ACR-368

Overview

ACR-368 (prexasertib; formerly LY2606368) is an investigational, intravenous checkpoint kinase inhibitor being developed primarily for biomarker-selected patients with platinum-resistant ovarian and endometrial cancers, and other solid tumors. It targets CHK1 and CHK2 and is being advanced with a proteomics-based companion diagnostic (OncoSignature). The FDA has granted Fast Track designation for ACR-368 monotherapy in OncoSignature-positive platinum‑resistant ovarian and endometrial cancers, and Breakthrough Device designations for the OncoSignature assays in ovarian and endometrial cancers. (ir.acrivon.com)

Mechanism of action

Prexasertib inhibits CHK1/CHK2, key regulators of S/G2 cell-cycle checkpoints activated by replication stress and DNA damage. Inhibition drives replication catastrophe and mitotic entry with unrepaired DNA, leading to tumor cell death. Pharmacodynamic studies in patients show decreased RAD51 foci and increased γ‑H2AX and other DNA damage markers, consistent with homologous recombination impairment; preclinical work in high‑grade serous ovarian cancer (HGSOC) models demonstrates monotherapy antitumor activity and synergy with PARP inhibition. (aacrjournals.org)

Efficacy

• Ovarian cancer
• BRCA wild‑type, recurrent HGSOC (single‑center phase 2): ORR 29% (8/28, ITT) in heavily pretreated patients; most had platinum‑resistant/refractory disease. (pubmed.ncbi.nlm.nih.gov)
• Multicenter phase 2 across resistant/refractory cohorts (N=169): ORR 12.1% in platinum‑resistant cohorts; 6.9% in platinum‑refractory cohort; disease control rates 37.1% (resistant) and 31.0% (refractory). (pubmed.ncbi.nlm.nih.gov)
• BRCA‑mutant HGSOC, heavily pretreated (phase 2, single‑arm): ORR 11% (2/18 evaluable); most had prior PARP inhibitor exposure. (ascopubs.org)

• Combination with olaparib (phase 1): signals of activity in PARP inhibitor–resistant BRCA‑mutant HGSOC (4/18 partial responses). (aacrjournals.org)

• Endometrial cancer (biomarker‑selected, ongoing)

• Company‑reported, prospective OncoSignature‑positive cohort in a registrational‑intent phase 2b: confirmed ORR 62.5% (95% CI, 30.4–86.5) presented at ESMO 2024; segregation of responses by OncoSignature status reported. Data are preliminary and not yet peer‑reviewed. (ir.acrivon.com)

• Other solid tumors

• Squamous cell carcinomas (phase 1b): single‑agent activity observed; ORR 15% in anal SCC and 5% in head and neck SCC; 3‑month clinical benefit rate 29% across squamous cohorts. (aacrjournals.org)
• Head and neck SCC with radiotherapy combinations (phase 1b): feasibility with cetuximab–RT established (MTD 30 mg/m²); small cohorts showed high radiographic response rates but interpretation limited by size and design. (pubmed.ncbi.nlm.nih.gov)
• Desmoplastic small round cell tumor (DSRCT), prexasertib + irinotecan (phase I/II): estimated ORR 23% at the RP2D (32% across all doses); median OS 19 months. (pubmed.ncbi.nlm.nih.gov)

Safety

Across trials, the predominant toxicities are myelosuppressive: - Very common grade 3/4 neutropenia and leukopenia; thrombocytopenia and anemia also observed. Febrile neutropenia was a dose‑limiting toxicity in combination settings and occurred infrequently as high‑grade events in monotherapy studies. Growth‑factor support is commonly used. (pubmed.ncbi.nlm.nih.gov)

In the chemoradiation head‑and‑neck study, non‑hematologic events consistent with RT/EGFR‑inhibitor combinations (e.g., mucositis/stomatitis, dysphagia, dermatitis) were common. (pubmed.ncbi.nlm.nih.gov)

Notes on ongoing development

Acrivon is conducting a multicenter, registrational‑intent phase 2 program using the ACR‑368 OncoSignature to prospectively select patients; preliminary efficacy signals (including endometrial cancer) have been disclosed by the sponsor and require independent peer‑review. The ACR‑368 program holds FDA Fast Track status, while the companion OncoSignature assays hold FDA Breakthrough Device designations (tests are investigational and not approved). (ir.acrivon.com)

Further reading

• Lee et al. Prexasertib in BRCA wild‑type recurrent HGSOC (phase 2, Lancet Oncology 2018). (pubmed.ncbi.nlm.nih.gov)
• Colombo et al. Phase 2 study in platinum‑resistant/refractory ovarian cancer (Gynecologic Oncology Reports 2022). (pubmed.ncbi.nlm.nih.gov)
• Do et al. Phase 1 prexasertib + olaparib with pharmacodynamic analyses (Clinical Cancer Research 2021). (aacrjournals.org)
• Colevas et al. Phase 1b in squamous cell carcinomas (Clinical Cancer Research 2018). (aacrjournals.org)
• Desmoplastic small round cell tumor phase I/II (prexasertib + irinotecan) results (JCO 2025). (pubmed.ncbi.nlm.nih.gov)
• Trial design and regulatory designations for OncoSignature‑guided phase 2 program (company communications; interpret with caution). (acrivon.com)

Last updated: Oct 2025