Olaparib

癌度医学临床招募资讯微信群（点击）对于存在EGFR基因突变的非小细胞肺癌，靶向药治疗是一线治疗的主要策略。在靶向药选择上可选第一代靶向药吉非替尼或厄洛替尼，也可以直接使用第三代靶向药奥希替尼。由于不管使用哪一种靶向药都不可避免耐药的问题，所以预防或克服靶向药的获得性耐药就成了提高患者生存期的重要问题。一线治疗中，铂类化疗联合EGFR靶向药可以延长肺腺癌患者的生存期。一项来自日本的多中心三期临床试验表明，第一代靶向药吉非替尼联合铂类双药化疗的无进展生存期显著优于吉非替尼单药，但是总生存期没有显著差异。来自印度的一项三期临床试验则表明，相同的治疗方案在无进展生存期和总生存期都具有优势，所以靶向药联合化疗是否总生存期更好还不能完全确定。1、靶向药和化疗的联合治疗缘起为什么要将靶向药和化疗联合使用，这里其实有相应的机制。有研究表明，将EGFR靶向药和化疗联合使用时，靶向药能减弱化疗药物的副作用。但是截止目前靶向药和化疗的同步使用总生存期数据是没有显著差异的。最近有一项发布在学术期刊的文章做了一项三期临床试验，研究者假设在EGFR靶向药初步治疗期间插入铂类双药化疗可预防靶向药的耐药，从而延长患者的生存期。而且肿瘤细胞对靶向药产生了应答，将化疗药物用上去之后可能更加有效，原因是EGFR靶向药减轻了肿瘤的负荷，所以化疗药物的效果也更好。这个治疗方案的二期临床试验使用吉非替尼联合顺铂加多西他赛一线治疗晚期肺癌，中位无进展生存时间达到了19.5个月，中位总生存时间达到了48个月，这是相当不错的数据，下面这部分内容是这个治疗方案的三期临床试验。本文参考文献刊例示意图2、与化疗搭配的靶向药延长了无进展生存期这是一项开放标签，多中心的随机三期临床试验，招募的是EGFR基因19外显子缺失突变和L858R突变的晚期肺腺癌患者，这些患者确诊后未使用任何系统治疗。患者等比例分组，一组患者一线使用靶向药治疗，另外一组患者则是使用靶向药联合化疗治疗。2015年12月至2020年10月期间，共计入组了501名患者。308名患者使用了一代靶向药吉非替尼，193名患者使用的是三代靶向药奥希替尼。联合用药的方式是：第1天至第56天给予靶向药治疗，然后停药2周时间，在第71天、第92天、第113天给予3个疗程的顺铂和培美曲塞。在第134天重新开始使用EGFR靶向药，一直到病情进展。靶向药和化疗联合延长了无进展生存期如上面的图示，如果是EGFR靶向药单药治疗的中位无进展生存期是12个月，而将EGFR靶向药和化疗搭配使用则中位无进展生存期达到了18个月。其中吉非替尼单药治疗的中位无进展生存期是9.5个月，而吉非替尼和化疗联合治疗的中位无进展生存期是14.4个月。而三代靶向药奥希替尼的区别就不明显，尽管靶向药单药和靶向药与化疗联合治疗的中位无进展生存期分别是20.4个月和25.2个月，但是两个曲线是没有显著拉开。3、总生存时间没有显著差异如果说到总生存期数据，那么可能就有点让人失望。因为没有显示出明显的区别。我们看下面的图示，不管是吉非替尼还是奥希替尼，总生存期曲线都没有明显地拉开。靶向药和化疗联合的总生存期数据癌度精选文章曾经有一个内容是源自这个治疗措施的二期临床试验，从逻辑上讲这个先靶向药后化疗，然后继续靶向药确实是延长了中位无进展生存期。尤其是将第一代靶向药吉非替尼用成了三代靶向药的效果。但是总生存期可能是没有显著拉开。当然患者总生存期的影响因素比较多，比如上面的研究患者病情进展之后用了什么治疗策略是多种多样的。上面的这个研究将具体用药措施写的很清楚，这个是可能很多患者对联合治疗误解地方，不是将靶向药和铂类化疗一直用个没完没了，那样患者所出现的不良反应会比较多，体质越来越差，对于后面的治疗是有影响的。究竟是不是选择靶向药和化疗搭配使用大家可以与主治医生沟通做决定，关于靶向药和化疗的联合使用、基因检测报告解读等问题欢迎大家加入癌度病友群交流。参考文献：Shintaro Kanda, et al, Randomized Phase III Study of EGFR Tyrosine Kinase Inhibitor and Intercalated Platinum-Doublet Chemotherapy for Non–Small Cell Lung Cancer Harboring EGFR Mutation, Clin Cancer Res; 2025. 往期推荐 胃癌进展后无药可用？新型CAR-T疗法IMC 001让90%的患者病情得以控制，有患者争取到手术机会!突破！80%实体瘤存在同一靶点PRL3，国际二期试验公布抗癌新药数据解决奥希替尼多种耐药位点，第四代EGFR靶向药H002于美国和中国同时启动临床试验，专治C797S类耐药位点！广谱抗癌药组合，奥拉帕利联合帕博利珠单抗有望成为BRCA1/2突变实体肿瘤的标准疗法！

New data from the Phase III PEACE III trial showed that XOFIGO ® (radium-223 dichloride) in combination with enzalutamide significantly improved prostate-specific antigen (PSA) response rates (≥90% at 6 and 12 months; 50.5% and 54.9% respectively) compared to enzalutamide alone (34.1% and 37.6% respectively) and the median time to alkaline phosphatase (ALP) normalization was 1.97 months for XOFIGO plus enzalutamide versus 4.47 months for enzalutamide alone (HR 1.42; 95% CI 1.13-1.80) among patients with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases Results from the Phase II COMRADE clinical trial demonstrated that the combination of olaparib with XOFIGO significantly improved radiographic progression-free survival (rPFS) compared to XOFIGO alone in mCRPC patients with bone metastases, with a median of 8.6 months versus 4.0 months (HR 0.51; 80% CI, 0.37-0.70; 2-sided p=0.005) Results from the two trials will be presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting WHIPPANY, N.J.--(BUSINESS WIRE)--New data from two clinical trials evaluating XOFIGO® (radium-223 dichloride) in patients with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases will be presented at the American Society of Clinical Oncology (ASCO) 2025 Annual Meeting on June 3, 2025. The studies in prostate cancer treatment with XOFIGO, offer potential new insights for patients with mCRPC with bone metastases. XOFIGO is indicated for the treatment of patients with CRPC, symptomatic bone metastases and no known visceral metastatic disease.1 It is the first and only alpha emitting radiopharmaceutical that treats bone metastases in mCRPC approved by the U.S. Food and Drug Administration (FDA). An analysis from the pivotal Phase III PEACE III trial, evaluating XOFIGO in combination with enzalutamide, an androgen receptor pathway inhibitor (ARPI), showed that adding six cycles of XOFIGO to enzalutamide improved prostate-specific antigen (PSA) and alkaline phosphatase (ALP) response rates.2 Notably, PSA response rates ≥90% at 6 and 12 months were 50.5% and 54.9%, respectively, in the combination arm compared to 34.1% and 37.6%, respectively, in the enzalutamide arm alone.2 The analysis also showed that for XOFIGO in combination with enzalutamide the median time to ALP normalization was 1.97 months compared to 4.47 months in the enzalutamide arm (HR 1.42; 95% CI, 1.13-1.80).2 The analysis follows the presentation of the full results from the PEACE III trial, presented as a late-breaking abstract during the Presidential Symposium at ESMO 2024.3 The results demonstrated that the addition of XOFIGO to enzalutamide significantly increased radiological progression-free survival (rPFS) among patients with mCRPC with bone metastases, with a 31% reduction in the risk of progression or death (HR 0.69; 95% CI, 0.54-0.87; p=0.0009) compared to enzalutamide alone.3 At the preplanned interim analysis conducted at 80% of the overall survival (OS) events, the hazard ratio (HR) for OS was 0.69 (95% CI 0.52-0.90; p=0.0031). The safety results were consistent with the established safety profile of XOFIGO, although authors noted the importance of administering bone protective agents (BPAs) to avoid fractures.3 The trial was a collaboration between the European Organization for Research and Treatment of Cancer (EORTC), Clinical Trial Ireland (CTI), the Canadian Urological Oncology Group (CUOG), the Latin American Cooperative Oncology Group (LACOG), and French UNICANCER Urogenital Tumor Study Group (GETUG). The results were consistent with the established safety profile of XOFIGO. Grade 3 or higher treatment emergent adverse events (TEAE) were recorded in 65.6% of patients in the combination arm compared to 55.8% of patients who received enzalutamide alone.2 The most frequent Grade 3 or higher TEAEs in the combination arm were hypertension (34%), fatigue (6%), fracture (5%), anemia (5%) and neutropenia (5%).2 Fractures (either treatment-emergent or post-treatment, symptomatic or pathologic, or with or without BPA use) were reported in 24.3% of patients in the combination arm and in 13.4% of patients in the enzalutamide arm.2 "The PEACE III trial has provided us with valuable insights into the benefits of combining XOFIGO with enzalutamide for patients with metastatic castration-resistant prostate cancer with bone metastases," said Dr. Murilo Luz, Urologic Oncologist, The Mount Sinai Hospital, New York and trial investigator. "This analysis highlights that the combination therapy achieved improvements on PSA and ALP, beyond the known radiographic progression free survival benefit. We are encouraged by these results with this potential compelling therapeutic option, which could provide an additional treatment option for patients." Data from the Phase II COMRADE trial were also presented at the ASCO 2025 Annual Meeting. Results demonstrated that the combination of olaparib with XOFIGO significantly improved radiographic progression-free survival (rPFS) in mCRPC patients compared to XOFIGO alone, with a median of 8.6 months versus 4.0 months (HR 0.51; 80% CI, 0.37-0.70; 2-sided p=0.005).4 56% of patients in the olaparib with XOFIGO and 35% of patients in the XOFIGO arms had grade ≥3 treatment-related adverse events, the most common adverse events on the olaparib with XOFIGO and XOFIGO arms were anemia (22.0%/18.0%), lymphocyte decrease (30.5%/9.1%), platelet decrease (6.8%/3.6%), and neutrophil decrease (5.1%/7.3%), respectively.4 "The results from the PEACE III and COMRADE trials underscore our dedication to exploring combinations, such as XOFIGO with enzalutamide or olaparib. We are hopeful these results will introduce another treatment option for patients with mCRPC and bone metastases who have not progressed viscerally,” said Christine Roth, Executive Vice President, Global Product Strategy and Commercialization and Member of the Pharmaceuticals Leadership Team at Bayer. About PEACE III (EORTC GUCG-1333) The PEACE III trial is an international, randomized, open-label, Phase III trial designed to investigate the efficacy and safety of XOFIGO in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. A total of 446 patients were randomized 1:1 to receive either XOFIGO 55 kBq/kg as an intravenous injection monthly for six cycles in combination with enzalutamide 160mg orally daily or enzalutamide 160mg orally daily. The primary endpoint was radiological progression-free survival (rPFS) by investigator assessment. Key secondary endpoints included overall survival (OS), time to subsequent systemic treatment, pain progression, and symptomatic skeletal event. This trial was a collaboration with several cancer cooperative groups: EORTC, CTI, CUOG, LACOG, and GETUG. About COMRADE II COMRADE is an open-label, randomized Phase II investigator-initiated trial in patients with metastatic castration resistant prostate cancer with bone metastases treated with a combination of olaparib, a PARP inhibitor, and XOFIGO compared to XOFIGO alone, 120 patients were randomized 1:1 to receive either olaparib plus XOFIGO or XOFIGO alone. The primary endpoint was radiographic progression-free survival (rPFS). About XOFIGO® (radium-223 dichloride) Injection1 XOFIGO is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease. Important Safety Information for Xofigo® (radium-223 dichloride) Injection Warnings and Precautions: Bone Marrow Suppression: In the phase 3 ALSYMPCA trial, 2% of patients in the Xofigo arm experienced bone marrow failure or ongoing pancytopenia, compared to no patients treated with placebo. There were two deaths due to bone marrow failure. For 7 of 13 patients treated with Xofigo bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients in the Xofigo arm and 2% in the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was similar for patients treated with Xofigo and placebo. Myelosuppression–notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia–has been reported in patients treated with Xofigo. Monitor patients with evidence of compromised bone marrow reserve closely and provide supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure Hematological Evaluation: Monitor blood counts at baseline and prior to every dose of Xofigo. Prior to first administering Xofigo, the absolute neutrophil count (ANC) should be ≥1.5 × 109/L, the platelet count ≥100 × 109/L, and hemoglobin ≥10 g/dL. Prior to subsequent administrations, the ANC should be ≥1 × 109/L and the platelet count ≥50 × 109/L. Discontinue Xofigo if hematologic values do not recover within 6 to 8 weeks after the last administration despite receiving supportive care Concomitant Use With Chemotherapy: Safety and efficacy of concomitantchemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued Increased Fractures and Mortality in Combination With Abiraterone Plus Prednisone/Prednisolone: Xofigo is not recommended for use in combination with abiraterone acetate plus prednisone/prednisolone outside of clinical trials. At the primary analysis of the Phase 3 ERA-223 study that evaluated concurrent initiation of Xofigo in combination with abiraterone acetate plus prednisone/prednisolone in 806 asymptomatic or mildly symptomatic mCRPC patients, an increased incidence of fractures (28.6% vs 11.4%) and deaths (38.5% vs 35.5%) have been observed in patients who received Xofigo in combination with abiraterone acetate plus prednisone/prednisolone compared to patients who received placebo in combination with abiraterone acetate plus prednisone/prednisolone. Safety and efficacy with the combination of Xofigo and agents other than gonadotropin-releasing hormone analogues have not been established Embryo-Fetal Toxicity: The safety and efficacy of Xofigo have not been established in females. Xofigo can cause fetal harm when administered to a pregnant female. Advise pregnant females and females of reproductive potential of the potential risk to a fetus. Advise male patients to use condoms and their female partners of reproductive potential to use effective contraception during and for 6 months after completing treatment with Xofigo Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations Fluid Status: Dehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting, which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia Injection Site Reactions: Erythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo Secondary Malignant Neoplasms: Xofigo contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms. However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow-up for patients on the trial Subsequent Treatment With Cytotoxic Chemotherapy: In the randomized clinical trial, 16% of patients in the Xofigo group and 18% of patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were reported in 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%). Please see the full Prescribing Information for Xofigo (radium 223 dichloride). About Oncology at Bayer Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The oncology franchise at Bayer includes six marketed products and several other assets in various stages of clinical development. Together, these products reflect the company’s approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated. About Bayer Bayer is a global enterprise with core competencies in the life science fields of health care and nutrition. In line with its mission, “Health for all, Hunger for none,” the company’s products and services are designed to help people and the planet thrive by supporting efforts to master the major challenges presented by a growing and aging global population. Bayer is committed to driving sustainable development and generating a positive impact with its businesses. At the same time, the Group aims to increase its earning power and create value through innovation and growth. The Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2024, the Group employed around 93,000 people and had sales of 46.6 billion euros. R&D expenses before special items amounted to 6.2 billion euros. For more information, go to www.bayer.com. © 2025 Bayer BAYER, the Bayer Cross and XOFIGO are registered trademarks of Bayer. Find more information at www.pharma.bayer.com Our online press service is just a click away: www.bayer.us/en/newsroom Follow us on Facebook: http://www.facebook.com/pharma.bayer Follow us on X: https://X.com/BayerUS Forward-Looking Statements This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer’s public reports which are available on the Bayer website at www.bayer.com. The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments. References XOFIGO ® (radium-223) Injection [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, December 2019. Choudhury A, et al. PSA and alkaline phosphatase changes in the EORTC-1333 PEACE-3 study evaluating the addition of six cycles of radium 223 in metastatic castration-resistant prostate cancer (mCRPC) starting enzalutamide. Abstract 5062. Presented at ASCO 2025. Gillessen S, et al. A randomized multicenter open label phase III trial comparing enzalutamide vs a combination of Radium-223 (Ra223) and enzalutamide in asymptomatic or mildly symptomatic patients with bone metastatic castration-resistant prostate cancer (mCRPC): First results of EORTC-GUCG 1333/PEACE-3. European Society of Medical Oncology 2025 (ESMO) LBA1. September 9, 2024. McKay RR, et al. A multicenter, randomized, phase 2, investigator-initiated ETCTN trial of olaparib + radium-223 vs. radium-223 in men with castration-resistant prostate cancer (CRPC) with bone metastases (BM) (COMRADE): Initial efficacy and biomarker analysis. Abstract 5007. Presented at ASCO 2025.