Phase I/II study to evaluate AZD9750, a novel androgen receptor proteolysis-targeting chimera, alone and in combination with other anticancer agents in patients with metastatic prostate cancer (ANDROMEDA).

Abstract

TPS5146 Background: The androgen receptor (AR) is a key driver of prostate cancer progression. AR pathway inhibitors (ARPIs) are standard of care for metastatic prostate cancer, but acquired resistance is inevitable and often involves reactivation of AR signaling via AR gene alterations such as amplifications or ligand binding domain mutations. The need remains for alternative strategies to target the AR. AZD9750 is a novel oral proteolysis-targeting chimera that potently degrades wild-type, mutant, and amplified forms of the AR. Preclinical data also showed significant antitumor benefit with AZD9750 as monotherapy and combined with the PARP1 selective inhibitor saruparib (AZD5305). ANDROMEDA (NCT07336446) is a first-in-human, phase I/II, open-label, multicenter study investigating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of AZD9750 as monotherapy and combined with saruparib in patients (pts) with metastatic castration-resistant prostate cancer. Methods: This study follows a modular design in which pts receive AZD9750 as monotherapy (Module 1) or combined with saruparib (Module 2; Table). Each module has 2 parts: monotherapy dose escalation or combination dose finding (Part A) and dose optimization and expansion (Part B). Eligible pts are ≥18 years of age with histologically or cytologically confirmed adenocarcinoma of the prostate and documented metastatic disease with serum testosterone level ≤50 ng/dL, evidence of disease progression, and ECOG performance status of 0 or 1. Pts should have previously received ARPIs and taxane-based chemotherapy, with the exception of no prior taxane-based chemotherapy in Module 1 Part B3. Primary endpoints include occurrence of dose-limiting toxicities (Part A only), incidence of adverse events (AEs) and AEs leading to treatment discontinuation (Parts A and B), and preliminary efficacy (ie, ≥50% decrease in prostate-specific antigen [PSA]; Part B only). Secondary endpoints include preliminary efficacy (ie, ≥50% and ≥90% decrease in PSA, objective response rates and progression-free survival per RECIST v1.1 and PCWG3 criteria, change in target lesion size per RECIST v1.1 criteria, time to PSA response, and time to PSA progression per PCWG3 criteria) and pharmacokinetic parameters (Parts A and B). This study is currently recruiting for monotherapy dose escalation. Clinical trial information: NCT07336446 . Study part Module 1: AZD9750 monotherapy Module 2: AZD9750 plus saruparib Part A A1. Dose escalationA2. Backfill cohorts Combination dose finding a Part B B1. Dose optimization a B2. Dose expansion b B3. Dose expansion b Combination dose expansion c a Recommended doses determined in Module 1 Part A; b To be opened once recommended phase II dose identified in Module 1 Part B1; c To be opened once combination dose identified in Module 2 Part A.