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

IF 2.3 3区医学 Q3 ONCOLOGY Urologic Oncology-seminars and Original Investigations Pub Date : 2025-03-01 Epub Date: 2025-02-27 DOI:10.1016/j.urolonc.2024.12.067

Christian Gratzke, Donald Vile, Zheng Hong Chen, Chris Garratt, Christian Poehlein, Jelena Todoric, Karim Fizazi, John Murray

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Abstract

Introduction

Androgen receptor (AR) somatic mutation activation is a resistance mechanism to AR-directed therapies (ADT) in metastatic castration-resistant prostate cancer (mCRPC). Upstream targeting of androgen biosynthesis may provide a therapeutic advantage over available AR-directed therapies in patients with mCRPC. Opevesostat (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. By blocking the first step of the enzymatic pathway, opevesostat has the potential to inhibit all steroid hormones involved in AR signaling activation. In the phase 1/2 CYPIDES study, opevesostat had antitumor activity in patients with heavily pretreated mCRPC, especially in those with AR ligand binding domain (AR-LBD) mutations. The randomized, open-label, phase 3 MK-5684-004 trial (NCT06136650) will evaluate the efficacy and safety of opevesostat versus abiraterone or enzalutamide in patients with molecularly unselected mCRPC previously treated with 1 prior NHA.

Methods

Eligible patients have mCRPC that progressed during ADT ≤6 months before screening and during/after 1 NHA for hormone-sensitive prostate cancer or non-mCRPC. 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). Primary end points are radiographic PFS per PCWG3-modified RECIST v1.1 by BICR and OS in 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; and safety. Recruitment is ongoing.

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3期mk-5684-004研究cyp11a1抑制剂opevesstat与新一代激素药物（nha）切换在转移性去势抵抗性前列腺癌患者既往nha后的疗效

在转移性去势抵抗性前列腺癌（mCRPC）中，雄激素受体（AR）体细胞突变激活是对AR定向治疗（ADT）的抵抗机制。在mCRPC患者中，雄激素生物合成的上游靶向治疗可能比现有的ar定向治疗具有治疗优势。Opevesostat (mk - 5684;ODM-208)是一种口服非甾体类细胞色素P450 11A1 （CYP11A1）抑制剂，CYP11A1是类固醇生物合成的第一步和限速步骤的催化剂。通过阻断酶促通路的第一步，opevesostat具有抑制所有参与AR信号激活的类固醇激素的潜力。在1/2期CYPIDES研究中，opevesstat对重度预处理的mCRPC患者具有抗肿瘤活性，特别是对AR配体结合域（AR- lbd）突变的患者。这项随机、开放标签的3期MK-5684-004试验（NCT06136650）将评估opevesstat与阿比特龙或恩杂鲁胺在先前接受1次NHA治疗的分子非选择性mCRPC患者中的疗效和安全性。方法适用于激素敏感性前列腺癌或非mCRPC的患者，在筛查前ADT≤6个月和1次NHA期间/之后进展为mCRPC。约1500例患者（375例有AR-LBD突变，1125例无AR-LBD突变）将按1:1随机分配，接受opevesostat 5 mg PO BID + 地塞米松1.5 mg和氟化可的松0.1 mg PO QD或醋酸阿比特龙1000 mg PO QD（如果既往有恩杂鲁胺/达罗鲁胺/阿帕鲁胺）或恩杂鲁胺160 mg PO QD（如果既往有阿比特龙）。主要终点分别为AR-LBD突变阳性和阴性疾病的pcwg3修饰的RECIST v1.1放射学PFS。次要终点包括开始第一次后续抗癌治疗或死亡的时间；pcwg3修改后的RECIST v1.1的ORR和DOR；和安全。招聘正在进行中。©2024美国临床肿瘤学会在获得许可的情况下重用。该摘要先前在2024年ASCO年会上发表。版权所有。

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来源期刊

Urologic Oncology-seminars and Original Investigations 医学-泌尿学与肾脏学

CiteScore

4.80

自引率

3.70%

发文量

297

审稿时长

7.6 weeks

期刊介绍： Urologic Oncology: Seminars and Original Investigations is the official journal of the Society of Urologic Oncology. The journal publishes practical, timely, and relevant clinical and basic science research articles which address any aspect of urologic oncology. Each issue comprises original research, news and topics, survey articles providing short commentaries on other important articles in the urologic oncology literature, and reviews including an in-depth Seminar examining a specific clinical dilemma. The journal periodically publishes supplement issues devoted to areas of current interest to the urologic oncology community. Articles published are of interest to researchers and the clinicians involved in the practice of urologic oncology including urologists, oncologists, and radiologists.