance.

A dedicated DDI cohort was incorporated into the CYPIDES trial, where patients with mCRPC received midazolam, a highly sensitive CYP3A4 substrate, both before and after seven days of continuous dosing with opevesostat at 5 mg twice daily.[24] The results of this study were highly favorable. The co-administration of opevesostat did not lead to any clinically significant alteration in the pharmacokinetics of midazolam. The geometric mean ratios (GMR) for midazolam's total exposure (AUC) and peak concentration () were close to 1.0, with the 90% confidence intervals for these ratios comfortably crossing 1.0, indicating no significant interaction.[24] The conclusion from this pivotal study is that opevesostat and its M1 metabolite do not act as clinically relevant inhibitors of CYP3A4-mediated metabolism. This clean DDI profile represents a significant clinical advantage, as it simplifies prescribing and reduces the risk of adverse events related to altered drug levels of concomitant medications. Unlike other agents such as abiraterone acetate, which is a CYP3A4 substrate and can be affected by strong inducers [20], opevesostat can be co-administered with a wide range of drugs without the need for dose adjustments or extensive medication review for CYP3A4 interactions.

4.3 Impact of Food on Bioavailability

To determine the appropriate instructions for administration relative to meals, a crossover study was conducted in 14 healthy male volunteers. Participants received a single 5 mg dose of opevesostat either in a fasted state or after a high-fat meal.[24] The study found that while food had a notable effect on the rate of absorption, it did not impact the overall extent of absorption. Specifically, the high-fat meal resulted in an approximately 41% decrease in the peak plasma concentration () and delayed the median time to reach that peak from 0.5 hours to 2.0 hours.[24] However, the total drug exposure, as measured by the area under the curve (AUC), remained unchanged between the fed and fasted states, with GMRs of approximately 0.97.[24] Since total exposure is generally more critical for determining the efficacy of a chronically administered drug, this finding is considered unlikely to have a significant impact on clinical practice, suggesting that opevesostat may be administered without strict regard to meals.[24]

5.0 The Opevesostat Clinical Development Program

The clinical development of opevesostat has been pursued through a systematic and ambitious program, progressing from first-in-human studies to a large-scale, global pivotal Phase 3 program designed to establish its efficacy and safety in distinct populations of patients with mCRPC. The program has recently expanded to explore its potential in other hormone-sensitive malignancies.

5.1 Foundational Data from the CYPIDES Phase 1/2 Trial (NCT03436485)

The CYPIDES trial was the foundational, first-in-human study for opevesostat. This open-label, non-randomized trial was designed to establish the initial safety, pharmacokinetic and pharmacodynamic profiles, and preliminary anti-tumor activity of the drug.[13] The study enrolled heavily pretreated patients with mCRPC who had already progressed on at least one novel ARPI and at least one taxane-based chemotherapy regimen.[14]

The Phase 1 dose-escalation portion of the trial successfully identified the primary on-target toxicity of adrenal insufficiency and determined that a dose of 5 mg administered twice daily (BID), in combination with supportive glucocorticoid and mineralocorticoid replacement, provided the optimal balance between potent steroidogenesis inhibition and manageable toxicity.[13] This dose was subsequently selected as the recommended Phase 2 dose (RP2D). The Phase 2 portion of CYPIDES consisted of expansion cohorts designed to further evaluate the RP2D and, critically, to test the hypothesis that activating mutations in the AR-LBD could serve as a predictive biomarker for response.[13]

5.2 The Pivotal OMAHA Phase 3 Program: Trial Designs and Strategic Objectives

Building on the promising signals from CYPIDES, Merck has launched a comprehensive Phase 3 program, named OMAHA, comprising two large, randomized trials. The concurrent execution of these two distinct trials represents a sophisticated, multi-pronged strategy to maximize the asset's potential market penetration while mitigating clinical development risk. This dual approach targets two different clinical settings in mCRPC: one trial aims to secure a position in a later-line, biomarker-enriched population with high unmet need, while the other targets a larger, earlier-line population, which represents a more substantial commercial opportunity.

5.2.1 OMAHA-003 (NCT06136624) / OMAHA1: The Post-NHA and Chemotherapy Setting

The OMAHA-003 trial (also referred to as OMAHA1) is a Phase 3, randomized, open-label study evaluating opevesostat in a heavily pretreated mCRPC population.[7] The trial is designed to enroll patients whose disease has progressed following treatment with both a next-generation hormonal agent (NHA) and one to two taxane-based chemotherapy regimens.[4] Patients are randomized to receive either opevesostat (with hormone replacement) or an NHA switch (abiraterone or enzalutamide).[30] The primary endpoint of the study is Overall Survival (OS), with the hypothesis that opevesostat will demonstrate superiority over the active comparator in this late-line setting.[30] The trial began in late 2023, with primary completion estimated for August 2028.[32]

5.2.2 OMAHA-004 (NCT06136650) / OMAHA2a: The Post-1 Prior NHA Setting

The OMAHA-004 trial (also referred to as OMAHA2a) targets an earlier and larger patient population.[6] This randomized, open-label Phase 3 study plans to enroll 1,500 patients with molecularly unselected mCRPC who have progressed after receiving only one prior NHA.[6] Patients in the investigational arm receive opevesostat 5 mg BID plus dexamethasone 1.5 mg QD and fludrocortisone 0.1 mg QD.[17] The comparator arm consists of an NHA switch to either abiraterone acetate (plus prednisone) or enzalutamide.[5] The study features dual primary endpoints: Radiographic Progression-Free Survival (rPFS) and Overall Survival (OS).[5] A key feature of the trial design is that these endpoints will be evaluated separately in cohorts of patients with and without AR-LBD mutations, effectively de-risking the study by allowing for a positive outcome even if the benefit is confined to the biomarker-positive subgroup. The trial is stratifying patients based on AR-LBD mutation status, metastatic volume, and prior docetaxel use for hormone-sensitive disease.[5]

5.3 Program Expansion: OMAHA-U01 Umbrella Study and Exploration in Other Malignancies

Beyond the two pivotal registration trials, the opevesostat program includes innovative platforms for future development.

OMAHA-U01 (MK-5684-01A / NCT06353386): This is an adaptive, rolling-arm, Phase 1/2 umbrella study designed for the efficient evaluation of opevesostat-based combination therapies in mCRPC.[34] This platform will allow for the rapid testing of novel therapeutic hypotheses, such as combining opevesostat with PARP inhibitors (olaparib) or chemotherapies (docetaxel, cabazitaxel), to identify synergistic effects and overcome additional resistance mechanisms.[36]

Expansion into Women's Cancers (NCT06979596): Recognizing the broader potential of a universal steroid synthesis inhibitor, Merck has initiated a Phase 2 basket trial to investigate opevesostat in other hormone-sensitive tumors.[9] This study will evaluate the safety and efficacy of the drug in patients with HER2-negative breast cancer, ovarian cancer, and endometrial cancer.[10] This strategic expansion is based on the strong biological rationale that blocking the synthesis of all steroid hormones, including estrogens (which are produced from androgen precursors), could be effective in these malignancies, potentially opening up significant new therapeutic avenues for opevesostat.

Trial Identifier	NCT Number	Phase	Target Population	Intervention vs. Comparator	Primary Endpoint(s)	Status
CYPIDES	NCT03436485	1/2	mCRPC post-NHA and taxane	Opevesostat monotherapy (dose escalation/expansion)	Safety, MTD, PK/PD, Preliminary Efficacy	Active, Not Recruiting 11
OMAHA-003 / OMAHA1	NCT06136624	3	mCRPC post-NHA and taxane	Opevesostat vs. NHA Switch (abiraterone or enzalutamide)	Overall Survival (OS)	Recruiting 30
OMAHA-004 / OMAHA2a	NCT06136650	3	mCRPC post-1 prior NHA	Opevesostat vs. NHA Switch (abiraterone or enzalutamide)	Radiographic Progression-Free Survival (rPFS) & OS	Recruiting 5
OMAHA-U01	NCT06353386	1/2	mCRPC	Opevesostat alone or in combination (e.g., with olaparib, docetaxel)	Safety, RP2D, Efficacy	Recruiting 34
Basket Trial	NCT06979596	2	Solid tumors (HER2- breast, ovarian, endometrial cancer)	Opevesostat-based combinations	Safety & Efficacy	Planned (Not Yet Recruiting) 10
Table 2: Overview of Key Clinical Trials in the Opevesostat Development Program.

6.0 Analysis of Clinical Efficacy in mCRPC

The clinical efficacy of opevesostat has been established through the comprehensive Phase 1/2 CYPIDES trial, which not only demonstrated anti-tumor activity in a heavily pretreated patient population but also revealed a powerful predictive biomarker that is now central to the drug's late-stage development strategy.

6.1 Primary and Secondary Efficacy Endpoints from the CYPIDES Trial

The primary efficacy assessments in the CYPIDES trial were based on standard oncologic endpoints, including Prostate-Specific Antigen (PSA) response rates and objective tumor response rates according to RECIST (Response Evaluation Criteria in Solid Tumors).[13] Across the 92 patients treated in Phase 1 and the initial AR-LBD mutation-positive cohort of Phase 2, opevesostat demonstrated clear evidence of anti-tumor activity.[13] The potent pharmacodynamic effect of the drug was confirmed by the rapid and profound suppression of circulating testosterone to undetectable levels within the first week of treatment, validating that the drug was hitting its target effectively in patients.[13]

6.2 The Critical Role of AR Ligand-Binding Domain (AR-LBD) Mutations as a Predictive Biomarker

The most significant efficacy finding from the CYPIDES trial was the stark difference in response rates between patients whose tumors harbored activating mutations in the AR-LBD and those with wild-type (non-mutated) AR. This observation strongly supports the core therapeutic hypothesis that opevesostat is particularly effective at overcoming this specific mechanism of resistance.

The data, summarized in Table 3, clearly illustrate this differential activity. In the Phase 2 cohort, which exclusively enrolled patients with AR-LBD mutations, the PSA50 response rate (defined as a decline in PSA of 50% or more from baseline) was 53.3%.[13] Later data cuts reported this rate as 55.6%.[28] In stark contrast, among patients with wild-type AR in the Phase 1 portion of the study, the PSA50 response rate was only 8.7%, with later analyses showing a rate of 16.7%.[13] A similar trend was observed for PSA30 responses (a ≥30% decline). Objective responses, signifying measurable tumor shrinkage, were also predominantly seen in the AR-LBD mutation-positive group, with an objective response rate (ORR) of approximately 20%, compared to a much lower rate in the wild-type group.[14] These findings provide compelling evidence that activating AR-LBD mutations function as a strong predictive biomarker for identifying patients most likely to benefit from opevesostat therapy.

Efficacy Endpoint	AR-LBD Mutation Positive	AR-LBD Mutation Negative (Wild-Type)	Source(s)
PSA50 Response Rate	53.3% - 55.6%	8.7% - 16.7%	13
PSA30 Response Rate	68% - 69.8%	29% - 30.0%	14
Objective Response Rate (ORR)	19% - 20.5%	0% - 5%	14
Table 3: Key Efficacy Outcomes from the CYPIDES Phase 1/2 Trial, Stratified by AR-LBD Mutation Status.

6.3 Comparative Context: Benchmarking Against Standard-of-Care Comparators

To fully appreciate the design and potential impact of the ongoing OMAHA Phase 3 trials, it is essential to benchmark the efficacy of the comparator agents, abiraterone acetate and enzalutamide. These are not placebo-controlled trials; opevesostat is being tested against an active and effective standard of care, setting a high bar for demonstrating superiority.

Abiraterone Acetate (Zytiga): In the pivotal COU-AA-302 trial in chemotherapy-naïve mCRPC, the combination of abiraterone acetate and prednisone extended median overall survival to 34.7 months, compared to 30.3 months for placebo plus prednisone.[39] In the post-chemotherapy setting (COU-AA-301), it improved median OS to 15.8 months versus 11.2 months for placebo.[40]

Enzalutamide (Xtandi): In the chemotherapy-naïve PREVAIL trial, enzalutamide demonstrated a 23% reduction in the risk of death and an 83% lower risk of radiographic progression compared to placebo.[41] In the post-chemotherapy AFFIRM trial, enzalutamide improved median OS to 18.4 months versus 13.6 months for placebo.[43]

The robust efficacy of these comparator agents underscores the challenge faced in the OMAHA program. The strong biomarker signal observed in the CYPIDES trial for patients with AR-LBD mutations provides the key scientific rationale for hypothesizing that opevesostat can outperform this active control, at least within this molecularly defined subgroup. Success in the OMAHA trials would require demonstrating a clinically meaningful improvement over these established therapies.

7.0 Safety and Tolerability Profile

The safety profile of opevesostat is well-characterized by the data from the CYPIDES Phase 1/2 trial. The observed adverse events are largely dominated by the predictable on-target effects of comprehensive steroid synthesis inhibition, which have proven to be manageable through dose optimization and appropriate supportive care.

7.1 On-Target Toxicity: Understanding and Managing Adrenal Insufficiency

The most common and clinically significant adverse event associated with opevesostat is treatment-related adrenal insufficiency, a direct and expected consequence of its mechanism of action.[13] During the Phase 1 dose-escalation part of the CYPIDES trial, where higher doses were explored, Grade 3 adrenal insufficiency was a frequent event, occurring in 36.2% of patients.[27] Serious events of this nature were reported in 34% of patients, with some requiring hospitalization for management with high-dose glucocorticoids.[15]

A critical outcome of the Phase 1 study was the identification of an optimized dose that mitigates this risk. The establishment of the 5 mg BID dose as the RP2D for Phase 2 led to a substantial reduction in the frequency and severity of adrenal insufficiency. In the Phase 2 cohort treated at this dose, the rate of Grade 3 adrenal insufficiency fell to 13.3%, with serious events occurring in only 6.7% of patients and the rate of hospitalization for this reason dropping to just 3.0%.[13] This demonstrates that while the on-target effect is unavoidable, its clinical consequences are highly manageable with the optimized dose and the mandated supportive care regimen, which includes daily co-administration of dexamethasone and fludrocortisone, as well as the provision of rescue hydrocortisone for patients to use during periods of illness or stress.[17]

7.2 Comprehensive Analysis of Treatment-Emergent Adverse Events (TEAEs)

A detailed analysis of the TEAEs from the CYPIDES trial is presented in Table 4. Virtually all patients in the trial experienced at least one TEAE, which is expected in this advanced cancer population receiving active therapy.[27] Grade 3 or higher events were common, reported in 70.2% of patients in Phase 1 and 80.0% in Phase 2.[27]

Aside from adrenal insufficiency, the most frequently reported adverse events (any grade) in the Phase 2 cohort included fatigue (37.8%), anemia (37.8%), asthenia (28.9%), dyspnea (26.7%), and peripheral edema (26.7%).[27] Common laboratory abnormalities included hyponatremia and hyperkalemia, consistent with mineralocorticoid deficiency. The most common Grade 3 or higher TEAEs in the Phase 2 cohort, beyond adrenal insufficiency, were anemia (13.3%), fatigue (6.7%), and hypertension (6.7%).[27] Despite the high overall incidence of TEAEs, the safety profile was considered clinically manageable, and deaths related to the study drug were not reported.[14]

Adverse Event (Preferred Term)	Phase 1 (All Doses) (N=47)	Phase 2 (5 mg BID) (N=45)
	Any Grade, n (%)	Grade ≥3, n (%)
Adrenal insufficiency	17 (36.2)	15 (31.9)
Anemia	16 (34.0)	7 (14.9)
Hyponatremia	15 (31.9)	6 (12.8)
Asthenia	14 (29.8)	2 (4.3)
Fatigue	14 (29.8)	0
Muscle spasms	14 (29.8)	0
Hyperkalemia	13 (27.7)	1 (2.1)
Edema peripheral	10 (21.3)	0
Tumor pain	10 (21.3)	4 (8.5)
ALT increased	10 (21.3)	1 (2.1)
Hypertension	8 (17.0)	5 (10.6)
Table 4: Summary of Common Treatment-Emergent Adverse Events from the CYPIDES Phase 1/2 Trial. Data adapted from.27

7.3 Populations of Concern as Indicated by Trial Exclusion Criteria

The exclusion criteria used across the opevesostat clinical trial protocols provide insight into patient populations who may be at higher risk for adverse events. A synthesis of these criteria reveals several key areas of concern. Patients with a pre-existing history of pituitary or adrenal dysfunction are excluded, as the drug's mechanism would directly exacerbate these conditions.[25] A significant emphasis is placed on cardiovascular health; patients with active or unstable cardiovascular disease, including recent myocardial infarction or stroke, uncontrolled hypertension, significant arrhythmias, or a history of long QTc syndrome, are ineligible for participation.[34] Other notable exclusions include patients with poorly controlled diabetes, active central nervous system metastases, active autoimmune diseases requiring systemic therapy, a history of seizures, or significant gastrointestinal conditions that could impair drug absorption.[47] These criteria help to define the patient population in which the drug has been studied and for whom the current risk-benefit profile is best understood.

8.0 Therapeutic Administration and Dosing Regimen

The administration and dosing regimen for opevesostat has been standardized based on the findings of the Phase 1/2 CYPIDES trial and is being uniformly applied in the ongoing Phase 3 OMAHA program.

Dosage: The established therapeutic dose of opevesostat is 5 mg, administered orally, twice daily (BID).[13] This dose was selected as the RP2D after the dose-escalation phase demonstrated it provided a favorable balance between potent pharmacodynamic effects (i.e., steroid suppression) and a manageable safety profile, particularly concerning adrenal insufficiency.[13]

Concomitant Therapy: Due to opevesostat's mechanism of action, which blocks the production of all endogenous steroids, concomitant hormone replacement therapy is a mandatory and integral part of the treatment regimen.[5] This supportive care is essential to prevent life-threatening adrenal crisis and manage the symptoms of glucocorticoid and mineralocorticoid deficiency. The standard replacement regimen consists of:

• Glucocorticoid Replacement: Dexamethasone, typically at a dose of 1 mg to 1.5 mg, administered orally once daily.[14]
• Mineralocorticoid Replacement: Fludrocortisone, at a dose of 0.1 mg, administered orally once daily.[14]
• Rescue Medication: Patients are also provided with hydrocortisone tablets to be used as a "stress dose" rescue medication in the event of intercurrent illness, trauma, surgery, or the emergence of symptoms of acute adrenal insufficiency.[25]

Administration: Opevesostat is supplied as an oral tablet.[45] The clinical pharmacology study on the effect of food on bioavailability indicated that while a high-fat meal can slow the rate of absorption, it does not affect the total drug exposure (AUC).[24] This suggests that the drug could potentially be administered without strict regard to meals, although final label recommendations will depend on the complete data from the Phase 3 program.

9.0 Strategic and Commercial Landscape

The development of opevesostat is underpinned by a significant strategic partnership and a clear vision for its potential role in the oncology market, extending from its initial indication in prostate cancer to future growth opportunities in other hormone-driven malignancies.

9.1 Development and Licensing Trajectory: The Orion-Merck Partnership

Opevesostat was discovered and advanced through initial development by the Finnish pharmaceutical company Orion Corporation.[1] Recognizing the potential of the asset but also the immense resources required for late-stage global development, Orion entered into a co-development and co-commercialization agreement with Merck (MSD).[7] This partnership leveraged Orion's discovery expertise with Merck's vast clinical development and commercialization infrastructure.

In a pivotal strategic move in July 2024, the collaboration was converted into an exclusive global license for Merck.[7] Under this new agreement, Merck assumed full responsibility for all past and future development and commercialization expenses, gaining sole global rights to opevesostat and other compounds from the CYP11A1 inhibitor program.[8] This transition is a classic example of a "big pharma" de-risking and asset maximization strategy. Orion successfully navigated the high-risk early stages of development, delivering a promising asset with clear proof-of-concept and a validated biomarker. The new deal structure allows Orion to offload the considerable financial burden and risk of the large-scale Phase 3 program while retaining substantial financial upside through a structured series of milestone payments and royalties.[50] For Merck, the deal secures a de-risked, late-stage asset with a novel mechanism that fits well within its oncology portfolio. The assumption of past development costs by Merck is a particularly strong signal of its confidence in the program's potential for success.

The financial terms of the exclusive license entitle Orion to receive up to $30 million in development milestones, up to $625 million in regulatory milestones, and up to $975 million in sales-based milestones. Additionally, Orion will receive tiered royalties on net sales, ranging from a low double-digit percentage up to a rate in the low twenties.[50] Orion will also continue to play a key role by retaining responsibility for the manufacture of both clinical and commercial drug supply for Merck.[50] Independent market analysis forecasts global sales for opevesostat reaching $207 million by 2030, a figure that could prove conservative if the pivotal trials demonstrate strong superiority over the standard of care.[7]

9.2 Potential Therapeutic Positioning in the Evolving mCRPC Treatment Paradigm

The clinical development strategy for opevesostat maps out a clear path for its potential positioning within the complex mCRPC treatment landscape. Based on the compelling efficacy data from the CYPIDES trial in patients with AR-LBD mutations, the most direct path to market would be for the treatment of heavily pretreated mCRPC patients who have failed both an NHA and taxane chemotherapy, particularly if they are biomarker-positive. This is the precise population being studied in the OMAHA-003 trial and represents a significant unmet medical need.

A more transformative and commercially significant positioning would be achieved with a positive outcome in the OMAHA-004 trial. Success in this study would position opevesostat as a superior alternative to the common practice of switching between existing NHAs (e.g., from abiraterone to enzalutamide or vice versa) in an earlier-line setting. Given the drug's unique mechanism of action, it provides a strong scientific rationale for use after progression on any prior AR-pathway inhibitor, potentially establishing it as the preferred second-line NHA-class agent.

9.3 Future Growth Vectors: Expansion into Breast, Ovarian, and Endometrial Cancers

A key element of the long-term strategy for opevesostat is the expansion beyond prostate cancer. The recent initiation of a Phase 2 basket trial (NCT06979596) to evaluate the drug in breast, ovarian, and endometrial cancers marks a significant broadening of its potential therapeutic application.[9] This strategic move is grounded in the biological principle that subtypes of these cancers are also driven by steroid hormone signaling (e.g., estrogen receptor-positive breast cancer). The steroidogenesis pathway that produces estrogens is downstream of the synthesis of androgen precursors. Therefore, by blocking CYP11A1, opevesostat inhibits the production of the foundational molecules required for estrogen synthesis, in addition to androgens. If this hypothesis is proven correct in the clinic, it would dramatically increase the potential patient population for opevesostat and extend its commercial lifecycle well beyond prostate cancer.

10.0 Expert Synthesis and Future Directions

Opevesostat emerges from this comprehensive analysis as a highly promising, first-in-class investigational agent with a rationally designed and scientifically elegant mechanism of action. As a potent, selective inhibitor of CYP11A1, it offers a more complete blockade of the steroidogenesis pathway than any currently available therapy. This upstream inhibition effectively eliminates the entire pool of steroid hormones and precursors that can drive androgen receptor signaling, representing a novel strategy to combat the key mechanisms of resistance that limit the durability of current standards of care in metastatic castration-resistant prostate cancer.

The clinical data to date from the CYPIDES trial are compelling. Opevesostat has demonstrated clear anti-tumor activity in a heavily pretreated mCRPC population, and critically, has revealed a strong predictive biomarker in the form of activating AR-LBD mutations. The safety profile is characterized by a predictable and manageable on-target toxicity of adrenal insufficiency, the risk of which has been substantially mitigated through dose optimization and a standardized hormone replacement regimen. The favorable clinical pharmacology profile, particularly the lack of significant CYP3A4-mediated drug-drug interactions, further enhances its clinical utility. Backed by a robust strategic partnership between Orion and Merck, the asset is now being advanced through a well-designed, ambitious pivotal Phase 3 program.

The future of opevesostat and its ultimate place in the therapeutic armamentarium now rests on the outcomes of this ongoing program. Several critical questions must be answered:

1. Biomarker Confirmation: Can the striking efficacy signal observed in patients with AR-LBD mutations in the CYPIDES trial be definitively confirmed in the randomized, controlled setting of the OMAHA-003 and OMAHA-004 trials?
2. Benefit in the Broader Population: Will opevesostat demonstrate a clinically meaningful benefit over an active NHA switch in the larger, AR-LBD wild-type population? The answer to this question, a key objective of the OMAHA-004 trial, will determine whether opevesostat becomes a niche, biomarker-driven therapy or a broadly used agent in the mCRPC landscape.
3. Long-Term Safety: How will the long-term safety and tolerability profile, particularly the management of chronic, iatrogenic adrenal insufficiency, compare to the known and well-established safety profiles of abiraterone and enzalutamide over years of treatment?
4. Broadening the Horizon: Will the drug's mechanism of universal steroid suppression translate to meaningful clinical activity in other hormone-sensitive malignancies, such as breast and endometrial cancer, as hypothesized in the newly initiated basket trial?

In conclusion, opevesostat represents one of the most promising new hormonal agents in the oncology pipeline. Its unique mechanism directly addresses a known vulnerability in the treatment of advanced prostate cancer. Contingent on positive outcomes from the pivotal OMAHA trials, opevesostat has the potential to become a significant new standard of care for patients with mCRPC and may ultimately find a role in a much broader range of hormone-dependent cancers.

Works cited

1. Opevesostat - Wikipedia, accessed October 8, 2025, https://en.wikipedia.org/wiki/Opevesostat
2. Opevesostat | C21H26N2O5S | CID 135151902 - PubChem, accessed October 8, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/135151902
3. Definition of opevesostat - NCI Drug Dictionary, accessed October 8, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/opevesostat
4. OMAHA-003: A phase 3 study of CYP11A1 inhibitor opevesostat versus next-generation hormonal agent (NHA) switch in metastatic castration-resistant prostate cancer (mCRPC) after NHA and taxane-based chemotherapy. - ASCO Publications, accessed October 8, 2025, https://ascopubs.org/doi/10.1200/JCO.2025.43.5_suppl.TPS286
5. Opevesostat Trial in mCRPC: Targeting Androgen Biosynthesis ..., accessed October 8, 2025, https://www.urotoday.com/video-lectures/suo-2024/video/4557-opevesostat-trial-in-mcrpc-targeting-androgen-biosynthesis-upstream-for-improved-outcomes-christian-gratzke.html
6. Phase 3 OMAHA-004 study of CYP11A1 inhibitor opevesostat, accessed October 8, 2025, https://ascopubs.org/doi/10.1200/JCO.2025.43.5_suppl.TPS301
7. Orion to hand over exclusive rights to MSD for prostate cancer therapy, accessed October 8, 2025, https://www.pharmaceutical-technology.com/news/orion-to-hand-over-exclusive-rights-to-msd-for-prostate-cancer-therapy/
8. Merck and Orion Announce Mutual Exercise of Option Providing Merck Global Exclusive Rights to Opevesostat, an Investigational CYP11A1 Inhibitor, for the Treatment of Metastatic Castration-Resistant Prostate Cancer, accessed October 8, 2025, https://www.merck.com/bdl_item/merck-and-orion-announce-mutual-exercise-of-option-providing-merck-global-exclusive-rights-to-opevesostat-an-investigational-cyp11a1-inhibitor-for-the-treatment-of-metastatic-castration-resistant-pr/
9. MSD Expands Opevesostat Clinical Program to Include Breast, Endometrial, and Ovarian Cancers - MedPath, accessed October 8, 2025, https://trial.medpath.com/news/12ff521504a5e886/msd-expands-opevesostat-clinical-program-to-include-breast-endometrial-and-ovarian-cancers
10. Opevesostat - Orion - AdisInsight - Springer, accessed October 8, 2025, https://adisinsight.springer.com/drugs/800050472
11. Opevesostat: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed October 8, 2025, https://go.drugbank.com/drugs/DB18818
12. What is Opevesostat used for? - Patsnap Synapse, accessed October 8, 2025, https://synapse.patsnap.com/article/what-is-opevesostat-used-for
13. Opevesostat - Drug Targets, Indications, Patents - Synapse, accessed October 8, 2025, https://synapse.patsnap.com/drug/4aa1be575e5e42af98751a88a5a35724
14. ESMO 2024: Opevesostat (MK-5684/ODM-208), an Oral CYP11A1 Inhibitor, in Metastatic Castration-Resistant Prostate Cancer (mCRPC): Updated CYPIDES Phase 2 Results - UroToday, accessed October 8, 2025, https://www.urotoday.com/conference-highlights/esmo-2024/esmo-2024-prostate-cancer/154774-esmo-2024-opevesostat-mk-5684-odm-208-an-oral-cyp11a1-inhibitor-in-metastatic-castration-resistant-prostate-cancer-mcrpc-updated-cypides-phase-2-results.html
15. Phase 1 results of the ODM-208 first-in-human phase 1-2 trial in patients with metastatic castration-resistant prostate cancer (CYPIDES). - ASCO, accessed October 8, 2025, https://www.asco.org/abstracts-presentations/ABSTRACT357822
16. Novel Treatment Targets in the Metastatic Castrate-Resistant Prostate Cancer Disease Space - UroToday, accessed October 8, 2025, https://www.urotoday.com/library-resources/advanced-prostate-cancer/147782-novel-treatment-targets-in-the-metastatic-castrate-resistant-prostate-cancer-disease-space.html
17. SUO 2024: Phase III MK-5684-004 Study of CYP11A1 Inhibitor ..., accessed October 8, 2025, https://www.urotoday.com/conference-highlights/suo-2024/suo-2024-prostate-cancer/156709-suo-2024-phase-iii-mk-5684-004-study-of-cyp11a1-inhibitor-opevesostat-versus-next-generation-hormonal-agent-switch-in-patients-with-metastatic-castration-resistant-prostate-cancer-after-1-prior-next-generation-hormonal-agent.html
18. Abiraterone acetate in the treatment of metastatic castration-resistant prostate cancer: review of clinical data - Open Access Journals, accessed October 8, 2025, https://www.openaccessjournals.com/articles/abiraterone-acetate-in-the-treatment-of-metastatic-castrationresistant-prostate-cancer-review-of-the-clinical-data.pdf
19. What is the mechanism of Abiraterone acetate? - Patsnap Synapse, accessed October 8, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-abiraterone-acetate
20. HOW ZYTIGA ® (abiraterone acetate) WORKS, accessed October 8, 2025, https://www.zytigahcp.com/how-zytiga-works/
21. What is the mechanism of Enzalutamide?, accessed October 8, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-enzalutamide
22. Evidence for the efficacy of enzalutamide in postchemotherapy metastatic castrate-resistant prostate cancer - PMC, accessed October 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3721441/
23. Enzalutamide therapy for advanced prostate cancer: efficacy, resistance and beyond in, accessed October 8, 2025, https://erc.bioscientifica.com/view/journals/erc/26/1/ERC-18-0289.xml
24. Abstract CT176: Pharmacokinetics (PK) of the novel nonsteroidal CYP11A1 inhibitor opevesostat (ODM-208/MK-5684): Interaction potential with midazolam and effect of food - AACR Journals, accessed October 8, 2025, https://aacrjournals.org/cancerres/article/85/8_Supplement_2/CT176/761812/Abstract-CT176-Pharmacokinetics-PK-of-the-novel
25. NCT06136598 | A Study of Opevesostat (MK-5684) in China Participants With Metastatic Castration-Resistant Prostate Cancer (mCRPC) (MK-5684-001) | ClinicalTrials.gov, accessed October 8, 2025, https://clinicaltrials.gov/study/NCT06136598?term=opevesostat&rank=5
26. Safety and Pharmacokinetics of ODM-208 in Patients With Metastatic Castration-resistant Prostate Cancer - NCI, accessed October 8, 2025, https://www.cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2021-14364
27. Targeted Inhibition of CYP11A1 in Castration-Resistant Prostate Cancer - PMC, accessed October 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10852404/
28. MK-5684 (ODM-208), a CYP11A1 inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC) with and without AR-LBD mutations: CYPIDES phase 2 results. - ASCO Publications, accessed October 8, 2025, https://ascopubs.org/doi/10.1200/JCO.2024.42.4_suppl.159
29. Merck obtains exclusive global rights to CYP11A1 inhibitor in mCRPC - Urology Times, accessed October 8, 2025, https://www.urologytimes.com/view/merck-obtains-exclusive-global-rights-to-cyp11a1-inhibitor-in-mcrpc
30. NCT06136624 | Study of Opevesostat (MK-5684) Versus Alternative NHA in mCRPC (MK-5684-003) | ClinicalTrials.gov, accessed October 8, 2025, https://clinicaltrials.gov/study/NCT06136624
31. CLINICAL TRIAL / NCT06136624 - UChicago Medicine, accessed October 8, 2025, https://www.uchicagomedicine.org/find-a-clinical-trial/clinical-trial/irb240166
32. Study of MK-5684 Versus Alternative NHA in mCRPC - Merck Clinical Trials, accessed October 8, 2025, https://www.merckclinicaltrials.com/trial/nct06136624/
33. Study of MK-5684 Versus Alternative NHA in mCRPC - MSD Clinical Trials, accessed October 8, 2025, https://www.msdclinicaltrials.com/trial/nct06136624/
34. Based Treatment Combinations or Opevesostat Alone in Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-5684-01A) | UCLA Health Clinical Trials and Research Studies, accessed October 8, 2025, https://www.uclahealth.org/clinical-trials/substudy-01a-safety-and-efficacy-opevesostat-mk-5684-based
35. Phase 1/2 OMAHA-01A substudy of oral CYP11A1 inhibitor opevesostat alone or in combination with other therapies for metastatic castration-resistant prostate cancer (mCRPC). - ASCO Publications, accessed October 8, 2025, https://ascopubs.org/doi/10.1200/JCO.2025.43.5_suppl.TPS300
36. Based Treatment Combinations or Opevesostat Alone in Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-5684-01A) | ClinicalTrials.gov, accessed October 8, 2025, https://www.clinicaltrials.gov/study/NCT06353386?term=NCT06353386&rank=1
37. Orion's collaborator, MSD, expands clinical development program for opevesostat to women's cancers, accessed October 8, 2025, https://www.orionpharma.com/newsroom/all-news/releases/press-releases/2025/orions-collaborator-msd-expands-clinical-development-program-for-opevesostat-to-womens-cancers/
38. Based Treatment Combinations or Opevesostat Alone in Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-5684-01A) | Clinical Research Trial Listing - CenterWatch, accessed October 8, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT06353386/substudy-01a-safety-and-efficacy-of-opevesostat-mk-5684-based-treatment-combinations-or-opevesostat-alone-in-participants-with-metastatic-castration-resistant-prostate-cancer-mcrpc-mk-5684-01a
39. mCRPC Progression on ADT | ZYTIGA® (abiraterone acetate), accessed October 8, 2025, https://www.zytigahcp.com/efficacy-and-safety/mcrpc-progression-on-adt/
40. mCRPC Following Chemotherapy Study | ZYTIGA® (abiraterone acetate), accessed October 8, 2025, https://www.zytigahcp.com/efficacy-and-safety/mcrpc-following-chemotherapy-study/
41. Clinical Trial Results | XTANDI® (enzalutamide), accessed October 8, 2025, https://www.xtandi.com/clinical-trials
42. Efficacy CRPC | HCP Site | XTANDI® (enzalutamide), accessed October 8, 2025, https://www.xtandihcp.com/crpc/efficacy
43. Enzalutamide: A Novel Antiandrogen for Patients with Castrate-Resistant Prostate Cancer, accessed October 8, 2025, https://aacrjournals.org/clincancerres/article/19/6/1335/205454/Enzalutamide-A-Novel-Antiandrogen-for-Patients
44. The Clinical Efficacy of Enzalutamide in Metastatic Prostate Cancer: Prospective Single-center Study | Anticancer Research, accessed October 8, 2025, https://ar.iiarjournals.org/content/37/3/1475
45. A Study of Opevesostat (MK-5684) in China Participants With Metastatic Castration-Resistant Prostate Cancer (mCRPC) (MK-5684-001) - ClinicalTrials.Veeva, accessed October 8, 2025, https://ctv.veeva.com/study/a-study-of-mk-5684-in-china-participants-with-metastatic-castration-resistant-prostate-cancer-mcrpc
46. Safety and Pharmacokinetics of ODM-208 in Patients With M... - Clinical Trial Discovery, accessed October 8, 2025, https://clinicaltrial.be/en/details/69417?per_page=20&only_recruiting=0&only_eligible=0&only_active=0
47. A Study of Opevesostat (MK-5684) Versus Alternative Next-generation Hormonal Agent (NHA) in Metastatic Castration-resistant Prostate Cancer (mCRPC) Post One NHA (MK-5684-004) - Clinical Trials | Stanford Medicine, accessed October 8, 2025, https://clinicaltrials.stanford.edu/trials/a/NCT06136650.html
48. Based Treatment Combinations or Opevesostat Alone in Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-5684-01A) - UCSD Clinical Trials, accessed October 8, 2025, https://clinicaltrials.ucsd.edu/trial/NCT06353386
49. Substudy 01A: Safety and Efficacy of Opevesostat (MK-5684)-Based Treatment Combinations or Opevesostat Alone in Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-5684-01A) - NCI, accessed October 8, 2025, https://www.cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-06341
50. Merck and Orion Exclusive Rights to Opevesostat for Metastatic Prostate Cancer, accessed October 8, 2025, https://www.clinicaltrialvanguard.com/news/merck-and-orion-exclusive-rights-to-opevesostat-for-metastatic-prostate-cancer/
51. Merck and Orion Announce Mutual Exercise of Option Providing ..., accessed October 8, 2025, https://www.merck.com/news/merck-and-orion-announce-mutual-exercise-of-option-providing-merck-global-exclusive-rights-to-opevesostat-an-investigational-cyp11a1-inhibitor-for-the-treatment-of-metastatic-castration-resistant-pr/
52. Merck Gets Exclusive Right to Orion's Opevesostat | American Pharmaceutical Review, accessed October 8, 2025, https://www.americanpharmaceuticalreview.com/1315-News/613880-Merck-Gets-Exclusive-Right-to-Orion-s-Opevesostat/