Massard, Christophe

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.

Abstract Purpose: To review key aspects of the design and conduct of early clinical trials (ECT) of immunotherapy agents. Experimental Design: The Methodology for the Development of Innovative Cancer Therapies Task Force 2019 included experts from academia, nonprofit organizations, industry, and regulatory agencies. The review focus was on methodology for ECTs testing immune-oncology therapies (IO) used in combination with other IO or chemotherapy. Results: Although early successes have been seen, the landscape continues to be very dynamic, and there are ongoing concerns regarding the capacity to test all new drugs and combinations in clinical trials. Conclusions: Optimization of drug development methodology is required, taking into account early, late, and lower grade intolerable toxicities, novel response patterns, as well as pharmacodynamic data.

5029 Background: Pembro had activity as monotherapy in pretreated advanced mCRPC. Data are presented here from cohort B (pembro + docetaxel/prednisone) of KEYNOTE-365 (NCT02861573), a phase 1b/2 umbrella study to test combinations in mCRPC. Methods: Pts who progressed on or became intolerant to ≥4 wk of abi or enza in the prechemotherapy mCRPC state and progressed within 6 mo before screening were eligible. Pts received pembro 200 mg IV with docetaxel 75 mg/m2 IV Q3W plus prednisone 5 mg orally twice daily. The primary end points were safety and PSA response rate (confirmed PSA decrease ≥50%). Key secondary end points were investigator-determined ORR (RECIST v1.1), disease control rate (DCR: CR+PR+SD ≥6 mo), time to PSA progression, rPFS, and OS. Results: 72 pts (median age, 68 y; visceral disease, 36%; measurable disease, 50%) began pembro + docetaxel. Median (95% CI) follow-up was 10 (8-12) mo. Efficacy is outlined in the table. Treatment-related AEs occurred in 69 (96%) pts; most frequent (≥30%) were alopecia (43%), fatigue (40%), and diarrhea (39%). Grade 3-5 treatment-related AEs occurred in 27 (38%) pts, including 2 deaths from treatment-related AEs (pneumonitis). Most commonly reported immune-mediated AEs were infusion-related reactions (11%) and colitis (10%). Conclusions: Pembro + docetaxel/prednisone has activity in pts with mCRPC who previously progressed on second-generation hormone therapy. AEs were considered mild for the treatment combination. Clinical trial information: NCT02861573. [Table: see text]

170 Background: Pembro had antitumor activity as monotherapy in pretreated advanced mCRPC (KEYNOTE-028; KEYNOTE-199). KEYNOTE-365 (NCT02861573) is a phase 1b/2 umbrella study testing combinations in mCRPC; we report early results from cohort B combining pembro + docetaxel in mCRPC. Methods: Pts who failed or became intolerant to ≥4 weeks of abi or enza in the pre-chemotherapy mCRPC state received pembro 200 mg IV with docetaxel 75 mg/m2 IV Q3W plus prednisone 5 mg orally twice daily. Pts also progressed within 6 months prior to screening as determined by either PSA progression or radiologic progression in bone or soft tissue. Response was evaluated by PSA levels Q3W and imaging Q9W for first year and Q12W thereafter. Primary end points: safety and PSA response rate (confirmed PSA decline ≥50%). Key secondary end points: investigator-determined ORR (RECIST v1.1), disease control rate (DCR: CR+PR+SD ≥6 mo), time to PSA progression, rPFS, and OS. Results: 72 pts (median age 68 years; PD-L1+ 29%; visceral disease 36%; measurable disease 50%) initiated pembro + docetaxel. Median (95% CI) follow-up was 10 (8-12) mo. Efficacy is outlined in table below. Treatment-related AEs occurred in 69 (96%) pts; most frequent (≥30%) were alopecia (43%), fatigue (40%), and diarrhea (39%). Grade 3-5 treatment-related AEs occurred in 27 (38%) pts, including 2 deaths due to treatment-related AEs (pneumonitis). Conclusions: Combination of pembro + docetaxel/prednisone has activity in pts with mCRPC previously failing anti-hormonal therapy. Observed safety profile for the combination was consistent with known safety profile of each component. Clinical trial information: NCT02861573. [Table: see text]