The U.S. Food and Drug Administration (FDA) has granted Fast Track designation to the combination of lunresertib (Debio 2513)*, a first-in-class oral PKMYT1 inhibitor, and zedoresertib (Debio 0123), a highly selective WEE1 inhibitor, for the treatment of adult patients with platinum-resistant or refractory ovarian cancer harboring CCNE1 amplification or deleterious FBXW7 or PPP2R1A mutations. Both investigational agents are being developed by Debiopharm, a Swiss-based biopharmaceutical company.
Timothy A. Yap, MBBS, PhD, FRCP, is a Medical Oncologist and Physician-Scientist based at the University of Texas MD Anderson Cancer Center. He is the Ransom Horne, Jr. Endowed Professor for Cancer Research and serves as Vice President and Head of Clinical Development and Therapeutics Discovery. Photo courtesy © 2026 The University of Texas MD Anderson Cancer Center/AACR. Used with permission.This regulatory milestone closely follows the first clinical data presentation from the MYTHIC trial (NCT04855656), a Phase I study evaluating this combination in patients with advanced solid tumors with specific genomic alterations. The data were featured in an oral presentation by Timothy A. Yap, MBBS, PhD, FRCP, of The University of Texas MD Anderson Cancer Center at the annual meeting of the American Association for Cancer Research (AACR), held April 17 – 22, 2026.[1]
Addressing an Urgent Unmet Need in Ovarian Cancer
Approximately 70% of women diagnosed with ovarian cancer who relapse after initial treatment develop platinum-resistant disease. In the United States, this accounts for a substantial, albeit not precisely enumerated, portion of the roughly 20,000 to 21,000 new ovarian cancer cases diagnosed annually.[2]
Platinum-resistant ovarian cancer harboring CCNE1 amplification, or deleterious mutations in FBXW7 or PPP2R1A, poses a substantial therapeutic challenge, with limited effective options for patients whose tumors progress despite standard platinum-based regimens. These alterations often drive high-grade serous ovarian cancer (HGSOC) and are associated with chemotherapy resistance and poor prognosis.
“Cancers with these specific alterations represent areas of unmet clinical need with no available standard-of-care targeted treatment options,” Yap explained.
“This combination of zedoresertib and lunresertib demonstrated strong synergy in preclinical studies, and we have now demonstrated its great potential as a novel therapeutic option for patients across multiple tumor types – especially for those with ovarian cancer,” Yap said.
“Patients with cancers harboring CCNE1 amplification and FBXW7 and PPP2R1A mutations represent areas of unmet clinical need, for which this combination could provide a new treatment option,” he added.
The FDA’s Fast Track designation is intended to accelerate the development and review of treatments for serious conditions with high unmet medical need, providing more frequent engagement with the agency and potential eligibility for Priority Review and Accelerated Approval.
“The FDA’s decision to grant Fast Track designation for this combination therapy validates our synthetic lethality approach to treating high-unmet-need cancers,” commented Esteban Rodrigo Imedio, MD, MSc, Executive Medical Director, Oncology at Debiopharm.
“This designation, coming immediately after the MYTHIC data presentation at AACR, highlights the potential of combining lunresertib and zedoresertib to offer a meaningful new option for biomarker-selected ovarian cancer patients who have exhausted platinum-based therapies,” Imedio added.
Synthetic Lethality Through Dual DDR Inhibition
The WEE1 protein is a critical gatekeeper of the cell cycle that helps cancer cells survive DNA damage by ensuring that DNA repair occurs before cell division. Inhibiting WEE1 with zedoresertib, therefore, pushes cancer cells with DNA damage – such as those with CCNE1 amplification-induced replication stress – into mitosis earlier, leading to cell death through apoptosis. Similarly, lunresertib, a highly selective PKMYT1 kinase inhibitor that regulates the cell cycle via a different pathway, creates synthetic lethality in tumors with specific genetic mutations, such as FBXW7 or PPP2R1A, or CCNE1 amplification.
Both zedoresertib and lunresertib work well together across multiple tumor types in vivo, showing durable regressions following both continuous and intermittent treatment with zedoresertib. The combination, which was well-tolerated in preclinical studies, exploits synthetic lethality by simultaneously inhibiting two key regulators of the DNA Damage Response (DDR) pathway—PKMYT1 and WEE1. Cancer cells, especially those with CCNE1 amplification or FBXW7/PPP2R1A mutations, are highly reliant on DDR mechanisms to survive the genomic instability characteristic of rapid cell division and proliferation. Disabling both PKMYT1 and WEE1 disrupts the G2/M and S-phase checkpoints, preventing cancer cells from repairing DNA damage and ultimately triggering cell death.
Promising Activity and Tolerability in MYTHIC Phase I Study
In the MYTHIC trial, 54 patients with advanced solid tumors (including ovarian, colorectal, pancreatic, and breast cancers) and relevant genetic alterations were treated with escalating doses of zedoresertib (150–260 mg) plus lunresertib (60 or 80 mg). Among RECIST-evaluable patients, 55.5% experienced tumor shrinkage, and the combination showed a manageable safety profile. The most common ≥ Grade 3 treatment-related adverse events were anemia (9.3%), neutropenia (7.4%), and palmar-plantar erythrodysesthesia (7.4%), with no Grade 5 events observed. Dose-limiting toxicities occurred in 9.3% of patients.
Importantly, 81.3% of ovarian cancer patients with CCNE1 amplification or FBXW7/PPP2R1A mutations achieved tumor shrinkage, and the clinical benefit rate was 93.8%. The combination’s tolerability and activity in this biomarker-defined population highlight its potential to address the urgent needs of patients with platinum-resistant or refractory disease.
Future Directions
The MYTHIC study continues to enroll patients to further evaluate the safety and efficacy of the lunresertib + zedoresertib combination in advanced, biomarker-selected solid tumors. Collaboration with Repare Therapeutics supports the ongoing development of this novel therapeutic strategy. The combination could represent a new precision medicine standard of care for patients with platinum-resistant ovarian cancer and other hard-to-treat, genomically defined malignancies.
“If this combination is successful and well tolerated, it could be a significant milestone, especially in ovarian cancers where these alterations are more common,” Yap concluded.
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Note: * Lunresertib (Debio 2513; previously known as RP-6306) was developed by Repare Therapeutics and is licensed to Debiopharm
Clinical trials
Study of Lunresertib Alone or in Combination With RP-3500 or Debio 0123 in Patients With Advanced Solid Tumors (MYTHIC) – ClinicalTrials.gov ID NCT04855656
Reference
[1] Yap TA, Aggarwal R, Fontana E, Hojgaard M, Carneiro BA, Duska L, LoRusso P, Yadav S, Lheureux S, Mathews C, Moy RH, Lakhani N, Weiss M, Tymon-Rosario J, Colon-Otero G, Garrido-Laguna I, E. Lee EK, Rodrigo Imedio E, Wessen J, Piggott L, Dozio V, Luong N, Mas C, Schram AM. First data disclosure of the Phase I trial of the first-in-class combination of WEE1 inhibitor zedoresertib with PKMYT1 inhibitor lunresertib in patients with advanced solid tumors harboring CCNE1, FBXW7, or PPP2R1A genomic alterations. In: Proceedings of the 117th Annual Meeting of the American Association for Cancer Research; 2026 April 17-22; San Diego, CA.: AACR; 2026. Abstract nr CT022.
[2] Bogani G, Lopez S, Mantiero M, Ducceschi M, Bosio S, Ruisi S, Sarpietro G, Guerrisi R, Brusadelli C, Dell’Acqua A, Di Donato V, Raspagliesi F. Immunotherapy for platinum-resistant ovarian cancer. Gynecol Oncol. 2020 Aug;158(2):484-488. doi: 10.1016/j.ygyno.2020.05.681. Epub 2020 Jun 6. PMID: 32518015.
Featured image licensed under the Unsplash+ License.
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