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

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

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

A randomized, multicenter, open-label, phase 2 basket study of CYP11A1 inhibitor opevesostat in participants with selected solid tumors: study design of cohorts B and C of OMAHA-015 (ESGO 2026) - P2 | "In cohort C, approximately 80 participants will be randomly assigned 1:1 to either arm 5: oral opevesostat 5 mg BID plus daily corticosteroids; or arm 6: physician's choice of oral megestrol acetate 80 mg BID, alternating megestrol plus tamoxifen 20 mg BID, or oral letrozole 2.5 mg daily. Secondary end points include overall survival, objective response rate and duration of response per RECIST v1.1 assessed by BICR, as well as safety. OMAHA-015 is currently enrolling participants.Results Trial in progress abstractConclusion Trial in progress abstract"

Clinical • P2 data • Pan tumor • Carcinosarcoma • Endometrial Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Sarcoma • Solid Tumor • TP53

Design, synthesis, and biological evaluation of cytochrome P450 CYP11A1 inhibitors. (PubMed, Bioorg Med Chem Lett) - "Based on the clinical candidate Opevesostat, two series of 23 new compounds were designed and synthesized using a 4H-pyran-4-one core to explore structure-activity relationships at the C2 and C6 positions.Compound II-4 exhibited potent inhibitory activity (95.2% at 100 nM; IC₅₀ = 26.7 nM), comparable to Opevesostat (IC₅₀ = 20.4 nM). Importantly, II-4 showed superior selectivity against CYP1A2, 2C9, and 2D6 (2- to 4-fold improvement), attributed to hydrophobic interactions between its C6 methyl group and Ile 84.These results highlight II-4 as a promising lead compound with optimized activity and selectivity, providing valuable insights for overcoming resistance in prostate cancer therapy."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CYP1A2

Phase 1/2 OMAHA-U01 substudy 01A: Oral CYP11A1 inhibitor opevesostat alone or in combination with other therapies in participants with metastatic castration-resistant prostate cancer (mCRPC). (ASCO-GU 2026) - P1/2 | "Clinical Trial Registry Number: NCT06353386. The full, final text of this abstract will be available on Feb 23 at 05:00 PM EST."

Combination therapy • Metastases • P1/2 data • Castration-Resistant Prostate Cancer • Genito-urinary 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

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 | "Clinical Trial Registry Number: NCT06136650 . The full, final text of this abstract will be available on Feb 23 at 05:00 PM EST."

Metastases • P3 data • Castration-Resistant Prostate Cancer • Genito-urinary 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-003: Phase 3 trial of CYP11A1 inhibitor opevesostat versus androgen receptor pathway inhibitor (ARPI) switch in participants (pts) with metastatic castration-resistant prostate cancer (mCRPC) after ARPI and taxane-based chemotherapy. (ASCO-GU 2026) - P3 | "Clinical Trial Registry Number: NCT06136624 . The full, final text of this abstract will be available on Feb 23 at 05:00 PM EST."

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

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

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

A randomized, multicenter, open-label, phase 2 basket study of CYP11A1 inhibitor opevesostat in participants with selected solid tumors: study design of cohorts B and C of OMAHA-015 (SGO 2026) - No abstract available

Clinical • P2 data • Pan tumor • Oncology • Solid Tumor

A Study to Evaluate Opevesostat (MK-5684) in Male Participants With Moderate Hepatic Impairment (MK-5684-009) (clinicaltrials.gov) - P1 | N=16 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Recruiting ➔ Active, not recruiting

Enrollment closed • Hepatology

OMAHA-004: 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) (clinicaltrials.gov) - P3 | N=1314 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Recruiting

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

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) (clinicaltrials.gov) - P1/2 | N=220 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Mar 2028 ➔ Jan 2029 | Trial primary completion date: Mar 2028 ➔ Jan 2029

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

A Study to Evaluate the Effect of MK-5684 in Male Participants With Severe Renal Impairment (RI) and With End-stage Renal Disease (ESRD) (MK-5684-010) (clinicaltrials.gov) - P1 | N=24 | Completed | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Completed

Trial completion • Chronic Kidney Disease • Nephrology • Renal Disease

OMAHA-004: 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) (clinicaltrials.gov) - P3 | N=1314 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial primary completion date: Dec 2030 ➔ May 2028

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

A Study to Evaluate the Effect of MK-5684 in Male Participants With Severe Renal Impairment (RI) and With End-stage Renal Disease (ESRD) (MK-5684-010) (clinicaltrials.gov) - P1 | N=24 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Recruiting ➔ Active, not recruiting

Enrollment closed • Chronic Kidney Disease • Nephrology • Renal Disease

CYP11A1 inhibitor opevesostat (MK-5684) alone or in combination with other therapies for participants (pts) with metastatic castration-resistant prostate cancer (mCRPC): the phase 1/2 OMAHA-U01 substudy 01A (DGU 2025) - P1/2 | "In the efficacy phase, pts will be randomly assigned 1:1:1:1 to receive opevesostat (5 mg PO BID), opevesostat 5 mg PO BID + olaparib (RP2D), opevesostat 5 mg PO BID + docetaxel (RP2D), and opevesostat 5 mg PO BID + cabazitaxel (RP2D). The primary end point for the safety phase is safety/tolerability. Primary end points for the efficacy phase are safety and PSA response rate per Prostate Cancer Working Group criteria (reduction from baseline in PSA of ≥50% at consecutive assessments ≥3 wk apart)."

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

OMAHA1: Study of Opevesostat (MK-5684) Versus Alternative NHA in mCRPC (MK-5684-003) (clinicaltrials.gov) - P3 | N=1310 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Recruiting

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

A Study of Opevesostat (MK-568)4 in Japanese Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-5684-005) (clinicaltrials.gov) - P1 | N=6 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Jan 2026 ➔ Apr 2026 | Trial primary completion date: Jan 2026 ➔ Apr 2026

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

OMAHA-004: 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) (clinicaltrials.gov) - P3 | N=1500 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Recruiting ➔ Active, not recruiting

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

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 | Not yet recruiting ➔ Recruiting | Trial completion date: Jul 2030 ➔ Nov 2027 | Trial primary completion date: Jul 2030 ➔ Nov 2027

Enrollment open • Pan tumor • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

OMAHA-004: Phase 3 trial of CYP11A1 inhibitor opevesostat versus next-generation hormonal agent (NHA) switch in participants with metastatic castration-resistant prostate cancer after 1 prior NHA (UAA 2025) - No abstract available

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