Abstract PS1-08-15: 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

Abstract Background: Ribosomal s6 kinase (RSK) is situated at the convergence of the PI3K and ERK-MAPK pathways and plays a crucial role in cell growth and survival. It has been reported that up to 70% of breast tumors have a high expression of RSK, which is an indicator of poor prognosis in patients with breast cancer. RSK2 binds directly to estrogen receptor alpha (ERα) to promote tumor growth and the development of breast cancer in mice. RSK 1-4 have been linked to endocrine therapy (ET) and CDK4/6 inhibitor (CDK4/6i) resistance, which are common in patients with HR+/HER2- advanced or metastatic breast cancer (mBC). RSK drives resistance by promoting the G2/M phase of the cell cycle and bypassing G1/S control. PMD-026 is a first-in-class oral small molecule RSK inhibitor that halts G2/M progression and blocks growth in pre-clinical models of CDK4/6i resistance. In addition, PMD-026 inhibits the nuclear translocation of RSK2 (with no change to levels of nuclear ERα), reduces ERα transcription as a single agent equal to or better than fulvestrant or elacestrant, and synergizes with fulvestrant, oral selective estrogen receptor degraders (SERDs) or vepdegestrant to substantially inhibit tumor growth in CDK4/6i sensitive and resistant models. Combining PMD-026 and fulvestrant reduced ERα transcription by 84% as demonstrated by ELISA and yielded a 7000-fold improvement in the inhibition of tumor growth in soft agar assays. Design: Dauntless-1 is a Phase 2a study of PMD-026 plus fulvestrant in locally advanced or metastatic HR+/HER2 breast cancer patients with high RSK expression (>50%) previously treated with a CDK4/6i + ET combination (NCT04115306). Primary objectives are safety and progression-free survival. Secondary objectives are duration of response, overall response by RECIST V1.1, and overall survival. Exploratory objectives will evaluate these endpoints in the context of select mutations (ESR1, PIK3CA, TP53) and bone-only metastasis. Results: To date for the Dauntless-1 study, 30 patients have been screened for RSK2 expression (67% high, 13% intermediate, 20% low). All patients with high RSK2 expression experienced >12-month durability of response while on treatment with a CDK4/6i + ET regimen. The pharmacokinetics of 2 patients receiving PMD-026 at the initial starting dose of 200 mg Q12h were evaluated and compared to Phase 1 monotherapy results. The combination with fulvestrant increased the levels of PMD-026 with a median of 2.5 µM across 24 hr compared to 1 µM as a monotherapy. Higher than expected exposure with the combination relative to PMD-026 monotherapy was also associated with G3 rash and elevated transaminases, which resolved when PMD-026 was held. To date, PMD-026 at the new starting dose of 100 mg Q12h has been well tolerated with no rash or hepatotoxicity. Based on pharmacokinetic modelling, PMD-026 exposure at 100 mg Q12h is expected to cover the synergy range with fulvestrant. Conclusions: RSK2 is highly expressed in most front-line mBC patients receiving CDK4/6i + ET therapy. PMD-026 inhibits ER signalling and is highly synergistic with fulvestrant in preclinical studies, the translation of which into potentially meaningful clinical benefit is being explored in the Dauntless-1 study. Citation Format: H. T. Khong, M. Beeram, R. Wesolowski, H. S. Han, N. J. Palaskas, J. Margolis, J. Peguero, N. Sharp, H. Rugo, A. Jayanthan, S. E. Dunn, J. Leveque, S. A. Wander. 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 [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-08-15.