This novel combination of ATR inhibitor berzosertib with irinotecan did not lead to objective responses in patients with TP53-mutated, advanced gastroesophageal adenocarcinoma. The combination regimen was well tolerated without unexpected adverse events. This trial was registered with ClinicalTrials.gov (NCT03641313).

P3, N=594, Active, not recruiting, AstraZeneca | Trial completion date: Oct 2025 --> Oct 2026

P1/2, N=84, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Sep 2025 --> Sep 2026 | Trial primary completion date: Sep 2025 --> Sep 2026

HCC1937 and HCC1937-R Talazoparib (TAL) resistant cells were treated with Elimusertib (ELI) alone as ATR inhibitor (ATRi) and ELI and TAL combination. Therefore, the dual targeting of ATR and PARP is a promising modality to reverse PARPi resistance with the downregulation of ATR-Chk1 based DNA damage response. However, further preclinical and clinical investigations should be required to elucidate the underlying molecular mechanisms behind ATRi and PARPi interactions in TNBC cells.

P1/2, N=156, Terminated, Repare Therapeutics | Trial completion date: Dec 2025 --> Nov 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Mar 2025 --> Nov 2024; Sponsor decided to terminate study early therefore, the Phase 2 portion was not conducted

P1/2, N=132, Active, not recruiting, Aprea Therapeutics | Recruiting --> Active, not recruiting

Berzosertib 270 mg/m2 and irinotecan 180 mg/m2 was the RP2D. The combination is associated with manageable side effects and promising disease activity in ATM mutant solid tumors.

Baseline low ctDNA levels predict response to targeted therapy, potentially suggesting shared mechanisms between high ctDNA release and resistance to therapy. Both baseline ctDNA levels and on-treatment dynamics are a promising surrogate endpoint for drug development, with clearance of ctDNA being a robust cross-therapy surrogate for outcome.

Cisplatin combined with elimusertib was associated with hematologic toxicity requiring significant dose de-escalation. Elimusertib PK was consistent with prior studies. Only modest activity was observed. Further clinical evaluation of elimusertib plus cisplatin is not warranted.

P1, N=12, Active, not recruiting, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany | Recruiting --> Active, not recruiting

P1, N=52, Active, not recruiting, Massachusetts General Hospital | Recruiting --> Active, not recruiting | Trial completion date: May 2025 --> May 2026 | Trial primary completion date: May 2024 --> Apr 2025

P1, N=120, Active, not recruiting, EMD Serono Research & Development Institute, Inc. | Recruiting --> Active, not recruiting