CYP11A1 inhibitor MK-5684 versus next-generation hormonal agent (NHA) switch in patients with metastatic castration-resistant prostate cancer (mCRPC) after NHA and taxane-based chemotherapy: Phase 3 MK-5684-003 trial.

TPS5113 Background: Androgen receptor (AR) signaling remains a key driver of prostate cancer even after progression on androgen-directed therapies. Activating AR ligand binding domain (AR-LBD) somatic point mutations are a common mechanism of resistance to androgen-directed therapies in patients with mCRPC. MK-5684 (ODM-208) is an oral, nonsteroidal inhibitor of cytochrome P450 11A1 (CYP11A1), which catalyzes the first and rate-limiting step of steroid biosynthesis. Inhibition of CYP11A1 by MK-5684 suppresses the production of all steroid hormones and their precursors that may promiscuously activate the AR signaling pathway. In the phase 1/2 CYPIDES trial, MK-5684 showed antitumor activity in patients with heavily pretreated mCRPC, especially in those with AR-LBD mutations. The randomized, open-label, phase 3 MK-5684-003 trial (NCT06136624) is evaluating the efficacy and safety of MK-5684 versus NHA switch in patients with mCRPC previously treated with NHA and taxane-based chemotherapy. Methods: Eligible patients havemCRPC (unselected for AR-LBD mutations) that progressed on androgen deprivation therapy ≤6 months before screening and during or after treatment with 1 NHA for nonmetastatic (nm) hormone-sensitive prostate cancer (HSPC), nmCRPC, mHSPC, or mCRPC for ≥8 weeks (≥14 weeks with bone progression), and also progressed during or after 1 or 2 taxane-based chemotherapies for mCRPC. Approximately 1200 patients (300 with and 900 without AR-LBD mutations) will be randomly assigned 1:1 to receive MK-5684 5 mg PO BID (+ dexamethasone 1.5 mg and fludrocortisone 0.1 mg QD) or enzalutamide 160 mg PO QD (if prior abiraterone) or abiraterone acetate 1000 mg PO QD (+ prednisone 5 mg BID; if prior enzalutamide/darolutamide/apalutamide). Randomization to treatment will be stratified by measurable disease (yes/no), disease AR-LBD mutation status (positive/negative), and prior cabazitaxel use (yes/no). Treatment will continue until radiographic disease progression (verified per Prostate Cancer Working Group 3 PCWG3–modified RECIST v1.1 by blinded independent central review BICR), unacceptable toxicity, or other discontinuation criteria are met. Tumor assessments will be performed every 8 weeks up to week 24, then every 12 weeks thereafter. Dual primary end points are radiographic PFS (per PCWG3-modified RECIST v1.1 by BICR) and OS in patients with AR-LBD mutation-positive and -negative disease, separately. 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 progression; time to first symptomatic skeletal-related event; and safety and tolerability. Enrollment is ongoing. Clinical trial information: NCT06136624 .