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.

TPS5114 Background: Activating androgen receptor (AR) somatic mutation is a known mechanism of resistance to AR-directed therapies in mCRPC, and it may permit continued hormone dependence. Upstream targeting of androgen biosynthesis may provide a therapeutic advantage over available AR-directed therapies in patients with mCRPC. MK-5684 (ODM-208) is an oral, nonsteroidal inhibitor of cytochrome P450 11A1 (CYP11A1), a catalyst of the first and rate-limiting step of steroid biosynthesis. Thus, MK-5684 has the potential to suppress the production of all steroid hormones and precursors that may activate the AR signaling pathway. MK-5684 demonstrated antitumor activity in patients with heavily pretreated mCRPC, especially in those with AR ligand binding domain (AR-LBD) mutations, in the phase 1/2 CYPIDES study. The efficacy and safety of MK-5684 in patients with molecularly unselected mCRPC after 1 prior NHA will be evaluated in the randomized, open-label, phase 3 MK-5684-004 study (NCT06136650). Methods: Eligible patients have mCRPC unselected for AR-LBD mutations that progressed during androgen deprivation therapy ≤6 months before screening and during or after 1 NHA for hormone-sensitive prostate cancer (HSPC) or nonmetastatic CRPC for ≥8 weeks (≥14 weeks with bone progression). 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). Randomization will be stratified by metastasis (bone only/liver/other), AR-LBD mutation status (positive/negative), and prior docetaxel for HSPC (yes/no). Treatment will continue until unacceptable toxicity, radiographic disease progression (verified per Prostate Cancer Working Group 3 PCWG3–modified RECIST v1.1 by BICR), or other discontinuation criteria are met. Tumor assessments will be performed every 8 weeks through 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 (PSA) progression; PSA response rate; time to first symptomatic skeletal-related event; and safety and tolerability. Recruitment is ongoing. Clinical trial information: NCT06136650 .