Abstract CT075: Lack of CTPS2 expression exposes synthetic lethal vulnerability to selective CTPS1 inhibition: A phase 1 dose escalation study of dencatistat (STP938) with safety expansion in biomarker selected cohorts

Abstract Background: Pyrimidine synthesis is a therapeutic vulnerability in cancer but inhibition results in toxicity to normal cells. Differential targeting of CTP synthase 1 (CTPS1), sparing the CTPS2 isoenzyme, is a therapeutic strategy in lymphoid cancers, supported by human genetic studies, that can potentially avoid toxicity; however, CTPS2 activity may compensate in epithelial tumours. Loss of CTPS2 protein expression characterises 25% of solid tumours and is predicted to expose a synthetic lethal vulnerability to CTPS1 inhibition. Dencatistat (STP938) is a first in class oral CTPS1 inhibitor showing >1,300-fold selectivity over CTPS2. In preclinical studies, CTPS2 expression was confirmed as a key modulator of response to CTPS1 inhibition, and dencatistat induced tumour regression in an in vivo model of CTPS2 negative ovarian cancer. Study design: The study comprises a standard 3+3 phase 1a dose escalation design, in which intra-patient dose escalation is encouraged, followed by a phase 1b safety expansion. The dose escalation study is recruiting participants with high grade advanced tumours who have exhausted standard of care therapy (excluding haematological cancers, salivary gland tumours and low grade tumours of any tissue). In addition, participants with high grade serous ovarian cancer whose tumours lack expression of CTPS2 (per central laboratory testing by immunohistochemistry) are eligible for backfill into cleared cohorts during dose escalation. The recommended phase 2 dose (RP2D) will be nominated based on safety, tolerability, target engagement and early signs of clinical efficacy. The phase 1b safety expansion study will recruit participants with CTPS2 negative ovarian, lung or endometrial cancer who will receive treatment at the RP2D. Standard inclusion criteria apply; patients with ECOG performance score >2 (>1 for phase 1a in France) or active/symptomatic CNS metastases are not eligible. The primary objectives of the study are to evaluate the safety and tolerability of single agent dencatistat and to determine the RP2D for further development. Secondary objectives comprise evaluation of pharmacokinetic properties and preliminary clinical activity. Exploratory endpoints include evaluation of target engagement, molecular features associated with response, and determination of drug metabolites. The study opened to enrolment in the UK, France and USA in September 2024 and is currently in dose escalation (NCT06297525). The phase 1b study is expected to commence mid-2026 and will include additional centres in Spain. Citation Format: Donna M. Graham, David Sommerhalder, Douglas Orr, Rowan Miller, Neeharika Makani, David O'Malley, Ira Winer, Philip A. Beer, Karen Smith, Maureen Higgins, John R. Hawse, Xiyin Wang, Saravut J. Weroha, Christophe Massard, Patricia Roxburgh. Lack of CTPS2 expression exposes synthetic lethal vulnerability to selective CTPS1 inhibition: A phase 1 dose escalation study of dencatistat (STP938) with safety expansion in biomarker selected cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT075.