(UroToday.com) The 2024 American Society of Clinical Oncology (ASCO) Annual Meeting held in Chicago, IL was host to a prostate, testicular, and penile cancers trials in progress poster session. Dr. Evan Yu presented the ongoing phase 3 MK-5684-003 trial comparing the CYP11A1 inhibitor, MK-5684, to a next-generation hormonal agent (NHA) switch in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing following a prior NHA and taxane-based chemotherapy.
Prostate cancer can remain dependent on hormone signaling even after progression on androgen receptor (AR)–directed therapies. Somatic activating point mutations in the AR ligand binding domain (AR-LBD) are a common mechanism of resistance to AR-directed therapies in mCRPC patients. Opevesostat (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 from cholesterol. Inhibition of CYP11A1 by opevesostat can potentially suppress the production of all steroid hormones and precursors that may promiscuously activate the AR signaling pathway.
In the phase I/II CYPIDES trial, opevesostat demonstrated antitumor activity in patients with heavily pretreated mCRPC, especially in the subset of patients with AR-LBD mutations.1 The randomized, open-label, phase 3 MK-5684-003 trial (NCT06136624) will evaluate the efficacy and safety of opevesostat versus NHA switch in patients with molecularly unselected mCRPC previously treated with a NHA and taxane-based chemotherapy. The randomization will be stratified by:
- Presence or absence of measurable disease
- Detection of AR-LBD mutations in circulating tumor DNA
- Prior receipt of cabazitaxel
The study design is summarized below. In brief, this trial will randomize 1,200 patients with molecularly unselected mCRPC who experienced disease progression following prior treatment with a NHA and taxane-based chemotherapy in a 1:1 fashion to either:
- Opevesostat 5 mg orally twice daily + dexamethasone 1.5 mg and fludrocortisone 0.1 mg orally once daily
- NHA switch: Abiraterone acetate 1,000 mg orally once daily + prednisone 5 mg orally twice daily or enzalutamide 160 mg orally once daily
Treatment will continue until radiographic progressive disease (verified per Prostate Cancer Working Group 3 [PCWG3]-modified RECIST v1.1 by blinded independent central review [BICR]), unacceptable toxicity, or withdrawal of consent.
The primary objective of this study is to separately evaluate the following for opevesostat versus abiraterone acetate or enzalutamide in patients with AR-LBD mutation–positive and –negative mCRPC:
- Radiographic progression-free survival (rPFS) per PCWG3–modified RECIST v1.1 by BICR
- Overall survival (OS)
Secondary outcomes include the following:
- 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 from randomization to pain progression as determined by item 3 of the Brief Pain Inventory–Short Form [BPI-SF] and by the Analgesic Quantification Algorithm score)
- Time to prostate-specific antigen (PSA) progression (time from randomization to the date of PSA progression)
- Time to first symptomatic skeletal-related event (SSE; time from randomization to the first occurrence of an SSE)
- Safety and tolerability
The complete patient eligibility criteria are summarized below:
The statistical analytic plans for the efficacy, safety, and PROs are summarized below:
The current status of the trial at the time of presentation is illustrated below:
Presented by: Evan Yu, MD, Professor, Department of Medicine, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA
Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, May 31 – Tues, June 4, 2024.
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