azenosertib (ZN-c3) / Zentalis Pharma - LARVOL DELTA

WEE1 inhibition as a therapeutic strategy in triple-negative breast cancer: Evaluating single agent and combination activity of azenosertib in preclinical models (AACR 2026) - "We demonstrated in vitro and in vivo evidence that TNBC models are susceptible to WEE1 inhibition. Our findings suggest that azenosertib as a single agent, or in combination with standard-of-care therapies, may be a potential treatment strategy for TNBC and warrants further exploration."

IO biomarker • Preclinical • Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • CCNE1

Phase 1 dose escalation results of the WEE1 inhibitor, azenosertib (A), in combination with encorafenib (E) and cetuximab (C) in patients (pts) with previously treated BRAF V600E mutant metastatic colorectal cancer (mCRC). (ASCO 2025) - P1 | "The combination of A+E+C was well tolerated at the MTD and yielded response rates in BRAFi-naïve mCRC pts which exceeded the historical data from the E+C doublet."

Clinical • Combination therapy • Metastases • P1 data • Atrial Fibrillation • Cardiovascular • Colorectal Cancer • Fatigue • Neutropenia • Oncology • Solid Tumor • BRAF • CYP2C19 • CYP3A4

TETON: A Study of Azenosertib (ZN-c3) in Women With Recurrent or Persistent Uterine Serous Carcinoma (clinicaltrials.gov) - P2 | N=92 | Completed | Sponsor: K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc | Recruiting ➔ Completed | Trial completion date: May 2025 ➔ Oct 2025 | Trial primary completion date: Nov 2024 ➔ Oct 2025

Trial completion • Trial completion date • Trial primary completion date • Endometrial Cancer • Endometrial Serous Adenocarcinoma • Oncology • Uterine Cancer

ZN-c3-003: A Study of Azenosertib (ZN-c3) in Combination With Gemcitabine in Subjects With Osteosarcoma (clinicaltrials.gov) - P1/2 | N=31 | Completed | Sponsor: K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc | Active, not recruiting ➔ Completed | N=84 ➔ 31

Enrollment change • Trial completion • Oncology • Osteosarcoma • Pediatrics • Sarcoma • Solid Tumor

MAMMOTH: A Study of Azenosertib (ZN-c3) and Niraparib in Subjects With Platinum-Resistant Ovarian Cancer (clinicaltrials.gov) - P1/2 | N=117 | Completed | Sponsor: K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc | Active, not recruiting ➔ Completed | Trial completion date: May 2025 ➔ Jan 2026 | Trial primary completion date: May 2025 ➔ Oct 2025

Monotherapy • Platinum resistant • Trial completion • Trial completion date • Trial primary completion date • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor

ZN-c3-001: A Study of Azenosertib (ZN-c3) in Participants With Solid Tumors (clinicaltrials.gov) - P1 | N=274 | Completed | Sponsor: K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc | Recruiting ➔ Completed | N=146 ➔ 274 | Trial completion date: Aug 2023 ➔ May 2025 | Trial primary completion date: May 2023 ➔ May 2025

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

DNA fiber-based replication phenotypes distinguish WEE1-inhibitor response in high-grade endometrial cancer patient-derived organoids (PDOs) treated with azenosertib (AACR 2026) - "DNA-fiber assays measured: (i) fork speed (CldU+IdU as ongoing replication forks), (ii) replication fork stability under RS caused by hydroxyurea (HU), using the IdU:CldU ratio after WEE1i+HU, and (iii) single-stranded (ss)DNA gap formation via the S1 nuclease assay (WEE1i±S1). Four PDOs were profiled: DF4850 and DF4161 (WEE1i-sensitive; IC50s1500nM). In high-grade EC PDOs, azenosertib uniformly slows replication forks, but fork stability under HU and S1-detectable gap formation distinguish WEE1i-sensitive (DF4850, DF4161) from insensitive (DF042, DF4968) models. These mechanism-anchored DNA-fiber readouts merit prospective evaluation as predictive and pharmacodynamic biomarkers for WEE1 inhibitors in high-grade EC. Additional biomarker analyses, including immunohistochemical analyses of RS proteins, are ongoing and will be presented."

Clinical • Carcinosarcoma • Endometrial Cancer • Oncology • Sarcoma • Solid Tumor • TP53

Real-world treatment patterns and outcomes reveal distinct clinical trajectories of patients with Cyclin E1-positive ovarian cancer (AACR 2026) - "The treatment regimens used in early lines were consistent between TLOv and ReSET cohorts and reflected current SOC, including partial use of PARPi in 1L maintenance and a preference for doxorubicin-based regimens in 2L for platinum-resistant patients. RWD represents a reliable and up-to-date source of treatment and outcomes information for HGSOC patients. Clean identification of lines and intent of treatment as well as availability of direct or surrogate Cyclin E1 expression status were key to highlighting the unmet need of patients with Cyclin E1 positive tumors, informing azenosertib's development."

Clinical • HEOR • Real-world • Real-world evidence • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • BRCA • CCNE1

Zentalis Pharmaceuticals to Present Two Posters at the American Association for Cancer Research (AACR) Annual Meeting 2026 (GlobeNewswire) - "Preclinical evidence supports azenosertib ADC combinations as potential promising therapeutic strategies for Triple-Negative Breast Cancer. Demonstration of Cyclin E1 protein overexpression as an indicator for poor prognosis in ovarian cancer patients with real world data."

Preclinical • Real-world • Ovarian Cancer • Triple Negative Breast Cancer

Testing the Combination of the Anticancer Drugs Trastuzumab Deruxtecan (DS-8201a) and Azenosertib (ZN-c3) in Patients With Stomach or Other Solid Tumors (clinicaltrials.gov) - P1 | N=48 | Recruiting | Sponsor: National Cancer Institute (NCI) | Suspended ➔ Recruiting

Enrollment open • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor • CCNE1

Azenosertib in Uterine Serous Carcinoma: Biomarker Study (clinicaltrials.gov) - P2 | N=25 | Recruiting | Sponsor: Joyce Liu, MD | Trial completion date: Jan 2027 ➔ Jan 2028 | Trial primary completion date: Jan 2026 ➔ Jan 2027

Biomarker • dMMR • MSI-H • Trial completion date • Trial primary completion date • Endometrial Serous Adenocarcinoma • Oncology • Solid Tumor • Uterine Cancer • PD-L1

Azenosertib in combination with bevacizumab as maintenance therapy in patients with advanced ovarian cancer: part 2 of a phase 1b study (ESGO 2026) - P1, P2 | "Introduction/Background Most patients with Stage III/IV ovarian cancer (OC) relapse following initial carboplatin-paclitaxel chemotherapy, and effective novel therapies are needed. In dose expansion, patients with platinum-sensitive HGSOC in 2L who progressed while on a PARP inhibitor for 1L maintenance receive azenosertib at the recommended dose with bevacizumab. The primary objective is safety/tolerability; secondary objectives include preliminary clinical activity of the combination as assessed by progression-free survival and time-to-progression for the dose expansion cohort.Results NAConclusion NA"

Clinical • Combination therapy • Metastases • P1 data • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • BRCA • CCNE1

Testing the Combination of the Anticancer Drugs Trastuzumab Deruxtecan (DS-8201a) and Azenosertib (ZN-c3) in Patients With Stomach or Other Solid Tumors (clinicaltrials.gov) - P1 | N=48 | Suspended | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Suspended

Trial suspension • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor • CCNE1

ZN-c3 + Gemcitabine in Pancreatic Cancer (clinicaltrials.gov) - P2 | N=12 | Active, not recruiting | Sponsor: Brandon Huffman, MD | Recruiting ➔ Active, not recruiting | N=34 ➔ 12

Enrollment change • Enrollment closed • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

ZAP-IT: ZN-c3 + Carboplatin + Pembrolizumab in mTNBC (clinicaltrials.gov) - P1/2 | N=78 | Active, not recruiting | Sponsor: Filipa Lynce, MD | Recruiting ➔ Active, not recruiting

Enrollment closed • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Negative Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD4 • HER-2 • PGR

Cyclin E1 is a Predictive Biomarker of Azenosertib Benefit in Platinum-Resistant Ovarian Cancer (PROC): Outcomes from Part 1b of the DENALI Study (GOG-3066) (SGO 2025) - No abstract available

Biomarker • Oncology • Ovarian Cancer • Solid Tumor • CCNE1

Correlation of cyclin E1 expression and clinical outcomes in a phase 1b dose-escalation study of azenosertib (ZN-c3), a WEE1 inhibitor, in combination with chemotherapy (CT) in patients (pts) with platinum-resistant or refractory (R/R) epithelial ovarian, peritoneal, or fallopian tube cancer (EOC). (ASCO 2023) - P1b | " This open-label, multicenter study (NCT04516447) assessed azenosertib + paclitaxel (PAC), carboplatin (Carbo), gemcitabine (GEM), or pegylated liposomal doxorubicin (PLD) in pts with metastatic high-grade serous EOC after ≤2 lines of CT including platinum CT. Azenosertib + CT is well tolerated and has encouraging clinical activity, with durable responses in pts with platinum R/R EOC. Pts with Cyclin E1 overexpressing tumors, a subgroup with suboptimal benefits from CT, demonstrated significant improvements in ORR and PFS vs pts with tumors having low expression. These data support a planned trial of azenosertib + CT vs CT alone in Cyclin E1 overexpressing platinum R/R EOC."

Clinical • Clinical data • Combination therapy • P1 data • Anemia • Fallopian Tube Cancer • Fatigue • Hematological Disorders • Leukopenia • Neutropenia • Oncology • Ovarian Cancer • Solid Tumor • Thrombocytopenia • CCNE1

Anticipated 2026 Milestones (GlobeNewswire) - "DENALI Part 2a dose confirmation expected in first half of 2026; Confirmatory ASPENOVA Phase 3 trial initiation expected in first half of 2026. The planned Phase 3 trial is expected to be conducted concurrently with DENALI Part 2; DENALI Part 2 topline readout on track and expected by year end 2026. DENALI Part 2, if successful, has the potential to support an accelerated approval, subject to FDA feedback."

New P3 trial • P2 data • Platinum resistant • Trial status • Ovarian Cancer

A phase i/ii single-arm trial of azenosertib (zn-c3) combined with carboplatin and pembrolizumab in patients with metastatic triple-negative breast cancer (zap-it) (SABCS 2025) - "A phase II study assessing the efficacy of the WEE1 inhibitor adavosertib with cisplatin in 34 patients with mTNBC treated with 0-1 prior lines of chemotherapy showed an ORR of 26% (Keenan. A maximum of 78 patients will be enrolled. To our knowledge this is the first and only ongoing study testing the combination of a WEE1 inhibitor with carboplatin and a checkpoint inhibitor for the treatment of breast cancer."

Clinical • IO biomarker • Metastases • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDK1 • HER-2 • PD-L1 • WEE1

Indicators of Response to the Wee1 Inhibitor Adavosertib in Acute Myeloid Leukemia (ASH 2023) - P1/2 | "Wee1 is a nuclear kinase that regulates cell cycle progression by inhibiting Cdk1, which is essential for G2 to M phase transition. In addition, high CD34 expression in resistant samples suggests that immature stem and progenitor cells may be less susceptible to Wee1i. In summary, targeting of Wee1 in AML – as studied in NCT05682170 azenosertib study - may be effective for a molecularly defined subset of patients."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • AFDN • CD34 • CDC37 • CDK1 • CDK2 • GLI2 • S100A16

Phase 2 DENALI clinical trial remains on track and has the potential to support an accelerated approval, subject to FDA feedback (GlobeNewswire) - "Enrollment is ongoing in DENALI Part 2a of the Phase 2 DENALI clinical trial (NCT05128825) of azenosertib in patients with Cyclin E1-positive PROC....The Company expects to disclose topline data from DENALI Part 2 (Part 2a and Part 2b) by year end 2026."

P2 data • Platinum resistant • Trial status • Ovarian Cancer

TETON Phase 2 trial in uterine serous carcinoma (USC) completed enrollment (GlobeNewswire) - "Results from the TETON trial are planned for publication in the first half of 2026."

Enrollment closed • P2 data • Uterine Cancer

ACR-2316 is a novel, differentiated, clinical-stage WEE1/PKMYT1 inhibitor designed by Acrivon's Generative Phosphoproteomics AP3 Platform for optimal pro-apoptotic pathway effects in tumor cells resulting in superior preclinical activity (AACR-NCI-EORTC 2025) - "In cellular TE assays, ACR-2316 displayed more potent WEE1 TE than all benchmark WEE1 inhibitors (azenosertib, adavosertib, Debio0123), while simultaneously targeting MYT1... WEE1 inhibitor-induced MYT1 activation constitutes a resistance mechanism that may limit the clinical efficacy of WEE1 inhibition. ACR-2316 is a potent, selective WEE1/MYT1 inhibitor that displays superior preclinical efficacy via its differentiated profile optimized by AP3 pathway-based structure-activity relationships in the intact cell. Acrivon's ongoing Phase 1 ACR-2316 monotherapy trial in solid tumors has already demonstrated clinical activity during dose escalation prior to reaching Recommended Phase 2 Dose."

Preclinical • Tumor cell • Oncology • Solid Tumor • BRAF • CDK1 • CDK2 • PKMYT1 • PLK1

Cyclin E1 Positive Protein Status is a Predictive Biomarker of Azenosertib Benefit in Platinum-Resistant Ovarian Cancer: Part 2 of the DENALI Study (GOG-3066) (AACR-NCI-EORTC 2025) - P2 | "Prior therapy requirements include bevacizumab, PARPi for patients harboring BRCA 1/2 mutation or HRD, and mirvetuximab for patients with high folate receptor alpha expression. The endpoints are objective response rate, duration of response, progression-free survival and clinical benefit rate by RECIST v1.1, CA-125 response by Gynecologic Cancer Intergroup criteria, and safety. An Independent Data Monitoring Committee has been chartered for this study."

Biomarker • Platinum resistant • Oncology • Ovarian Cancer • Solid Tumor • BRCA • BRCA1 • BRCA2 • CCNE1 • FOLR1 • MUC16

Results From the Phase 1 Dose Escalation and Dose Expansion Study of Azenosertib, a WEE1 Inhibitor, in Patients With Advanced Solid Tumors (AACR-NCI-EORTC 2025) - P2 | "As of December 2, 2024, 193 patients (PROC, n=69; USC, n=35; other solid tumors, n=89) received a total daily dose (300-500mg) of azenosertib, continuously or intermittently (5:2 or 4:3). The median age was 65 years and 98% of patients had ECOG PS ≤1; median number of prior lines of therapy was 5 (PROC), 3 (USC) and 4 (other solid tumors). The most common treatment-related adverse events (TRAEs) were nausea (61%), fatigue (59%), and diarrhea (52%)."

Clinical • Metastases • P1 data • Endometrial Serous Adenocarcinoma • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • Uterine Cancer • CCNE1