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

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

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

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

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

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

Azenosertib in combination with bevacizumab as maintenance therapy in patients with advanced ovarian cancer: part 2 of a phase 1b study (ESGO 2026) - No abstract available

Clinical • Combination therapy • Metastases • P1 data • Oncology • Ovarian Cancer • Solid Tumor

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

Rationale for the use of Azenosertib in Early Line Treatment of Cyclin E1-Positive High-Grade Serous Ovarian Cancer (AACR-NCI-EORTC 2025) - P1 | "To evaluate if combining azenosertib with SOC bevacizumab offers an advantage in 1L maintenance, we tested the combination in two homologous recombination proficient, cyclin E1-high xenograft models (OVCAR3, OV5308) with differing sensitivities to anti-VEGF. Safety and tolerability of the combination is currently being assessed in the maintenance setting of an ongoing phase 1b study (NCT04516447). The preclinical and retrospective clinical data support developing azenosertib in cyclin E1-positive HGSOC patients in an early treatment setting, with preclinical evidence suggesting added benefit when combined with SOC anti-VEGF in 1L maintenance."

High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • BRCA • CCNE1 • WEE1

Global pharmacodynamic effects uncovered with AP3 phosphoproteomic profiling of novel WEE1/PKMYT1 inhibitor ACR-2316 reveals the critical importance of PLK1 for ACR-2316's superior preclinical activity and differentiated mechanism of action (AACR-NCI-EORTC 2025) - "The clinical WEE1 inhibitors azenosertib and Debio0123, and the PKMYT1 inhibitor lunresertib were administered in parallel at maximum tolerated/formulable doses... ACR-2316 is a potential first- and best-in-class dual inhibitor of WEE1 and PKMYT1, rationally designed using Acrivon's proprietary AP3 platform to deliver superior single-agent efficacy. Potent activation of PLK1, together with CDK1/2, is essential for the superior activity of ACR-2316. ACR-2316 has shown clinical activity in its ongoing Phase 1b monotherapy trial in solid tumors during dose escalation."

PK/PD data • Preclinical • Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • CDK1 • PKMYT1 • PLK1 • RRM2 • WEE1

Trial in Progress: Phase 1 Study of Trastuzumab Deruxtecan (DS-8201a) in Combination with Azenosertib (ZN-c3) in HER2-Expressing/ Amplified Gastric/ Gastroesophageal Junction Cancer and Other Solid Tumors with HER2 Expression (AACR-NCI-EORTC 2025) - P1 | "3) Prior treatment with a WEE1 inhibitor or T-DXd. The study is recruiting in the United States through the NCI ETCTN (NCT06364410)."

Combination therapy • P1 data • Esophageal Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor • HER-2

Inducing mitotic catastrophe in high replicative stress castration resistant prostate cancer through inhibition of WEE1 (AACR-NCI-EORTC 2025) - " We determined the half-maximal inhibitory concentrations (IC₅₀) of two WEE1 inhibitors, AZD1775 (adavosertib) and ZN-c3 (azenosertib), in a panel of LNCaP-derived prostate cancer cell lines: LNCaP (parental), LNCaP-AR (androgen receptor amplification), and LNCaP-DKO (RB1 and TP53 double knockout). Our findings demonstrate that mCRPC models with G1 checkpoint mutations and inherently high replicative stress are more susceptible to WEE1i, revealing a potential predictive biomarker that can be leveraged for therapeutic efficacy."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • CDK1 • RB1 • TP53

Determination of total and unbound levels of a potent Wee1 inhibitor, ZN-c3, in human plasma, CSF, and brain tumor by a validated LC-MS/MS method. (EANO 2025) - "A sensitive and rapid bioanalytical method is developed and validated to quantify total and unbound ZN-c3 levels in human plasma, CSF and glioblastoma tissue. This method has been applied to assess the brain penetration profile of ZN-c3 in preclinical animal models and will be employed in an upcoming clinical trial investigating ZN-c3 in glioblastoma patients."

Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Zentalis Pharmaceuticals Announces Four Azenosertib Posters Presentations at AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (GlobeNewswire) - "Presentations feature data from first-in-human Phase 1 study including Cyclin E1 biomarker findings, supporting late-stage development of azenosertib."

P1 data • Platinum resistant • Trial status • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • High Grade Serous Ovarian Cancer

ZN-c3-016: ZN-c3 in Adult Participants With Metastatic Colorectal Cancer (clinicaltrials.gov) - P1 | N=44 | Terminated | Sponsor: K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc | Trial completion date: Sep 2026 ➔ Jul 2025 | Active, not recruiting ➔ Terminated; Study terminated due to change in therapeutic landscape.

Trial completion date • Trial termination • Colorectal Cancer • Oncology • Solid Tumor • BRAF

Completed strategic restructuring announced in January 2025, supporting late-stage clinical development of azenosertib (GlobeNewswire) - "The Company has operationally completed the restructuring and does not expect to incur further associated related non-recurring expenses. This restructuring prioritizes the late-stage development of azenosertib and extends the Company’s cash runway into late 2027, beyond the Company’s anticipated DENALI Part 2 topline data."

Commercial • Platinum resistant • Ovarian Cancer

Zentalis Pharmaceuticals Reports Second Quarter 2025 Financial Results and Operational Progress (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. DENALI Part 2, if successful, has the potential to support an accelerated approval, subject to FDA review."

P2 data • Platinum resistant • Trial status • Ovarian Cancer

Targeting WEE1 Kinase for Breast Cancer Therapeutics: An Update. (PubMed, Int J Mol Sci) - "Adavosertib's clinical promise was challenged by inter-individual variations in response and side effects. Because of these promising preclinical outcomes, other WEE1 kinase inhibitors (Azenosertib, SC0191, IMP7068, PD0407824, PD0166285, WEE1-IN-5, Zedoresertib, WEE1-IN-8, and ATRN-1051) are being developed, with several currently being evaluated in clinical trials or as an adjuvant to chemotherapies...Reliable predictors of clinical responses based on mechanistic insights remain an important unmet need. Herein, we review the role of WEE1 inhibition therapy in breast cancer."

Journal • Review • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDC25C • CDK1 • CDK2 • GNRP • PKMYT1 • STING

The 12-Ethynylmonocarba-closo-dodecaborate Anion: A Ligand for Metal Alkynide Complexes (M = Li, Na, Ca, Zn). (PubMed, Inorg Chem) - "X-ray crystallography and NMR spectroscopy reveal unique coordination geometries, including a rare chair-shaped Li4C2O2 unit in 2a, multinuclear units in 2b-c, and a hexagonal Zn3C3 unit in 2d. Subsequent nucleophilic reactions with benzophenone afford propargylic alcohols (3) with high efficiency, demonstrating their utility in selective synthetic routes for complex molecular assembly. This work not only highlights the reactivity of alkali and alkaline-earth metals in monocarborane metal acetylides but also offers valuable insights into their structural characteristics and potential applications in advanced materials and catalytic systems."

Journal

INK4A/B as predictive biomarkers for enhanced efficacy of dual WEE1 and PKMYT1 inhibition in CDK4/6 inhibitor-resistant breast cancer (AACR 2025) - "This study aimed to identify predictive biomarkers of response to WEE1/PKMYT1 dual inhibition while maintaining manageable toxicity. Evaluating WEE1 inhibitors (adavosertib or azenosertib) in combination with the PKMYT1 inhibitor (lunresertib) across CDK4/6i-R and TNBC models, including patient-derived xenografts (PDXs) and organoids, demonstrated significant tumor suppression, with the novel dual WEE1/PKMYT1 inhibitor SGR-3515 showing comparable efficacy... Dual inhibition of WEE1 and PKMYT1 presents a compelling therapeutic strategy for CDK4/6i-R breast cancer and TNBC. Elevated baseline levels of INK4A and INK4B are strongly associated with enhanced treatment responses, highlighting their potential as predictive biomarkers for selecting patients likely to benefit from WEE1/PKMYT1 dual inhibition therapy."

Biomarker • Clinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • CDKN2A • CDKN2B • ER • HER-2 • PKMYT1