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

Business Updates: Regulatory Update (Zentalis Pharma Press Release) - "Met with the FDA in a Type D meeting regarding the Company’s accelerated approval strategy, including dose. The FDA had no objection to the continued study of the selected monotherapy dose of azenosertib at the 400mg once daily on a 5-days-on, 2-days-off schedule (400mg QD 5:2) in patients with Cyclin E1-positive PROC, selected based on a pre-specified interim analysis from DENALI Part 2a. The FDA acknowledged the DENALI Part 2 study population, including the 2c cohort, has the potential to support an accelerated approval pathway, subject to the strength of the data and the landscape of approved agents at the time of regulatory action."

FDA event • Platinum resistant • Fallopian Tube Cancer • Ovarian Cancer • Peritoneal Cancer

AZENOSERTIB MONOTHERAPY IN PATIENTS WITH RECURRENT OR PERSISTENT UTERINE SEROUS CARCINOMA: RESULTS FROM A PHASE 2 CLINICAL TRIAL (IGCS 2026) - P2 | "As of 15 December 2025, 92 patients received azenosertib continuously (200 mg [n=10] or 300 mg [n=33]), or intermittently (400 mg 5:2 [n=49]). Overall, the most common treatment-related adverse events (TRAEs) were nausea (54.3%), fatigue (51.1%), and diarrhea (42.4%). TRAEs led to treatment interruption or reduction in 56.5% and discontinuation in 7.6% of patients."

Clinical • Monotherapy • P2 data • Endometrial Serous Adenocarcinoma • Oncology • Uterine Cancer

WEE1 kinase in cancer: Molecular mechanisms and inhibitor insights. (PubMed, EXCLI J) - "We have also summarized the clinical development of major WEE1 inhibitors such as adavosertib, azenosertib (ZN-c3), and Debio 0123. See also the graphical abstract(Fig. 1)."

Journal • Review • Oncology • Targeted Protein Degradation • CDK1 • TP53

Azenosertib in platinum-resistant ovarian cancer (PROC): overall survival analysis from Part 1b of the DENALI study (GOG-3066) (ESMO 2026) - No abstract available

Clinical • Platinum resistant • Oncology • Ovarian Cancer • Solid Tumor

DENALI Part 2 Enrollment and Integrated Topline Readout (Zentalis Pharma Press Release) - "Enrollment in DENALI Parts 2a and 2b is complete....DENALI Part 2c is currently enrolling. The integrated dataset of DENALI Parts 2a, 2b, and 2c is designed to support accelerated approval in the Cyclin E1 biomarker-selected patient population, subject to regulatory review. The Company expects to provide a topline readout in 1H 2027 to allow for data maturation post full enrollment."

Enrollment status • P2 data • Fallopian Tube Cancer • Ovarian Cancer • Peritoneal Cancer

ASPENOVA: A phase 3 study of azenosertib monotherapy versus standard of care chemotherapy in cyclin E1-positive platinum-resistant ovarian cancer (PROC) (ESMO 2026) - No abstract available

Monotherapy • P3 data • Platinum resistant • Oncology • Ovarian Cancer • Solid Tumor • 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

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

Targeted Pathway Inhibition in Patients With Pancreatic Cancer (clinicaltrials.gov) - P1 | N=90 | Recruiting | Sponsor: OHSU Knight Cancer Institute | Trial primary completion date: Jun 2026 ➔ Jun 2027

Trial primary completion date • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Molecular Response Assessment From Circulating Tumor DNA in Patients With Ovarian Cancer Treated With the WEE1 Inhibitor Azenosertib. (PubMed, JCO Precis Oncol) - "Our findings support the validity and potential clinical utility of ctDNA-based MR as a minimally invasive, rapid, and reliable early surrogate end point in HGSOC."

Biomarker • Circulating tumor DNA • Journal • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • TP53

Development and Validation of a Cyclin E1 Immunohistochemistry Laboratory-Developed Test (LDT) for the Selection of Patients With High-Grade Serous Ovarian Cancer (HGSOC) to be Treated With a WEE1 Inhibitor, Azenosertib (CAP 2026) - P2 | "The LDT reagents and protocol are suitable for prospective biomarker screening and detection of Cyclin E1–positive protein expression in patients with HGSOC as a clinical trial assay. Selection and enrollment are ongoing in a phase 2 multicenter study (DENALI, NCT05128825) for azenosertib monotherapy in PROC. Harismendy owns stock in Zentalis Pharmaceuticals."

Clinical • Laboratory-developed test • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • CCNE1

Zentalis Pharmaceuticals to Present at the European Society for Medical Oncology (ESMO) Congress 2026 (GlobeNewswire) - "Rapid oral presentation to highlight overall survival data from the DENALI Part 1b study of azenosertib....'The data will showcase the long-term survival benefits demonstrated by azenosertib in patients with Cyclin E1-positive platinum-resistant ovarian cancer in this study and further support our strategic focus on advancing azenosertib in registration-intended monotherapy trials for this biomarker-selected patient population with high unmet need'."

P2 data • Platinum resistant • Ovarian Cancer

The WEE1 inhibitor azenosertib broadly enhances efficacy of antibody-drug conjugates with topoisomerase I and microtubule inhibitor payloads. (PubMed, iScience) - "Azenosertib enhanced the activity of free TOP1i agents and TOP1i-based ADCs (trastuzumab deruxtecan [T-DXd] and sacituzumab govitecan), increasing DNA damage and apoptosis, and extended the duration of response while overcoming T-DXd resistance in patient-derived xenografts. Synergistic effects were also observed with MTI agents and MTI-based ADCs (mirvetuximab soravtansine, tisotumab vedotin, and enfortumab vedotin), associated with exacerbated mitotic defects and prolonged mitotic arrest. All combinations enhanced efficacy and were well tolerated in vivo. These findings position azenosertib as a broadly applicable enhancer of cytotoxic-payload ADCs, offering a promising strategy for patients with advanced solid tumors."

Journal • Oncology • Solid Tumor • TOP1

Azenosertib plus paclitaxel for platinum-resistant ovarian cancer: Results from a phase 1b study. (ASCO 2026) - P1 | "Pts were assigned to 1 of 4 cohorts: carboplatin, gemcitabine, pegylated liposomal doxorubicin, or PAC (80 mg/m2 IV on Days 1, 8 and 15 of 28-day cycles). Azeno plus PAC showed promising clinical activity and tolerability in pts with PROC. ORR and median DOR were improved when compared historically with PAC monotherapy supporting the continued evaluation of this regimen in PROC and other indications. OR and median DOR."

P1 data • Platinum resistant • Neutropenia • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor

ZAP-IT: ZN-c3 + Carboplatin + Pembrolizumab in mTNBC (clinicaltrials.gov) - P1 | N=7 | Terminated | Sponsor: Filipa Lynce, MD | Phase classification: P1/2 ➔ P1

Phase classification • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Negative Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD4 • HER-2 • PGR

A Possibility of Synthetic Lethality: Wee1 Kinase as a Promising Treating Target for Cancer. (PubMed, Med Res Rev) - "Wee1 is the fastest progressing member in clinical research, and its inhibitors such as AZD-1775 and ZN-c3 are under clinical evaluation. We further summarize design principles for targeted degradation of Wee1 and outline combination strategies grounded in synthetic lethality, and we curate recent preclinical and ongoing clinical advances with discussion of biomarker-guided enrollment and dosing schedules. By linking structural mechanisms to pharmacology and clinical placement, this review provides an actionable framework for next-generation Wee1-directed drug design and translation in oncology."

Journal • Review • Oncology • Targeted Protein Degradation • PKMYT1 • TP53

ZAP-IT: ZN-c3 + Carboplatin + Pembrolizumab in mTNBC (clinicaltrials.gov) - P1/2 | N=7 | Terminated | Sponsor: Filipa Lynce, MD | N=78 ➔ 7 | Trial completion date: Sep 2029 ➔ Feb 2026 | Active, not recruiting ➔ Terminated | Trial primary completion date: Mar 2027 ➔ Feb 2026; Zentalis terminated contract due to concern for toxicity safety from previously reported serious adverse events.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • Hormone Receptor Negative Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD4 • HER-2 • PGR

The selective WEE1 inhibitor azenosertib shows synergistic anti-tumor activity with encorafenib + cetuximab in multiple BRAFV600E models (AACR 2025) - "Similarly, treatment of multiple BRAFV600E patient-derived xenograft (PDX, N=3) models of CRC resulted in synergistic triplet TGI (80%, 102%, 103%) and some tumor regression compared against monotherapy azenosertib (43%, 19%, 51%) or the E + C doublet (49%, 65%, 87%). Taken together, our results suggest that the in vitro and in vivo combination of azenosertib with E + C enhances tumor growth inhibition over single agent azenosertib or doublet E + C therapy, and may be an effective treatment option for patients with BRAFV600E mCRC."

Colorectal Cancer • Oncology • Solid Tumor

DENALI Parts 2b and 2c are currently enrolling (GlobeNewswire) - "DENALI Part 2 is designed to support a potential accelerated approval pathway in the Cyclin E1 biomarker-selected patient population, subject to regulatory review. The Company expects to complete enrollment in all cohorts of DENALI Part 2 and provide a topline readout by year-end 2026."

Enrollment status • P2 data • Platinum resistant • Fallopian Tube Cancer • High Grade Serous Ovarian Cancer • Peritoneal Cancer

ASPENOVA: A Study of Azenosertib (ZN-c3) Versus Investigator's Choice Chemotherapy in Subjects With Platinum-Resistant High-Grade Serous Ovarian, Primary Peritoneal, or Fallopian Tube Cancers Positive for Cyclin E1 Protein Expression (clinicaltrials.gov) - P3 | N=420 | Recruiting | Sponsor: K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc | Not yet recruiting ➔ Recruiting

Enrollment open • Platinum resistant • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Solid Tumor • BRCA • BRCA1 • BRCA2 • CCNE1

ASCO 2026 Abstract Acceptance (GlobeNewswire) - "Announced that the American Society of Clinical Oncology (ASCO) has accepted an abstract for presentation at the 2026 ASCO Annual Meeting featuring results from Part 1 of the Phase 1b MUIR trial, focusing on an evaluation of azenosertib in combination with paclitaxel in platinum-resistant ovarian cancer (PROC). The data will showcase combinability and activity in an all-comer setting, demonstrating the broad potential for azenosertib in multiple lines of ovarian cancer and other tumor types."

P1 data • Platinum resistant • Ovarian Cancer

MUIR Part 2 dose expansion evaluating azenosertib in combination with bevacizumab as maintenance therapy in ovarian cancer (GlobeNewswire) - "The dose expansion cohort of Part 2 is currently open for enrollment of azenosertib in combination with bevacizumab in second-line platinum-sensitive ovarian cancer (PSOC) patients for maintenance treatment, whose disease progressed while on a PARP inhibitor."

Platinum sensitive • Trial status • Ovarian Cancer

ZN-c3 + Gemcitabine in Pancreatic Cancer (clinicaltrials.gov) - P2 | N=12 | Active, not recruiting | Sponsor: Brandon Huffman, MD | Trial primary completion date: Jun 2026 ➔ Aug 2025

Trial primary completion date • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

Zentalis Pharmaceuticals Announces First Patient Dosed in ASPENOVA Phase 3 Trial of Azenosertib in Patients with Cyclin E1-Positive Platinum-Resistant Ovarian Cancer (GlobeNewswire) - "The company is pursuing accelerated approval based on the ongoing registration-intended DENALI Phase 2 trial, with a topline readout expected by year-end 2026, while simultaneously advancing ASPENOVA as the confirmatory study to satisfy FDA requirements for conversion to full approval....Zentalis expects to complete enrollment in all cohorts of DENALI Part 2 (2a, 2b, 2c) and provide a topline readout by year-end 2026."

P2 data • Platinum resistant • Trial status • Ovarian Cancer