A phase 1, first-in-human study of DS9051, a novel targeted protein degradation molecule, in patients with advanced/metastatic adrenocortical carcinoma (ACC) or metastatic castration-resistant prostate cancer (mCRPC).

Abstract

TPS3179 Background: ACC and mCRPC are difficult-to-treat malignancies. mCRPC typically progresses despite androgen deprivation and androgen receptor pathway inhibitor (ARPI) therapy, with or without taxanes. Similarly, treatment options for ACC are limited and prognosis is generally unfavorable. DS9051 is a targeted protein degradation molecule that has been designed to selectively degrade a key protein involved in the development and progression of both ACC and mCRPC via a novel mechanism. It leverages the ubiquitin-proteasome system, where DS9051 acts as a bridge to link the target protein and E3 ligase, initiating ubiquitination and degradation of the target protein. Methods: DS9051-079 (NCT07189403) is a Phase 1, first-in-human, open-label, multicenter study of DS9051 (N≈40). Patients must be adults with histologically confirmed advanced or metastatic ACC (Stage III–IV) or mCRPC and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with ACC must have measurable disease per Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST 1.1) that is not amenable to radical surgical resection or definitive radiotherapy. Further inclusion criteria for patients with mCRPC include prior treatment with ≥1 line of ARPI therapy for castration-sensitive or -resistant prostate cancer for ≥12 weeks and with ≥1 line of chemotherapy (or not amenable to chemotherapy). These patients must also have ≥1 of the following criteria: prostate-specific antigen (PSA) progression per Prostate Cancer Working Group 3 (PCWG3) criteria, bone disease progression per PCWG3 criteria, or soft tissue disease progression per RECIST 1.1. Patients will receive DS9051 orally at escalating doses. The primary objective is to assess the safety and tolerability of DS9051 and to determine the maximum tolerated dose and/or recommended dose for expansion. Safety endpoints include dose-limiting toxicities and treatment-emergent adverse events. Secondary endpoints for both tumor types include objective response rate, disease control rate, clinical benefit rate, and duration of response (all assessed by the investigator, per RECIST 1.1 for ACC and per PCWG3 criteria for mCRPC); for ACC, progression-free survival (PFS) will be assessed by the investigator per RECIST 1.1, and for mCRPC, radiographic PFS and PSA decline will be assessed by the investigator per PCWG3 criteria. Enrollment is ongoing. Clinical trial information: NCT07189403 .