Open Menu
Meetings & Education
Meetings & Education
Research & Data
Practice & Patients
Career Development
News & Initiatives
Get Involved
Dauntless-1, a phase 2 clinical trial to evaluate PMD-026, a first-in-class pan-RSK inhibitor, combined with fulvestrant to overcome resistance to CDK4/6 inhibitors in advanced or metastatic HR+/HER2- breast cancer.
Background:
Resistance to CDK4/6 inhibitors (CDK4/6i) is common for many patients with HR+/HER2- advanced or metastatic breast cancer, therefore new strategies are urgently needed to overcome this challenge. Ribosomal S6 kinases (RSK1-4) are implicated in breast cancer growth and resistance, and they are activated by the PI3K and MAPK pathways, which are linked to CDK4/6i resistance. As a convergence point of these pathways, RSK drives resistance by promoting the G2/M phase of the cell cycle and bypassing G1/S control. Inhibiting RSK with PMD-026, a first-in-class oral small molecule inhibitor, halts G2/M progression and blocks growth in CDK4/6i-resistant models, including those cross-resistant to abemaciclib and palbociclib.
RSK also complexes with estrogen receptor alpha (ERα), enhancing transcription and tumor growth. PMD-026 disrupts this interaction, showing activity in both ESR1 wild-type and mutant HR+/HER2- models, making it a promising partner for endocrine therapies. It synergizes with fulvestrant and oral SERDs, achieving significant growth inhibition in preclinical models, including a 7000-fold improvement with fulvestrant in soft agar assays. Nuclear translocation of RSK is a key driver of breast cancer in mice and serves as a biomarker for RSK signalling activity. In the Phase 1/1b monotherapy study, PMD-026 was generally well-tolerated, and it reduced the risk of progression or death in patients by 93% in a subset of RSK2 high metastatic breast cancer patients.
Methods:
Dauntless-1 is a Phase 2a study for locally advanced or metastatic HR+/HER2- breast cancer patients previously treated with a CDK4/6i in combination with endocrine therapy (NCT04115306). It is designed to prospectively enroll RSK2+ (≥50% nuclear staining with ≥2+ staining intensity) patients to evaluate PMD-026 in combination fulvestrant. Fulvestrant will be dosed per the package insert (500 mg IM, Day 1 and 15 of the first 28-day cycle, then Day 1 of every cycle thereafter) in combination with PMD-026 at the RP2D (200 mg, PO, Q12h), determined in the dose-finding portion of the study. The combination regimen will have a safety lead-in cohort of 6 patients. The SRC will review the safety data after the sixth patient has been treated for at least 28 days. If determined to be safe, up to 14 additional patients will receive the combination for a total of 20 patients. A Bayesian safety monitoring rule will be used to evaluate the rate of DLTs during expansion.
Primary objectives will be safety, pharmacokinetics, and progression free survival. Secondary objectives include duration of response, overall response and overall survival. Exploratory objectives will evaluate PMD-026 in the context of mutations (ESR1, PIK3CA, AKT1, p53, KRAS) at baseline using ctDNA.
Disclaimer
This material on this page is ©2025 American Society of Clinical Oncology, all rights reserved. Licensing available upon request. For more information, please contact licensing@asco.org
Author Details
Sandra Dunn
Phoenix Molecular Designs, Vancouver, BC, Canada
Authors chevron_right
Associated Organizations chevron_right
Abstract Details
Meeting
2025 ASCO Annual Meeting
Session Type
Poster Session
Session Title
Breast Cancer—Metastatic
Track
Breast Cancer
View MoreAbstract Disclosure
open_in_new
Your Privacy
ASCO is committed to transparency regarding our websites and the ways we process data. When you visit our site, we may store or retrieve information on your browser, mostly in the form of cookies. This information might be about you, your preferences, your location, or your device and is mostly used to make the site work as you expect it to and to personalize your web experience with us.
Because we respect your right to privacy, you can choose not to allow some or all types of cookies. Click on the different category headings to find out more about the types of cookies used on our websites and change your default settings to match your preferences. Please read these carefully. Blocking some types of cookies may impact your experience on the site, including our ability to personalize the content you receive from us.
For a full explanation of the personal and non-personal information we collect on our site, including how we use that information and your rights regarding that information, please review our Privacy Policy. Use of our website is also subject to our Terms of Use.
Allow All
Manage Consent Preferences
Essential Website Cookies
Always Active
These cookies are necessary for the website to function and are sometimes referred to as “strictly necessary” cookies. They make sure the website delivers you information and services in an optimal way.
They are often set in response to an action you take, such as changing your cookie preferences, setting your privacy preferences, logging in to our website, asking the site to remember you on subsequent pages, or filling in forms. These cookies do not identify you personally.
You can set your browser to block or alert you about all cookies, including essential website cookies, but some parts of the site will not work as a result.
Cookies Details‎
Performance and Functionality Cookies
Performance and Functionality Cookies
These cookies enhance the performance and functionality of our websites and the services we provide. For example, these cookies can keep track of your visitor session in between visits, enable you to share content through social media, use embedded media players, and use comment features. They also help us balance website load and improve site speed and performance.
All information these cookies collect is aggregated and therefore anonymous. These cookies may be set by us or by third party providers whose services we have added to our websites. These cookies are non-essential, but without these cookies, certain functionality or enhanced features may become unavailable.
Cookies Details‎
Personalization and Analytics Cookies
Personalization and Analytics Cookies
These cookies collect information that is used to help us understand how our websites and content are used, help us customize our websites and application for you in order to enhance your experience, and help us improve the content that ASCO creates to better meet our members’ and visitors’ needs. Examples include cookies that show us which content might be most popular with our visitors, understand browsing history of our users, understand the effectiveness of our own advertising, and enable us to recommend content to individual users based on their profile and activities on the website.
These cookies may be set by us or by third party providers whose services we have added to our websites.
These cookies are non-essential to the functionality of the site and may contain information that enables us or our third party providers to identify you and build a profile of your interests. Without these cookies, you will not be able to have a customized or personalized experience within our website.
Cookies Details‎
Advertising Cookies and Social Media Cookies
Advertising Cookies and Social Media Cookies
Advertising (or Targeting) cookies are third party cookies that may be set through our site by our advertising partners. They may be used by those companies to build a profile of your interests and show you relevant ads on other sites.
Social Media Cookies are cookies set by a range of social media services that we have added to the site to enable you to share our content with your friends and networks. They are capable of tracking your activities across other sites and building a profile of your interests. This may impact the content and messages you see on other websites you visit.
These cookies and the data collected by the third parties may be combined with data from other users or data about your activity on other sites. While the data collected on our site is aggregate or non-personal, the data may be used by such third parties to link you on other platforms or otherwise identify you.
If you do not allow these cookies, you may experience less targeted advertising.
Cookies Details‎
Back Button
Cookie List
Search Icon
Filter Icon
Clear
checkbox labellabel
ApplyCancel
ConsentLeg.Interest
checkbox labellabel
checkbox labellabel
checkbox labellabel
View Cookies
Name
cookie name
Save Settings
Download