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

The WEE1 Inhibitor Azenosertib Shows Synergistic Anti-Tumor Effects with Microtubule Inhibitor-Based Antibody Drug Conjugates (ADCs) In Preclinical Models (SGO 2025) - No abstract available

Preclinical • Oncology

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

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) | Initiation date: Jul 2025 ➔ Feb 2025

Trial initiation date • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor

Azenosertib in Uterine Serous Carcinoma: Biomarker Study (clinicaltrials.gov) - P2 | N=25 | Recruiting | Sponsor: Joyce Liu, MD | Not yet recruiting ➔ Recruiting

Biomarker • Enrollment open • Endometrial Serous Adenocarcinoma • Oncology • Solid Tumor • Uterine Cancer

Zentalis Pharmaceuticals Announces Multiple Data Presentations at Society of Gynecologic Oncology 2025 Annual Meeting on Women’s Cancer (GlobeNewswire) - "Preclinical data of azenosertib demonstrating antitumor effects with microtubule inhibitor based ADCs...Zentalis Pharmaceuticals....announced multiple presentations, including an oral presentation with updated clinical data from the ongoing Phase 2 DENALI clinical trial of azenosertib in patients with platinum-resistant ovarian cancer (PROC), at the Society of Gynecologic Oncology (SGO) 2025 Annual Meeting on Women’s Cancer, to be held on March 14-17 in Seattle, Washington."

P2 data • Preclinical • Ovarian Cancer

Combined inhibition of ribonucleotide reductase and WEE1 induces synergistic anticancer activity in Ewing's sarcoma cells. (PubMed, BMC Cancer) - "Our findings show that combined inhibition of RNR and WEE1 was effective against Ewing's sarcoma in vitro. They thus provide a rationale for the evaluation of the potential of combined targeting of RNR and WEE1 in Ewing's sarcoma in vivo."

Journal • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • CASP3 • CASP7 • CHEK1

Updated azenosertib monotherapy clinical data from its ZN-c3-001 study (GlobeNewswire) - P1 | N=146 | NCT04158336 | Sponsor: Zentalis Pharmaceuticals, Inc | "As of the December 2, 2024 data cutoff, results from ZN-c3-001 showed encouraging ORR and median duration of response (mDOR) at a total daily dose level ≥ 300mg in patients with Cyclin E1+ PROC who were dosed at an intermittent schedule (n=23). In these patients, an ORR of 34.8% (8/23; 95% CI: 16.4-57.3) and an mDOR of 5.2 months (95% CI: 2.8, 6.9) were observed. Full efficacy results at a total daily dose level ≥ 300mg across biomarker status and tumor types will be shared in the presentation....In the ZN-c3-001 study, as of the December 2, 2024 data cutoff, azenosertib was shown to be tolerable at a total daily dose level ≥ 300mg (n=193) across all tumor types and regardless of biomarker status, with no Grade 3+ gastrointestinal treatment-related adverse events (TRAEs) observed and low rates of Grade 3+ hematological toxicity, with the majority of hematological toxicity events being Grade 3."

P1 data • Solid Tumor

Updated azenosertib clinical data from DENALI study (GlobeNewswire) - P2 | N=102 | DENALI (NCT05128825) | Sponsor: Zentalis Pharmaceuticals, Inc | "Results from DENALI Part 1b show an Objective Response Rate (ORR) of ~35% in response-evaluable, heavily-pretreated patients with Cyclin E1+ platinum-resistant ovarian cancer (PROC); Across monotherapy cohorts in key clinical studies, well-characterized safety and tolerability profile shows no new safety signals; Company aligned with FDA on seamless study design for DENALI Part 2 in patients with Cyclin E1+ PROC; study expected to begin 1H 2025; Topline data from registration-intent DENALI Part 2 anticipated by year end 2026."

P2 data • Trial status • Ovarian Cancer

Zentalis Pharmaceuticals Announces Strategic Restructuring to Support Late-Stage Azenosertib Development (GlobeNewswire) - "Zentalis Pharmaceuticals...announced a restructuring of its business operations and research and development organization to support execution of late-stage development for its WEE1 inhibitor product candidate, azenosertib, and extend its cash runway beyond a data readout from its potentially registration-enabling DENALI Part 2 study, anticipated by the end of 2026."

Commercial • P2 data • Fallopian Tube Cancer • Ovarian Cancer • Peritoneal Cancer

ZN-c3-016: ZN-c3 in Adult Participants With Metastatic Colorectal Cancer (clinicaltrials.gov) - P1 | N=44 | Active, not recruiting | Sponsor: K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc | Phase classification: P1/2 ➔ P1 | N=82 ➔ 44 | Trial primary completion date: Aug 2026 ➔ Jul 2024

Enrollment change • Phase classification • Trial primary completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor • BRAF

Results from ZN-c3-016 study in colorectal cancer (GlobeNewswire) - "The dose-finding phase of the ZN-c3-016 study is fully enrolled (n= 44). 34 patients were BRAF-inhibitor naïve and 10 had previously been treated with a BRAF-inhibitor. Topline results as of the November 25, 2024 data cutoff can be found in the appendix of the presentation. While the results in BRAF inhibitor naïve patients were encouraging, the Company decided not to advance into the dose expansion phase of the study due to resource prioritization and an evolving treatment landscape."

P1/2 data • Trial status • Colorectal Cancer • Gastrointestinal Cancer

Updated azenosertib clinical data from MAMMOTH study (GlobeNewswire) - P1/2 | N=117 | MAMMOTH (NCT05198804) | Sponsor: Zentalis Pharmaceuticals, Inc | "As of the December 2, 2024 data cutoff, in the monotherapy arm of the MAMMOTH study at both 300mg QD 5:2 and 400mg QD 5:2 regardless of biomarker status, similar rates of treatment-related serious adverse events (SAEs) were observed across dose levels. There was a low rate of treatment-related Grade 3+ hematological toxicity with the majority being Grade 3 events. There was a low rate of TRAEs leading to treatment discontinuation 5.6% in the 400mg arm (n=2)....In the combination arms of the study, where azenosertib was dosed on a concurrent or alternating schedule with niraparib, although no new safety signals were observed, efficacious exposures of azenosertib were not reached, and the Company is not proceeding further with development of the combination with niraparib."

P1/2 data • Trial status • Ovarian Cancer

The Selective WEE1 Inhibitor Azenosertib Shows Synergistic Antitumor Activity with KRASG12C Inhibitors in Preclinical Models. (PubMed, Cancer Res Commun) - "Finally, analysis of biomarkers from in vitro and in vivo tumor samples displayed increases in protein markers of RS, DNA damage, and apoptosis after combination treatment. Taken together, our results suggest that the combination of azenosertib with KRASG12C inhibitors enhances tumor growth inhibition over single agent therapy and may be an effective treatment strategy for patients with KRASG12C tumors."

Journal • Preclinical • CNS Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Psychiatry • Solid Tumor • KRAS

The Selective WEE1 Inhibitor Azenosertib Shows Synergistic Antitumor Activity with KRASG12C Inhibitors in Preclinical Models (Cancer Res Commun) - "In vitro combination of azenosertib with multiple KRASG12C inhibitors demonstrated synergistic cell growth inhibition across a panel of KRASG12C cell lines in both 2D and 3D assays. In vivo studies demonstrated azenosertib exhibited significant monotherapy activity as well as synergistic tumor growth inhibition (TGI) when combined with KRASG12C inhibitors, including tumor regression in CDX models of NSCLC, CRC, and PDAC."

Preclinical • Colorectal Cancer • Non Small Cell Lung Cancer • Pancreatic Ductal Adenocarcinoma

Zentalis Pharmaceuticals Announces Azenosertib Fast Track Designation... (GlobeNewswire) - "Zentalis Pharmaceuticals, Inc...today announced that the FDA has granted Fast Track Designation to azenosertib for the treatment of patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer (PROC) who are positive via Cyclin E1 immunohistochemistry for protein levels...In addition, this week npj Precision Oncology published a paper from Zentalis researchers highlighting the role of Cyclin E1/CDK2 activation in predicting sensitivity to azenosertib. 'The data in this manuscript provide functional and mechanistic demonstration that preclinical models with high levels of Cyclin E1 activation are particularly sensitive to azenosertib inhibition, along with supporting clinical data from select patients enrolled in azenosertib clinical studies,'..."

Fast track • Preclinical • Fallopian Tube Cancer • Ovarian Cancer • Peritoneal Cancer

Zentalis Pharmaceuticals Announces…Virtual Corporate Event to Present Updated Data from Azenosertib Clinical Studies (GlobeNewswire) - "On January 29, 2025, at 8:00am ET Zentalis will host a webcast to present data from its studies of azenosertib in PROC...including the following: i) Topline results from 102 patients enrolled in Part 1b of the Phase 2 DENALI study (ZN-c3-005) of azenosertib monotherapy in platinum resistant high-grade serous ovarian cancer; ii) Final results from patients treated at therapeutic doses in the Phase 1b ZN-c3-001 azenosertib monotherapy trial in solid tumors, including 69 PROC patients; iii) Topline data from 61 patients in the monotherapy arm of the Phase 1/2 MAMMOTH (ZN-c3-006) trial of azenosertib as a monotherapy and in combination with PARP inhibitor (niraparib) in PARP-resistant PROC in partnership with GSK; iv) Presentation of design of registration-intent study and a regulatory update; v) Initial data from the Phase 1 ZN-c3-016 azenosertib + BEACON regimen (encorafenib + cetuximab) trial in BRAF mutant metastatic colorectal cancer in partnership with Pfizer."

Clinical • P1 data • P1/2 data • P2 data • Colorectal Cancer • Ovarian Cancer • Peritoneal Cancer • Solid Tumor

Cyclin E1/CDK2 activation defines a key vulnerability to WEE1 kinase inhibition in gynecological cancers (NPJ Precis Oncol, Nature) - "Models with high Cyclin E1 expression showed higher baseline levels of replication stress and enhanced cellular responses to azenosertib treatment. We found azenosertib synergized with different classes of chemotherapy and described distinct underlying mechanisms."

Preclinical • Ovarian Cancer • Uterine Cancer

Cyclin E1/CDK2 activation defines a key vulnerability to WEE1 kinase inhibition in gynecological cancers (NPJ Precis Oncol, Nature) - "Models with high Cyclin E1 expression showed higher baseline levels of replication stress and enhanced cellular responses to azenosertib treatment. We found azenosertib synergized with different classes of chemotherapy and described distinct underlying mechanisms."

Preclinical • Ovarian Cancer • Uterine Cancer

ZAP-IT: ZN-c3 + Carboplatin + Pembrolizumab in MTNBC (clinicaltrials.gov) - P1/2 | N=78 | Recruiting | Sponsor: Filipa Lynce, MD | Suspended ➔ Recruiting

Enrollment open • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

ZN-c3-016: ZN-c3 in Adult Participants with Metastatic Colorectal Cancer (clinicaltrials.gov) - P1/2 | N=82 | Active, not recruiting | Sponsor: K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Metastases • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor • BRAF

Targeting DNA damage response modulates antiphagocytic signals to convert radiotherapy into a systemic immunotherapy to treat metastatic colorectal cancer (SITC 2024) - "Azenosertib (WEE1i), Ceralasertib (ATRi) and Olaparib (PARPi) were used, and cells were stained after 24hr with antibodies against CD47, MHC-I, and PD-L1. Conclusions Our results show treatment of colorectal cancer cell lines MC38, HCT116, and HT29 with RT alone induces the expression of antiphagocytic signals, however, in cells concurrently treated with DDR inhibitors the induction of these signals was attenuated. This decrease in antiphagocytic and increase in prophagocytic signals in combination groups was associated with increased phagocytosis of tumor cells by macrophages."

IO biomarker • Metastases • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CALR • CDC37 • HSP90AA1 • PD-1

Azenosertib is a Selective WEE1 Kinase Inhibitor with Broad-spectrum Antitumor Activity in Preclinical Models and Encouraging Clinical Activity in Patients with Solid Tumors (CRD 2024) - No abstract available

Preclinical • Oncology • Solid Tumor

PHASE 1 RESULTS OF THE WEE1 INHIBITOR, AZENOSERTIB, IN COMBINATION WITH GEMCITABINE IN ADULT AND PEDIATRIC PATIENTS WITH RELAPSED OR REFRACTORY OSTEOSARCOMA (CTOS 2024) - No abstract available

Clinical • Combination therapy • P1 data • Oncology • Osteosarcoma • Sarcoma • Solid Tumor

ZN-c3-004: A Study of ZN-c3 in Women With Recurrent or Persistent Uterine Serous Carcinoma (clinicaltrials.gov) - P2 | N=76 | Recruiting | Sponsor: K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc | Active, not recruiting ➔ Recruiting

Enrollment open • Endometrial Serous Adenocarcinoma • Oncology • Uterine Cancer

Zentalis Pharmaceuticals Announces Executive Leadership Changes Supporting Planned Registrational Clinical Studies of Azenosertib (GlobeNewswire) - "Zentalis Pharmaceuticals, Inc...announced changes to its executive leadership team to support the Company as it plans and executes registrational studies for its lead product candidate, azenosertib."

Clinical • Gynecologic Cancers • Oncology • Solid Tumor