opevesostat (MK-5684) / Orion Corp, Merck (MSD) - LARVOL DELTA

IDeate-Prostate02: A phase 1/2, open-label umbrella substudy of ifinatamab deruxtecan-based treatment combinations or as monotherapy in participants with previously treated metastatic castration-resistant prostate cancer. (ASCO-GU 2026) - P1/2 | "Two monotherapy arms, each with ~80 to ~120 participants, will enroll participants into the Efficacy Phase; Arm 1: docetaxel and Arm 2: I-DXd. Two I-DXd combination arms will enroll participants into the Safety Lead-in (n~10), followed by Efficacy (n~50) phases: Arm 3: I-DXd+MK-5684, and Arm 4: I-DXd+ARPI...Previously presented at 26th Annual Meeting of the Society of Urologic Oncology; December 2–5, 2025; Phoenix, AZ. bid, twice daily; IV, intravenously; po, orally; q3w, every 3 weeks; qd, once daily."

Clinical • First-in-human • Metastases • Monotherapy • P1/2 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD276

IDeate-Prostate02: A PHASE 1/2, OPEN-LABEL UMBRELLA SUBSTUDY OF IFINATAMAB DERUXTECAN-BASED TREATMENT COMBINATIONS OR AS MONOTHERAPY IN PARTICIPANTS WITH PREVIOUSLY TREATED METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (SUO 2025) - P1/2 | "Two monotherapy arms (Arm 1 [docetaxel] and Arm 2 [I-DXd]) will enroll participants into the Efficacy Phase, and 2 I-DXd combination arms (Arm 3: I-DXd+MK-5684; and Arm 4: I-DXd+ARPI [abiraterone acetate or enzalutamide; prior treatment dependent]) will enroll into the Safety Lead-in, followed by Efficacy Phase. Recruitment is ongoing. "

Clinical • Metastases • Monotherapy • P1/2 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD276

CYP11A1 INHIBITOR OPEVESOSTAT ALONE OR IN COMBINATION WITH OTHER THERAPIES FOR PARTICIPANTS WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER: THE PHASE 1/2 OMAHA-01A SUBSTUDY (SUO 2025) - P1/2 | "In the efficacy phase, participants will be randomized 1:1:1:1 to receive opevesostat alone (5 mg PO BID; N≤100), or in combination with olaparib, docetaxel or cabazitaxel at the RP2D (~40 participants each). Secondary end points include ORR, DOR and radiographic PFS per PCWG-modified RECIST v1.1, and OS. "

Combination therapy • Metastases • P1/2 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Hormone Sensitive Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

Opevesostat (MK-5684/ODM-208), an oral CYP11A1 inhibitor, in metastatic castration-resistant prostate cancer (mCRPC): Updated CYPIDES phase II results (ESMO 2024) - P1/2 | "53.0% and 36.8% had previously received both abiraterone and enzalutamide, and 69.7% and 64.7% had received cabazitaxel in patients with and without AR-LBD mutation respectively. Administration of Opevesostat to heavily pre-treated mCRPC patients shows promising antitumor activity. PSA50 responses were most frequent among patients harbouring activating AR-LBD mutations."

Metastases • P2 data • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

Preliminary phase II results of the CYPIDES study of ODM-208 in metastatic castration-resistant prostate (mCRPC) cancer patients (ESMO 2022) - P1/2 | "51% patients had previously received both abiraterone and enzalutamide, and 65% patients both docetaxel and cabazitaxel. Conclusions Administration of ODM-208 to heavily pre-treated mCRPC patients with AR LBD mutation was highly effective in blocking the production of steroid hormones and showed promising antitumor activity. NCT03436485."

Clinical • P2 data • Oncology • Prostate Cancer

The pharmacokinetics and the pharmacodynamic effect of ODM-208, an inhibitor of cholesterol side-chain cleavage enzyme (CYP11A1) (ESMO 2022) - P1/2 | "Conclusions ODM-208 exposure increased and decreased again almost dose-proportionately while concentrations of ODM-208 were similar on days 1 and 8. It was shown that ODM-208 can reach systemic plasma levels capable for excessively reducing serum testosterone levels in a wide dose range."

PK/PD data • Oncology • Prostate Cancer

OMAHA-004: Phase 3 trial of CYP11A1 inhibitor opevesostat versus androgen receptor pathway inhibitor (ARPI) switch in participants with metastatic castration-resistant prostate cancer (mCRPC) after a prior ARPI. (ASCO-GU 2026) - P3 | "Prior ARPI plus docetaxel for HSPC is permitted if participants received no more than 6 cycles of docetaxel without radiographic disease progression. Approximately 1314 participants will be randomized 1:1 to opevesostat 5 mg orally twice-daily plus dexamethasone 1.5 mg and fludrocortisone 0.1 mg orally once daily or abiraterone acetate 1000 mg orally once daily plus prednisone 5 mg orally twice daily (if prior enzalutamide, darolutamide, or apalutamide) or enzalutamide 160 mg orally once-daily (if prior abiraterone)...Other secondary end points include time to initiation of first subsequent anticancer therapy or death, objective response rate and duration of response per PCWG3-modified RECIST v1.1 by BICR, time to pain progression; time to prostate-specific antigen (PSA) progression, PSA response rate, time to first symptomatic skeletal-related event, and safety and tolerability. Enrollment is ongoing."

Metastases • P3 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Hormone Sensitive Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

CYP11A1 inhibitor MK-5684 versus next-generation hormonal agent (NHA) switch in patients with metastatic castration-resistant prostate cancer (mCRPC) after 1 prior NHA: Phase 3 MK-5684-004 study. (ASCO 2024) - P3 | "Prior NHA + docetaxel for HSPC is permitted if patients received ≤6 cycles of docetaxel without radiographic disease progression. Approximately 1500 patients (AR-LBD mutation–positive, 375 patients; AR-LBD mutation–negative, 1125 patients) will be randomly assigned 1:1 to receive MK-5684 5 mg PO BID + dexamethasone 1.5 mg and fludrocortisone 0.1 mg PO QD or abiraterone acetate 1000 mg PO QD + prednisone 5 mg PO BID (if prior enzalutamide/darolutamide/apalutamide) or enzalutamide 160 mg PO QD (if prior abiraterone)...Secondary end points include time to initiation of first subsequent anticancer therapy or death; ORR and DOR per PCWG3-modified RECIST v1.1 by BICR; time to pain progression; time to prostate-specific antigen (PSA) progression; PSA response rate; time to first symptomatic skeletal-related event; and safety and tolerability. Recruitment is ongoing."

Clinical • Metastases • P3 data • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Pain • Prostate Cancer • Solid Tumor

OMAHA-004: Phase 3 trial of the steroidogenesis inhibitor opevesostat versus androgen receptor pathway inhibitor (ARPI) switch in participants with metastatic castration-resistant prostate cancer after a prior ARPI (AUA 2026) - P3 | "Approximately 1314 pts will be randomized 1:1 to opevesostat 5 mg orally twice daily (BID) + dexamethasone 1.5 mg and fludrocortisone 0.1 mg orally once daily or abiraterone acetate 1000 mg orally once daily + prednisone 5 mg orally BID (if prior enzalutamide, darolutamide, or apalutamide) or enzalutamide 160 mg orally once daily (if prior abiraterone). Stratification factors are metastatic site (bone only vs liver vs other), AR ligand binding mutation (AR-LBDm) status (positive vs negative), and prior docetaxel treatment for HSPC (yes vs no)...Other secondary end points include time to initiation of first subsequent anticancer therapy or death, objective response rate and duration of response per PCWG3-modified RECIST v1.1 by BICR, time to pain progression; time to prostate-specific antigen (PSA) progression, PSA response rate, time to first symptomatic skeletal-related event, and safety and tolerability. Enrollment is ongoing."

Metastases • P3 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Hormone Sensitive Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor • Urology

PHASE 3 MK-5684-004 STUDY OF CYP11A1 INHIBITOR OPEVESOSTAT VERSUS NEXT-GENERATION HORMONAL AGENT (NHA) SWITCH IN PATIENTS WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER AFTER 1 PRIOR NHA (SUO 2024) - P3 | "Approximately 1500 patients (375 with, 1125 without AR-LBD mutations) will be randomly assigned 1:1 to receive opevesostat 5 mg PO BID + dexamethasone 1.5 mg and fludrocortisone 0.1 mg PO QD or abiraterone acetate 1000 mg PO QD (if prior enzalutamide/darolutamide/apalutamide) or enzalutamide 160 mg PO QD (if prior abiraterone). This abstract was previously presented at the 2024 ASCO Annual Meeting. ."

Clinical • Metastases • P3 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Hormone Sensitive Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

CYPIDES: Safety and Pharmacokinetics of ODM-208 in Patients With Metastatic Castration-resistant Prostate Cancer (clinicaltrials.gov) - P1/2 | N=204 | Active, not recruiting | Sponsor: Orion Corporation, Orion Pharma | Trial completion date: Jul 2026 ➔ Oct 2026 | Trial primary completion date: Jul 2026 ➔ Oct 2026

First-in-human • Trial completion date • Trial primary completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

A Drug-Drug Interaction Study of Itraconazole and Opevesostat (MK-5684) in Healthy Adult Male Participants (MK-5684-017) (clinicaltrials.gov) - P1 | N=14 | Completed | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Completed

Trial completion

Safety and pharmacokinetics of odm-208 in patients with metastatic castration-resistant prostate cancer (clinicaltrialsregister.eu) - P1/2 | N=129 | Completed | Sponsor: Orion Corporation | Active, not recruiting ➔ Completed

Trial completion • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

Phase 1/2 OMAHA-U01 substudy 01A: Oral steroidogenesis inhibitor opevesostat alone or in combination with other therapies in participants with metastatic castration-resistant prostate cancer (mCRPC). (ASCO 2026) - P1/2 | "Participants will be randomly assigned 1:1:1:1 to receive opevesostat 5 mg PO BID, opevesostat 5 mg PO BID plus olaparib (RP2D), opevesostat 5 mg PO BID plus docetaxel (RP2D), or opevesostat 5 mg PO BID plus cabazitaxel (RP2D). Secondary end points include objective response rate and radiographic progression-free survival per PCWG-modified RECIST v1.1 by blinded independent central review (BICR), overall survival, duration of response by BICR, time to first subsequent anticancer therapy, and time to pain progression. The predefined eligibility cap for pts with AR-LBDm-negative status has been reached, and the study is currently only enrolling pts with AR-LBDm-positive status."

Combination therapy • Metastases • P1/2 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Hormone Sensitive Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

OMAHA-004: Phase 3 trial of the steroidogenesis inhibitor opevesostat versus androgen receptor pathway inhibitor (ARPI) switch in participants with metastatic castration-resistant prostate cancer (mCRPC) after a prior ARPI. (ASCO 2026) - P3 | "Prior ARPI plus docetaxel for HSPC is permitted if participants received no more than 6 cycles of docetaxel without radiographic disease progression. Approximately 1314 participants will be randomized 1:1 to opevesostat 5 mg orally twice-daily plus dexamethasone 1.5 mg and fludrocortisone 0.1 mg orally once daily or abiraterone acetate 1000 mg orally once daily plus prednisone 5 mg orally twice daily (if prior enzalutamide, darolutamide, or apalutamide) or enzalutamide 160 mg orally once-daily (if prior abiraterone)...Other secondary end points include time to initiation of first subsequent anticancer therapy or death, objective response rate and duration of response per PCWG3-modified RECIST v1.1 by BICR, time to pain progression; time to prostate-specific antigen (PSA) progression, PSA response rate, time to first symptomatic skeletal-related event, and safety and tolerability. Enrollment is ongoing."

Metastases • P3 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Hormone Sensitive Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

Study design of OMAHA-015: A phase 2 basket study of steroidogenesis inhibitor opevesostat in participants with selected solid tumors. (ASCO 2026) - P2 | "Exclusion criteria include any line of cytotoxic chemotherapy (chemo) or PARP inhibitor in the inoperable or noncurative advanced/metastatic setting and prior treatment with both fulvestrant and exemestane in the metastatic setting...In cohort C, ~80 pts will be randomized 1:1 to arm 5: opevesostat 5 mg PO BID + daily corticosteroids; or arm 6: physician's choice of megestrol acetate 80 mg PO BID, alternating megestrol + tamoxifen 20 mg PO BID, or letrozole 2.5 mg PO daily...Secondary end points include overall survival, clinical benefit rate (cohort A only), objective response rate, and duration of response per RECIST v1.1 assessed by BICR, and safety. The study is currently enrolling."

P2 data • Pan tumor • Breast Cancer • Carcinosarcoma • Endometrial Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Sarcoma • Solid Tumor • ER • HER-2 • PGR • TP53

A Drug-Drug Interaction Study of Itraconazole and Opevesostat (MK-5684) in Healthy Adult Male Participants (MK-5684-017) (clinicaltrials.gov) - P1 | N=14 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Recruiting ➔ Active, not recruiting

Enrollment closed

OMAHA-003: Study of Opevesostat (MK-5684) Versus Alternative NHA in mCRPC (MK-5684-003) (clinicaltrials.gov) - P3 | N=1310 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Aug 2028 ➔ Feb 2030

Trial completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

A Drug-Drug Interaction Study of Itraconazole and Opevesostat (MK-5684) in Healthy Adult Male Participants (MK-5684-017) (clinicaltrials.gov) - P1 | N=14 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Not yet recruiting ➔ Recruiting

Enrollment open

A Study of Opevesostat (MK-568)4 in Japanese Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-5684-005) (clinicaltrials.gov) - P1 | N=7 | Completed | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Completed

Trial completion • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

HSK46575, a potent CYP11A1 inhibitor, demonstrates promising monotherapy and synergistic efficacy with SOCs for the treatment of castration-resistant prostate cancer (CRPC) (AACR 2026) - "A CYP11A1 inhibitor, ODM-208, showed a decrease in prostate-specific antigen levels of 50% (PSA50) in about 50% patients with AR LBD mutation (AR-mut), but lower response in CRPC patients with wild type AR (AR-wt) in phase1/2 studies...Model mice were treated with HSK46575 and/or other mechanic drugs, including PARP inhibitor (Olaparib), docetaxel or EZH2 inhibitor... Preliminary clinical data confirm the manageable safety profile and promising antitumor activity of HSK46575, particularly in patients harboring AR-LBD mutations. Furthermore. HSK46575 exhibits strong synergistic efficacy when combined with docetaxel or targeted agents (PARPi or EZH2i) in CRPC xenograft models."

Clinical • Late-breaking abstract • Monotherapy • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

A Drug-Drug Interaction Study of Itraconazole and Opevesostat (MK-5684) in Healthy Adult Male Participants (MK-5684-017) (clinicaltrials.gov) - P1 | N=14 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

New P1 trial

A Study of MK-5684 in People With Certain Solid Tumors (MK-5684-015/OMAHA-015) (clinicaltrials.gov) - P2 | N=250 | Recruiting | Sponsor: Merck Sharp & Dohme LLC

Pan tumor • Platinum resistant • Trial initiation date • Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • HER-2

HSK46575: A best-in-class, long lasting, small molecular CYP11A1 inhibitor for the treatment of castration-resistant prostate cancer (CRPC) (AACR 2025) - "Approximately half of the castration-resistant prostate cancer (CRPC) patients will benefit from abiraterone or enzalutamide treatment initially...Notably, 2.5 mg/kg/day dosage of HSK46575 exhibited superior efficacy compared to Abiraterone (200 mg/kg/day) and ODM-208 (60 mg/kg/day)... HSK46575 potently blocks the CYP11A1 enzymatic activity and the biosynthesis of Preg and TE at low nM concentrations in vitro. In normal male rats, the inhibition of both Preg and TE by HSK46575 was dose-dependent and long-lasting. In the LNCap (with AR-T877A) castrated xenograft model, HSK46575 significantly inhibited tumor growth and serum PSA level at a low dosage of 1 mg/kg/day."

Late-breaking abstract • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Discovery of ACE-232: a novel and highly potent non-steroidal CYP11A1 inhibitor (AACR 2025) - "In castrated mouse models, ACE-232 showed equal or superior efficacy in inhibiting tumor growth at 0.3 mg/kg QD in both VCaP and enzalutamide-resistant xLNCaP models, compared to ODM-208 at 30 mg/kg BID. GLP toxicology studies demonstrated a wide safety margin in both rats and dogs, with primary effects observed in the endocrine and reproductive organs, consistent with CYP11A1 inhibition. Based on these findings, an IND filing for ACE-232 with the FDA is planned for December 2024."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor