1663TiP - CYP11A1 inhibitor opevesostat (MK-5684) alone or in combination with other therapies for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): The phase I/II MK-5684-01A substudy

Background

Treatments with novel mechanisms of action continue to be needed for mCRPC. Opevesostat is an oral, nonsteroidal inhibitor of cytochrome P450 11A1 (CYP11A1), a catalyst of the first and rate-limiting step of steroid biosynthesis. In the phase 1/2 CYPIDES study, opevesostat demonstrated antitumor activity in pts with heavily pretreated mCRPC. MK-5684-U01 is an adaptive, open-label, rolling-arm, multicenter, phase 1/2 umbrella study that will evaluate the safety and efficacy of opevesostat-based investigational therapies in prostate cancer. Substudy 01A (NCT06353386) will evaluate opevesostat alone or in combination with other therapies in previously treated pts with mCRPC.

Trial design

Eligible pts are aged ≥18 years with mCRPC that progressed during androgen deprivation therapy ≤6 mo before screening, and also on/after receiving ≥8 wk (≥14 wk with bone progression) of 1-2 next-generation hormonal agents for metastatic or nonmetastatic hormone-sensitive prostate cancer and nonmetastatic or mCRPC. No more than 1 prior taxane-based chemotherapy for mCRPC is permitted. The substudy includes a safety lead-in phase for all opevesostat-based experimental combinations (∼10 pts in each arm) to establish the recommended phase 2 dose (RP2D), followed by an efficacy phase (opevesostat alone, ≤100 pts; opevesostat-based combinations, ∼40 pts each). In the efficacy phase, pts will be randomly assigned 1:1:1:1 to receive opevesostat alone (5 mg PO BID), opevesostat 5 mg PO BID + olaparib (RP2D), opevesostat 5 mg PO BID + docetaxel (RP2D), and opevesostat 5 mg PO BID + cabazitaxel (RP2D). The primary end point for the safety lead-in phase is safety/tolerability. Primary end points for the efficacy phase are safety and PSA response rate per Prostate Cancer Working Group (PCWG) criteria (reduction from baseline in PSA of ≥50% at consecutive assessments ≥3 wk apart); secondary end points include objective response, duration of response and radiographic progression-free survival per PCWG-modified RECIST v1.1 by blinded independent central review, and overall survival.

Clinical trial identification

NCT06353386; Release date: April 29th, 2024.

Editorial acknowledgement

Medical writing and/or editorial assistance was provided by Max Chang, PhD, and Panagiotis Xenopoulos, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and Orion Corporation, who are codeveloping opevesostat (MK-5684; ODM-208).

Funding

This study is supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and Orion Corporation, who are codeveloping opevesostat (MK-5684; ODM-208).

Disclosure

A. Hussain: Financial Interests, Institutional, Advisory Board: AstraZeneca, Bayer, Exelexis, Janssen Oncology, Merck; Financial Interests, Institutional, Research Funding: AstraZeneca, Bayer, FutureChem, Merck, Orion, POINT Pharama, Poseida, Regeneron; Financial Interests, Institutional, Local PI: Infinty, AstraZeneca, Regeneron, FutureChem, Pfizer, Bayer, Bristol Myers Squibb, Exelexis, PSI, Arravive, Nimbus, Infinity, Orion, Merck. C. Garratt: Financial Interests, Personal, Full or part-time Employment: Orion Corporation. C.H. Poehlein: Financial Interests, Personal, Full or part-time Employment, Employee and recipient of Stock: Merck & Co; Financial Interests, Personal, Stocks/Shares: Merck & Co; Non-Financial Interests, Member: ASCO, SITC, EAU. P.C. Fong: Financial Interests, Personal, Advisory Board: MSD. All other authors have declared no conflicts of interest.