Azenosertib

◆ 关键信息 ◆ •  Zentalis在ESMO公布WEE1抑制剂azenosertib Denali I期铂耐药卵巢癌（PROC）队列首次总生存分析：Cyclin E1阳性患者中位OS 15.9个月（阴性组7.5个月）、ORR 37.2%、中位缓解时长5.5个月，而标准单药化疗ORR仅4%至12% •  安全性：56.9%患者剂量中断、43.1%减量、19.6%停药，3级及以上以疲劳（16%）、血小板减少（12%）、贫血与中性粒细胞减少（各11%）为主；2024年曾因两例中性粒细胞缺乏性脓毒症死亡被FDA叫停，后恢复 •  口服给药是差异化卖点：Denali II期聚焦Cyclin E1阳性PROC、明年上半年读出拟支持FDA加速批准；III期Aspenova（420例）已入组；公司去年裁员40%保管线，现已启动上市前筹备并物色商业化伙伴 Zentalis Pharmaceuticals用一份总生存数据，为口服WEE1抑制剂azenosertib的上市前景添了重要砝码。在欧洲肿瘤内科学会（ESMO）年会上，公司公布了Denali研究I期部分铂耐药卵巢癌（PROC）队列的首次总生存分析：这些患者此前接受过1至5线治疗（中位3线，包括安维汀）。按生物标志物分层后，Cyclin E1阳性患者的中位总生存达15.9个月，阴性组为7.5个月——William Blair此前就指出，总生存超过15个月对该人群『极其令人鼓舞』。会上还披露，Cyclin E1阳性患者的客观缓解率为37.2%，中位缓解时长5.5个月。公司首席执行官Julie Eastland称，这是azenosertib在PROC单药治疗所有试验中看到的最高缓解率之一，缓解时长也正落在期望的5至6个月区间。 横向对比更能说明问题。首席医学官Ingmar Bruns指出，这类患者目前全球标准治疗仍是单药化疗，缓解率仅在4%至12%之间——azenosertib『是它的三倍以上』。公司认为这款药『非常有竞争力』：能提供与近期获批方案相近的获益，却『本质上只是一粒药』，对患者和医生而言都是全新的给药模式。机制上，WEE1是G1-S与G2-M细胞周期检查点的主调节器，负责拦截DNA受损的细胞；癌细胞因快速分裂累积大量DNA损伤，抑制WEE1等于撤掉哨卡，让它们带伤复制直至死亡。Eastland用了一个形象的比喻：『WEE1就像学校路口的交警——细胞停下来看看能不能进入下一个街区，不能就不放行。』 安全性数据同样经过了考验。治疗相关不良事件导致56.9%的患者剂量中断、43.1%减量、19.6%停药，21.6%发生严重TRAE；3级及以上以疲劳（16%）、血小板减少（12%）、贫血与中性粒细胞减少（各11%）最为常见。2024年，两例中性粒细胞缺乏性脓毒症死亡曾令FDA对临床试验按下暂停键（后解除），Bruns对此回应称，与单药化疗及新兴疗法相比，azenosertib的血液学毒性与中性粒细胞减少发生率『相当低』。商业化进程已在路上：Denali的II期部分聚焦Cyclin E1阳性PROC患者，明年上半年读出数据、目标是支持FDA加速批准；代号Aspenova的III期研究（拟入组420例）已经开始招募。去年公司曾裁员40%以集中现金保住这条管线，如今Eastland表示已着手上市前筹备、物色合适的合作伙伴——『Denali读出后我们就会行动，一旦有机会，近期就能在美国上市。』 ▎今日速览 •  勃林格殷格翰DLL3xCD3双抗obrixtamig联合化疗数据出炉：ESMO公布Ib期DAREON-9更新——60例二线小细胞肺癌患者接受obrixtamig联合拓扑替康，按相对剂量强度（RDI）分组后，低于80%组确认ORR为72%、不低于80%组为61%，两组中位PFS同为5.6个月，仅中位缓解时长（7.3对5.6个月）偏向高剂量组，缓解了无法足量接受拓扑替康的患者预后会更差的担忧。对照安进Imdelltra单药II期（ORR 40%、PFS 4.9个月）与III期化疗对照臂（PFS 3.2个月），obrixtamig组合具备竞争力，且III期定位不同：今年4月起一线SCLC患者入组（联合Tecentriq标准治疗），7月再启晚期肺外神经内分泌癌（NEC）III期。NEC方面，Ib期DAREON-7显示一线铂类联合化疗的中位PFS为7.7个月，DLL3高表达亚组达9.5个月、ORR 87.5%（低表达组65.0%）；而安进在NEC领域的开发仅限研究者发起的研究。 •  Pathos AI完成2.37亿美元E轮融资，由百时美施贵宝领投，同日宣布与BMS及Tempus AI达成神经系统方向的研发合作：Pathos出资5500万美元与Tempus签订五年合同，基于数十万神经系统疾病患者构建综合数据集，并用其Foundry平台（由多个AI智能体协同工作、实时呈现药物研发全流程信息）指导神经科学领域的适应性临床试验；BMS将参与探索阿尔茨海默病等神经疾病的新候选药。本轮延续了2025年5月3.65亿美元D轮与2024年10月6200万美元C轮的势头。公司管线包括自康宁杰瑞引进、已进入III期的TROP2/HER3双特异ADC（JSKN-106）、与阿斯利康合作的PROTAC（AZD4241）、自诺华授权的CBP/p300抑制剂（前列腺癌与多发性骨髓瘤），以及通过控股比利时DeuterOncology获得的MET抑制剂DO-2，E轮部分资金还将用于扩展Foundry平台。 •  Chutes & Ladders：深陷逆风的澳大利亚药企CSL请来GSK老将执掌——ViiV Healthcare掌门人Deborah Waterhouse将出任CSL新CEO，2027年2月1日上任；GSK欧洲总裁Lynn Baxter将于11月接替她在GSK的职务。CSL的2026年可谓流年不利：盈利下调、CEO更迭、50亿美元的资产负债表减记、股价下挫，多款重磅产品还面临日益加剧的竞争与降价压力。Waterhouse在GSK工作30年，2017年起执掌ViiV、2022年起兼任GSK Global Health总裁，此前曾任GSK澳大利亚与新西兰总裁。CSL董事长Brian McNamee表示，Waterhouse曾多次完成『延续商业表现、更新管线、简化运营』的多重任务。本期同栏目还有：Ironwood总裁Tom McCourt退休、首席商务官Tammi Gaskins明年接任CEO；CytoDyn任命Robert Hoffman为新CEO，推进CCR5抗体leronlimab在结直肠癌与三阴性乳腺癌的开发。 — ◆ — 来源：Fierce Biotech ｜ 原文链接：https://www.fiercebiotech.com/biotech/esmo-zentalis-already-dreaming-launching-wee1-drug-after-great-result ｜ 综合公司公告及公开资料

Median overall survival of 15.9 months in Cyclin E1-positive PROC, with 1–5 prior lines of therapy; safety profile in DENALI Part 1b was consistent with prior reportingMedian relative dose intensity was 84.6%, confirming high overall exposure to azenosertibDENALI Part 1b interim analysis adds to the body of evidence supporting Cyclin E1 protein expression as a predictive biomarker for azenosertib in platinum-resistant ovarian cancer SAN DIEGO, Oct. 23, 2026 (GLOBE NEWSWIRE) -- Zentalis® Pharmaceuticals, Inc. (Nasdaq: ZNTL), a clinical oncology innovator advancing late-stage development of investigational first-in-class WEE1 inhibitor azenosertib as a biomarker-driven treatment approach for ovarian cancer, today presented results from an interim analysis of the DENALI Part 1b study (GOG-3066) as of a May 22, 2026 data cutoff, including the first overall survival analysis for azenosertib, at the European Society for Medical Oncology (ESMO) Congress 2026 in Madrid, Spain. "These data continue to build the body of evidence supporting azenosertib as a potential treatment in Cyclin E1-positive platinum-resistant ovarian cancer, underpinning our development approach through the ongoing registration-intended DENALI Part 2 and ASPENOVA Phase 3 confirmatory trials. For patients with Cyclin E1-positive PROC who have limited effective treatment options, we are working to deliver something that has not existed — a targeted, oral treatment that offers more convenience and choice," said Julie Eastland, Chief Executive Officer of Zentalis Pharmaceuticals. "The overall survival results from DENALI Part 1b are particularly meaningful given the poor prognosis associated with Cyclin E1-positive tumors and the heavily pretreated nature of this trial patient population," said Fiona Simpkins, M.D., Professor at the University of Pennsylvania Perelman School of Medicine and Lead Investigator for the DENALI study and The GOG Foundation, Inc. (GOG-F). "The separation in median overall survival between Cyclin E1-positive and Cyclin E1-negative patients — 15.9 months versus 7.5 months — strongly supports Cyclin E1 protein expression as a clinically relevant and predictive patient selection biomarker for azenosertib. Taken together with the response data and manageable adverse events, these findings provide important evidence supporting continued development of azenosertib in this biomarker-selected population with high unmet need." Updated DENALI Part 1b Efficacy ResultsAs of the May 22, 2026 data cutoff, DENALI Part 1b enrolled 102 patients with PROC regardless of Cyclin E1 protein expression who had received between one and five prior lines of therapy, with prior bevacizumab required. This was a heavily pretreated population: 97% had received a taxane, 91% bevacizumab, 55% a PARP inhibitor, and 15% mirvetuximab soravtansine, with a median of three prior lines of therapy. Cyclin E1 status was retrospectively determined by immunohistochemistry using a proprietary cutoff, with 94 patients evaluable (Cyclin E1 IHC-positive: n=48, 51%; Cyclin E1 IHC-negative: n=46). Overall Survival (OS): Cyclin E1 IHC-positive (n=48): median OS of 15.9 months (95% CI, 8.7–21.2); 31 events had occurred (65%)Cyclin E1 IHC-negative (n=46): median OS of 7.5 months (95% CI, 5.8–12.3); 34 events had occurred (74%) Objective Response Rate (ORR) and Duration of Response (DOR): ORR in response-evaluable Cyclin E1 IHC-positive patients (n=43): 37.2% (95% CI, 23.0–53.3)ORR in all Cyclin E1 IHC-positive patients (n=48): 33.3% (95% CI, 20.4–48.4)Median DOR: 5.5 months (95% CI, 4.5–15.9) The updated ORR includes a patient with a confirmed response after the prior cutoff. The current median DOR of 5.5 months reflects a more mature dataset with less censoring than the prior cutoff, including two patients with particularly durable responses exceeding 15 and 20 months. SafetyThe safety profile was consistent with prior reporting. The most common treatment-related adverse events (TRAEs) were nausea, fatigue, diarrhea, thrombocytopenia, decreased appetite, anemia, and neutropenia. The most common non-hematologic Grade ≥3 TRAE was fatigue (16%). Grade ≥3 hematologic TRAEs included thrombocytopenia (12%), anemia (11%), and neutropenia (11%). The median relative dose intensity was 84.6%, confirming that overall exposure to azenosertib remained high despite dose modifications. TRAEs led to dose interruption in 56.9% of patients, dose reduction in 43.1%, and discontinuation in 19.6%. Serious TRAEs occurred in 21.6% of patients. The ESMO slides inclusive of the full interim analysis dataset presented at the medical meeting are available on the Zentalis website under scientific publications at the following link: https://zentalis.com/science/scientific-publications/ About the DENALI Clinical TrialDENALI is a multi-part Phase 2 registration-intended clinical trial (NCT05128825, GOG-3066) studying azenosertib in patients with PROC, conducted in collaboration with The GOG Foundation, Inc. (GOG-F). Part 1b enrolled 102 patients with PROC regardless of Cyclin E1 protein expression, all treated at 400 mg QD 5:2 (five days of once-daily administration of azenosertib, followed by two days without azenosertib). The primary endpoint was objective response rate per RECIST v1.1; secondary endpoints included duration of response, progression-free survival, overall survival, and safety. Part 2 is prospectively enrolling PROC patients with Cyclin E1 protein overexpression based on Zentalis' proprietary immunohistochemistry cutoff. Part 2, in total, is designed to support accelerated approval, pending positive study outcomes and further discussions with the FDA. The study design consists of the following parts: Part 2a: Dose confirmation evaluated two doses, 300 mg QD 5:2 and 400 mg QD 5:2, with approximately 30 patients enrolled per dose group. 400 mg QD 5:2 was selected as the optimal monotherapy dose. Recruitment at the 300 mg QD 5:2 dose level has been discontinued. All patients enrolled in Part 2a will contribute to the overall safety database submitted to the FDA.Part 2b: Enrollment expansion at the selected 400 mg QD 5:2 dose up to approximately 100 patients, including patients at this dose in Part 2a. Enrollment in this cohort is complete.Part 2c: Expansion of the study population, expected to enroll approximately 40 patients previously treated with a taxane-containing regimen for PROC. This cohort is currently enrolling. For physician and patient information about the DENALI trial, please visit www.denalitrial.com. About ASPENOVA Clinical TrialASPENOVA is a Phase 3 randomized, confirmatory clinical trial designed to support full approval of azenosertib in patients with Cyclin E1-positive PROC. The trial is expected to enroll approximately 420 patients and compare azenosertib monotherapy at 400mg QD 5:2 to investigator's choice of standard-of-care single-agent chemotherapy (paclitaxel, pegylated liposomal doxorubicin [PLD], gemcitabine, or topotecan) in this biomarker-selected population. The primary endpoint is progression-free survival (PFS); key secondary endpoints include overall survival (OS) and overall response rate (ORR). The trial design was based on feedback from the U.S. FDA regarding requirements for seeking approval under the accelerated approval pathway and requirements to support potential conversion to full approval. About AzenosertibAzenosertib is an investigational, potentially first-in-class, selective, and orally bioavailable inhibitor of WEE1 currently being evaluated in clinical studies in ovarian cancer and additional tumor types. WEE1 acts as a master regulator of the G1-S and G2-M cell cycle checkpoints, through negative regulation of both CDK1 and CDK2, to prevent replication of cells with damaged DNA. By inhibiting WEE1, azenosertib enables cell cycle progression, despite high levels of DNA damage, thereby resulting in the accumulation of DNA damage and leading to mitotic catastrophe and cancer cell death. Azenosertib is in late-stage development as a potential treatment for Cyclin E1-positive platinum-resistant ovarian cancer (PROC). There is currently no approved treatment option specifically for this biomarker-selected population which comprises approximately 50% of PROC patients. Cyclin E1 protein overexpression has been established as a sensitive and specific predictive biomarker for identifying patients who could potentially derive benefit from azenosertib treatment. About Zentalis PharmaceuticalsZentalis is a clinical oncology innovator developing a treatment approach for ovarian cancer and multiple tumor types. Leveraging therapeutics development and biomarker expertise, Zentalis is advancing monotherapy and combination studies of its investigational first-in-class WEE1 inhibitor, azenosertib. Focused on translating WEE1 science into clinical practice, we aim to equip physicians with a targeted, non-chemo, orally available medicine that enhances treatment experience, choice, and outcomes. Our mission: to unburden cancer patients with more convenience and care.​ For more information, please visit www.zentalis.com. Follow Zentalis on LinkedIn at www.linkedin.com/company/zentalis-pharmaceuticals Forward-Looking Statements This press release contains forward-looking statements within the meaning of the U.S. Private Securities Litigation Reform Act of 1995, as amended. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including, but not limited to, statements regarding the continued development of azenosertib; the clinical and therapeutic potential of azenosertib; the potential for azenosertib to be first-in-class; the broad franchise potential of azenosertib; the Company’s biomarker-driven strategy for azenosertib, including the ability of Cyclin E1 to be a highly selective and predictive biomarker for response to azenosertib; and our participation in conference presentations. The terms “anticipate,” “advance,” “believe,” “design,” “develop,” “expect,” “intent,” “look forward,” “on track,” “plan,” “position,” “potential,” “runway,” “strategy,” “support,” “target,” “upcoming,” and “will” and similar references are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: our limited operating history, which may make it difficult to evaluate our current business and predict our future success and viability; we have and expect to continue to incur significant losses; our need for additional funding, which may not be available; our substantial dependence on the success of azenosertib; our plans, including the costs thereof, of development of companion diagnostics; the outcome of preclinical testing and early trials may not be predictive of the success of later clinical trials; potential unforeseen events during clinical trials could cause delays or other adverse consequences; risks relating to the regulatory approval process or ongoing regulatory obligations; our product candidates may cause serious adverse side effects; inability to maintain our collaborations, or the failure of these collaborations; our reliance on third parties; effects of significant competition; the possibility of system failures or security breaches; risks relating to intellectual property; our ability to attract, retain and motivate qualified personnel, and risks relating to management transitions; significant costs as a result of operating as a public company; and the other important factors discussed under the caption “Risk Factors” in our most recently filed periodic report on Form 10-K or 10-Q and subsequent filings with the U.S. Securities and Exchange Commission (SEC) and our other filings with the SEC. Any such forward-looking statements represent management’s estimates as of the date of this press release. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change.ZENTALIS® and its associated logo are trademarks of Zentalis and/or its affiliates. All website addresses and other links in this press release are for information only and are not intended to be an active link or to incorporate any website or other information into this press release. Contact: Aron FeingoldVP, Investor Relations & Corporate Communicationsir@zentalis.com