The MK-5684-003 study, a Phase 3 trial, is evaluating the efficacy and safety of opevesostat versus next-generation hormonal agent (NHA) switch in patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received NHA and taxane-based chemotherapy. The trial design was presented at the 2024 Society of Urologic Oncology (SUO) annual meeting.
Background and Rationale
Androgen receptor (AR) signaling remains a key driver of prostate cancer progression, even in mCRPC patients undergoing androgen deprivation therapies (ADT). Somatic mutations in the AR ligand-binding domain (AR-LBD) occur in 20-25% of patients treated with novel hormonal agents, contributing to resistance. Opevesostat (MK-5684, ODM-208) is an oral, nonsteroidal inhibitor of cytochrome P450 11A1 (CYP11A1), the enzyme responsible for the first and rate-limiting step of steroid biosynthesis. By inhibiting CYP11A1, opevesostat reduces the production of steroid hormones and their precursors, aiming to suppress AR-driven resistance in mCRPC.
Study Design
The MK-5684-003 study (NCT06136624) is a randomized, open-label, phase 3 trial. Patients with mCRPC who have received at least two prior lines of therapy (NHA and taxane-based chemotherapy) are randomized 1:1 to either opevesostat 5 mg PO BID (+ dexamethasone 1.5 mg and fludrocortisone 0.1 mg QD) or a switch to either enzalutamide 160 mg PO QD (if prior abiraterone) or abiraterone acetate 1000 mg PO QD (if prior enzalutamide/darolutamide/apalutamide).
Randomization is stratified by:
- Presence or absence of measurable disease
- Detection of AR-LBD mutations in circulating tumor DNA
- Prior receipt of cabazitaxel
Inclusion and Exclusion Criteria
Key inclusion criteria include histologically confirmed adenocarcinoma of the prostate, progressive mCRPC, prior treatment with at least one NHA and one taxane-based chemotherapy regimen, and adequate organ function. Exclusion criteria include prior treatment with CYP11A1 inhibitors, symptomatic brain metastases, and active malignancy other than prostate cancer.
Outcomes
The primary endpoints are radiographic progression-free survival (rPFS) per Prostate Cancer Clinical Trials Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints include time from randomization to initiation of the first subsequent anticancer therapy or death (TFST), objective response rate (ORR) and duration of response (DOR) per PCWG3-modified RECIST v1.1 by BICR in patients with measurable disease, time to pain progression (TTPP), time to prostate-specific antigen (PSA) progression, time to first symptomatic skeletal-related event (SSE), and safety and tolerability.
Follow-up Assessments
Follow-up assessments for patients treated with opevesostat will focus on tumor response, PSA levels, adverse events, adrenal recovery, and patient-reported outcomes (PROs). Efficacy analysis will be conducted in the intention-to-treat population, safety analysis in all randomly assigned patients who received at least one dose of study treatment, and PROs analysis in all randomly assigned patients who received at least one dose of study treatment and have at least one PRO assessment available.
The MK-5684-003 study is currently ongoing at multiple sites.
