Platinum-resistant high-grade serous ovarian carcinoma (HGSOC) remains a significant therapeutic challenge, with limited effective options following failure of platinum-based chemotherapy. In a randomized Phase 2a clinical trial, the combination of low-dose alnodesertib (ART0380)—an oral, selective ATR kinase inhibitor—with gemcitabine demonstrated a significant improvement in progression-free survival (PFS) compared to gemcitabine alone. These findings support the rationale for targeting DNA damage response (DDR) pathways in cancers characterized by high replication stress and offer a promising new strategy for overcoming resistance to standard therapies. The study outcomes were presented at the 27th European Society of Gynaecological Oncology (ESGO), held February 26-28, 2026, in Copenhagen, Denmark.[1]
High-grade serous ovarian carcinoma (HGSOC) is the most common and lethal subtype of epithelial ovarian cancer. Despite initial responsiveness to platinum-based chemotherapy, the majority of patients experience disease relapse, ultimately developing resistance to platinum agents. This clinical scenario represents a critical unmet need, as treatment options are limited and outcomes are poor.
The DNA damage response (DDR) network plays a central role in maintaining genomic integrity, and its dysregulation is a hallmark of many solid tumors, including HGSOC. Ataxia telangiectasia and Rad3-related (ATR) protein kinase is a key regulator of the cellular response to replication stress, which is heightened in many cancers. ATR inhibition, particularly in combination with DNA-damaging agents such as gemcitabine (Gemzar®, Eli Lilly & Co),* is hypothesized to selectively enhance tumor cell death by overwhelming defective DNA repair mechanisms, offering a novel therapeutic approach for platinum-resistant disease.[2]
Study design
Researchers at Artios Pharma conducted a multicenter, randomized, open-label, Phase 2a trial (NCT04657068) evaluating the efficacy and safety of alnodesertib in combination with gemcitabine compared to gemcitabine monotherapy in patients with platinum-resistant HGSOC. Eligible patients were randomized 1:1, stratified by platinum-free interval, to receive either low-dose alnodesertib (50mg, orally, days 2–4 and 9–11) plus gemcitabine (800mg/m², IV, days 1 and 8) or gemcitabine alone, on a 21-day cycle. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), overall survival (OS), and safety.
Study results
A total of 64 patients were enrolled and randomized. The addition of low-dose alnodesertib to gemcitabine resulted in a statistically significant improvement in PFS compared to gemcitabine alone (hazard ratio for progression or death, 0.71; 29% relative risk reduction; one-sided p<0.1). The 6-month PFS rate was 34% in the combination arm, compared with 23% with gemcitabine monotherapy. Importantly, 41% of patients initially randomized to gemcitabine alone crossed over to receive the combination upon disease progression, with several experiencing meaningful, extended disease control.
Secondary endpoints of ORR and OS were similar between arms, with the OS analysis confounded by the high crossover rate. The combination regimen was generally well tolerated; the most frequent adverse events were asthenia, pyrexia, and hematologic and gastrointestinal toxicities. Grade ≥3 adverse events occurred in 66% of patients in the combination arm and 63% in the monotherapy arm, with increased rates of grade ≥3 anemia and thrombocytopenia observed in the combination group. No treatment-related deaths or cases of febrile neutropenia were reported.
These results provide proof-of-concept that ATR inhibition with alnodesertib, when combined with a DNA-damaging agent such as gemcitabine, can delay disease progression in patients with platinum-resistant HGSOC. The observed reduction in risk of progression or death, along with the manageable safety profile, supports further investigation of this therapeutic strategy in replication stress–driven malignancies.
This study adds to a growing body of evidence supporting DDR-targeted therapies in oncology. ATR is a critical mediator of the replication stress response, and its inhibition potentiates the cytotoxic effects of chemotherapy in tumors dependent on intact DDR pathways for survival. The clinical benefit observed in this trial suggests that alnodesertib may be particularly effective in settings of high replication stress, a feature common to HGSOC and other aggressive solid tumors.
Ongoing studies are evaluating higher doses of alnodesertib in combination with low-dose irinotecan in ATM-deficient colorectal and pancreatic cancers, further exploring the potential of DDR inhibition in a biomarker-driven context.
The combination of low-dose alnodesertib and gemcitabine met the primary endpoint of improved PFS in patients with platinum-resistant HGSOC, validating the approach of exploiting replication stress and DDR vulnerabilities in treatment-refractory cancers. These findings warrant expanded clinical investigation of alnodesertib-based regimens across tumor types characterized by high replication stress and underscore the promise of DDR-targeted strategies in modern oncology.
__
Note:* In late 2024, the Germany-based Cheplapharm Group acquired Gemzar® from Eli Lilly and Company. The transaction included the transfer of worldwide commercial rights (except South Korea). Gemcitabine, the active substance in Gemzar is included in the World Health Organization’s Model Lists of Essential Medicine.
** The authors thank all participating patients, their families, and the clinical trial teams. Study sponsored by Artios Pharma.
Clinical trials
A Study of ART0380 for the Treatment of Advanced or Metastatic Solid Tumors – ClinicalTrials.gov ID NCT04657068
Highlight of prescribing information
Gemcitabine (Gemzar®, Eli Lilly & Co)[Prescribing information]
References
[1] González Martín A, Manso L, Pérez-Fidalgo A, Quindós M, Estévez-García P, Pérez-Ramírez S, Puertes A, Bartolomé J, Barretina-Ginesta MP, Pardo B, Gaba L, Herrero A, Hierro C, Headley D, Smith GCM, Little N, Harrop B, Menon S, Smith IC, Rubio Pérez MJ. GEICO 114-O: A randomised phase 2a evaluation of the ATR inhibitor alnodesertib (ART0380) combined with gemcitabine for platinum-resistant high-grade serous ovarian cancer (HGSOC). Poster presentation/Abstract 386. In: International Journal of Gynecological Cancer, 36. DOI: 10.1016/j.ijgc.2025.103083 [Article]
[2] Groelly FJ, Fawkes M, Dagg RA, Blackford AN, Tarsounas M. Targeting DNA damage response pathways in cancer. Nat Rev Cancer. 2023;23(1):xx–xx. doi:10.1038/s41568-022-00535-5
Featured image courtesy: © 2018 -2026. Fotolia/Adobe. Used with permission.
DOI
