TOP2B

引言 DNA超螺旋（DNA supercoiling）是在DNA双螺旋结构的基础上进一步螺旋化形成的螺旋结构，根据手性方向不同分为正超螺旋和负超螺旋。DNA超螺旋能够影响基本生物过程，如DNA与蛋白质的结合，核小体的稳定，R-loop的形成，染色质三维结构，以及很多其他染色质的性质等。同时，DNA超螺旋也可通过影响增强子-启动子互作来影响转录过程，进而影响基因的表达。作为基于双螺旋结构的一种DNA的基本物理学性质，尽管DNA超螺旋在生物过程中有重要功能，但我们对于其在染色质和基因组中的动态调节过程、机理和功能的理解仍然十分有限。相比我们对其他很多染色质性质和结构的深入大量研究，这其中缺失的重要环节是一种准确、定量检测活细胞中基因组DNA超螺旋的可靠方法。 近日，美国国家卫生研究院癌症研究所的Chongyi Chen课题组在Nature Structural & Molecular Biology发表了题为 Topoisomerase-modulated genome-wide DNA supercoiling domains colocalize with nuclear compartments and regulate human gene expression 的研究成果。该研究团队利用azide-trimethypsoralen（ATMP）在活细胞中共价结合DNA超螺旋，通过DBCO介导的点击反应富集DNA超螺旋片段，之后进行建库和测序。与之前的定性检测方法相比，ATMP-seq可以极大地降低DNA序列偏差和全基因组背景噪音，尤其是核小体分布和染色质可及性造成的偏差，从而可以得到高分辨率的全基因组定量DNA超螺旋图谱，同时具有极高的可重复性。 图：ATMP-seq可得到高分辨率的全基因组定量DNA超螺旋图谱(Credit: Nature Structural & Molecular Biology) 研究人员首先观察到了基于基因转录而形成的局部正负超螺旋，位于基因附近几个Kb的范围内，并且揭示了转录强度、基因长度、以及几种不同的DNA拓扑异构酶对其的调控。有趣的是，全基因组DNA超螺旋图谱显示互相交替的正超螺旋和负超螺旋，从而形成了几百kb到Mb大小的DNA超螺旋结构域。研究表明，DNA拓扑异构酶中TOP1和TOP2B对DNA超螺旋结构域起到主要调节作用。通过药物抑制TOP1和TOP2，正负DNA超螺旋结构域的强度都得到增强，这表明了DNA拓扑异构酶在全基因组范围内解旋DNA超螺旋的重要作用。为了进一步区分TOP2A和TOP2B，以及去除药物可能的非特异性影响，该研究团队采用AID系统选择性敲除TOP1，TOP2A和TOP2B，结果表明相对于TOP2A来说，TOP1和TOP2B对DNA超螺旋结构域起到主要调节作用。另外，转录活动是这些全基因组超螺旋结构域的来源之一，可能与超螺旋扭转力矩沿染色质的物理传播有关，但具体的形成机理还有待深入研究。 研究人员进一步研究了DNA超螺旋结构域与各种染色质性质和结构，特别是染色质三维结构之间的关系。通过比对DNA超螺旋图谱与A/B compartments图谱，发现DNA超螺旋结构域与A/B compartments高度相关，负超螺旋与更为活跃的A compartments相关，而正超螺旋则与更加沉默的B compartments相关。更为有意思的是这一相关性并不局限于特定的物种，在果蝇细胞系中同样发现了DNA超螺旋结构域与A/B compartments的相关性。而与之前人们普遍猜测的DNA超螺旋可能与Topologically Associating Domains (TADs) 高度相关的猜测相反，DNA超螺旋结构域与TADs并无相关，反而是在TAD边界富集了大量的与转录相关的负超螺旋，但与cohesin，CTCF依然并无相关。 最后，研究人员分析了全基因组DNA超螺旋分布对基因转录表达的影响。首先，人类基因组DNA超螺旋结构域的动态分布随着细胞状态和细胞种类的变化而变化，暗示了他们可能对基因表达的影响。然后，研究人员通过敲除拓扑异构酶来改变人类全基因组DNA超螺旋结构域，然后分析其中基因转录活性的变化。在敲除关键DNA拓扑异构酶之后，负超螺旋结构域会积累更多负超螺旋，而在其中的基因转录会更加活跃。正超螺旋结构域会积累更多正超螺旋，而在其中的基因转录则基本不变。DNA超螺旋如何影响转录的具体分子机理还有待深入研究，但该结果表明DNA超螺旋的动态变化和调控确实会影响转录活性和人类基因的表达。 综上所述，这项工作开发了定量准确分析DNA超螺旋的方法ATMP-seq，并且初步研究了这一目前知之甚少的染色质和DNA的基本物理学性质。通过该方法可以观察到高分辨率的全基因组DNA超螺旋图谱和Mb大小的DNA超螺旋结构域，基因转录和DNA拓扑异构酶对DNA超螺旋结构域的调节作用，DNA超螺旋结构域与A/B compartments的高度相关，以及DNA超螺旋可影响基因转录与表达，初步揭示了DNA超螺旋在人类细胞基因组中的形成与调控机理，和其他染色质性质的互作，以及在染色质调节和功能中的重要性。 参考文献 https://www.nature.com/articles/s41594-024-01377-5 责编|探索君 排版|探索君 文章来源|“BioArt” End 往期精选 围观 一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版） 热文 Cell | 是什么决定了细胞的大小？ 热文 Nature | 2024年值得关注的七项技术 热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望 热文 CRISPR技术进化史 | 24年Cell综述

Annamycin demonstrated to be a more potent inhibitor of topoisomerase II-alpha and II-beta while remaining inactive against established cardiomyocyte cultures Results clearly aligned with lack of drug-related cardiotoxic events in patients treated with Annamycin in ongoing clinical trials; 100% of Annamycin subjects in multiple studies (N=82) continue to show no signs of cardiotoxicity during study A prominent treatment for many adult cancers and approximately 50% of all pediatric cancer patients are treated with a cardiotoxic anthracycline Annamycin composition of matter patent issued April 9th; Patent enables expansion into greater patient populations where cardiotoxicity remains an unmet need HOUSTON, April 10, 2024 /PRNewswire/ -- Moleculin Biotech, Inc, (Nasdaq: MBRX) (Moleculin or the Company), a clinical stage pharmaceutical company with a broad portfolio of drug candidates targeting hard-to-treat tumors and viruses, today announced positive preclinical data regarding the Company's next-generation anthracycline, Annamycin, was presented at the American Association for Cancer Research (AACR) Annual Meeting, taking place April 5-10, 2024 in San Diego, CA. The poster titled, Non-cardiotoxic Properties of Annamycin, a Clinically Evaluated Anthracycline and Potent Topoisomerase 2β Poison, was presented in the "Late-Breaking Research: Experimental and Molecular Therapeutics 2" session held on Monday, April 8th. The presented poster outlined results from the assessment and comparison of the potency of doxorubicin (a commonly prescribed anthracycline) and Annamycin, Moleculin's next-generation anthracycline, against topoisomerase II-alpha and II-beta and determine their impact on physiology of human cardiomyocytes demonstrating no pathologic changes in mice hearts following chronic in vivo exposure. "Cardiotoxicity continues to be a significant side effect limiting the clinical use of anthracyclines, despite anthracyclines representing some of the most important treatments available for AML and Advanced STS. These data, documenting lack of cardiotoxicity of Annamycin and aligned with the data demonstrated to date in our ongoing clinical trials, bolster our confidence in Annamycin potential to offer patients a safe and effective treatment option. Interestingly, the presented data demonstrates that Annamycin appears to be a significantly more potent inhibitor of topoisomerase II-beta than doxorubicin providing validation for additional studies to reevaluate the role of topoisomerase II-beta in anthracycline induced cardiotoxicity," commented Walter Klemp, Chairman and Chief Executive Officer of Moleculin. "Additionally, with our recently issued patent, which covers composition of matter protection across all indications, we have the potential to expand the development of Annamycin into greater patient populations in indications where cardiotoxicity remains a significant unmet need. We remain highly encouraged by Annamycin and committed to advancing its development," concluded Mr. Klemp. As part of the presented data, the potency of Annamycin and doxorubicin to inhibit topoisomerase II was tested in DNA relaxation assays using recombinant topoisomerase II-alpha and II-beta with kinetoplast as the DNA substrate. Annamycin and doxorubicin cytotoxicity was assessed in a panel of cancer cell lines cardiomyocytes (murine and human). In addition, the effects on cardiomyocyte physiology (beating rate, contraction, electric potential,) were assessed in human cardiomyocytes using the xCELLigence RTCA CardioECR. The pathophysiology of the heart after chronic exposure to the drugs was also evaluated in mice models. Key Data Highlights: Annamycin demonstrated to be a more potent topoisomerase II-alpha and II-beta poison than doxorubicin. In contrast to doxorubicin: Annamycin does not affect viability of established culture of human iPSCc cardiomyocytes (tested up to 1.5 μM) Annamycin does not affect contractility or the electric potential of the cardiomyocytes Rat cardiomyocytes (H9c2) appear to be resistant to ANN while sensitive to DOX Annamycin is well tolerated by the animals even at schedules exceeding the therapeutic dosage while ex vivo pathology examination of the mice confirmed no toxicity to the heart/myocardium. These data are clearly aligned with the lack of drug-related cardiotoxic events in Annamycin-treated patients in ongoing clinical trials The role of topoisomerase II-beta in cardiotoxicity of anthracyclines should be further investigated A video on the comparison of cardiotoxic effects of Annamycin and doxorubicin on human cardiomyocytes can be accessed here The Company also announced that the United States Patent and Trademark Office (USPTO) formally issued U.S. Patent number 11,951,118 titled, "Preparation of Preliposomal Annamycin Lyophilizate" (the '118 patent') to Moleculin and The University of Texas System Board of Regents. Annamycin is currently being evaluated in ongoing clinical trials for the treatment of relapsed or refractory acute myeloid leukemia (AML) and soft tissue sarcoma (STS) lung metastases. For more information about the ongoing trials, please visit clinicaltrialsregister.eu: EudraCT 2020-005493-10 or clinicaltrials.gov: NCT05319587; and clinicaltrials.gov: NCT04887298, respectively. About Moleculin Biotech, Inc. Moleculin Biotech, Inc. is a clinical stage pharmaceutical company with a growing pipeline, including Phase 2 clinical programs, for hard-to-treat tumors and viruses. The Company's lead program, Annamycin is a next-generation anthracycline designed to avoid multidrug resistance mechanisms with little to no cardiotoxicity. Annamycin is currently in development for the treatment of relapsed or refractory acute myeloid leukemia (AML) and soft tissue sarcoma (STS) lung metastases. Additionally, the Company is developing WP1066, an Immune/Transcription Modulator capable of inhibiting p-STAT3 and other oncogenic transcription factors while also stimulating a natural immune response, targeting brain tumors, pancreatic and other cancers, and WP1220, an analog to WP1066, for the topical treatment of cutaneous T-cell lymphoma. Moleculin is also engaged in the development of a portfolio of antimetabolites, including WP1122 for the potential treatment of viruses, as well as cancer indications including brain tumors, pancreatic and other cancers. For more information about the Company, please visit and connect on Twitter, LinkedIn and Facebook. Forward-Looking Statements Some of the statements in this release are forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, Section 21E of the Securities Exchange Act of 1934 and the Private Securities Litigation Reform Act of 1995, which involve risks and uncertainties. Forward-looking statements in this press release include, without limitation, the expected issuance of the patent discussed above, the pace of enrollment in Moleculin's clinical trials, the timing of Moleculin's ability to report topline data from its studies, the timing of the commencement of investigator-sponsored and/or externally funded clinical trials which are outside the control of Moleculin, and whether the results of Moleculin's preclinical animal models can be replicated in human trials. Although Moleculin believes that the expectations reflected in such forward-looking statements are reasonable as of the date made, expectations may prove to have been materially different from the results expressed or implied by such forward-looking statements. Moleculin has attempted to identify forward-looking statements by terminology including 'believes,' 'estimates,' 'anticipates,' 'expects,' 'plans,' 'projects,' 'intends,' 'potential,' 'may,' 'could,' 'might,' 'will,' 'should,' 'approximately' or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. These statements are only predictions and involve known and unknown risks, uncertainties, and other factors, including those discussed under Item 1A. "Risk Factors" in our most recently filed Form 10-K filed with the Securities and Exchange Commission (SEC) and updated from time to time in our Form 10-Q filings and in our other public filings with the SEC. Any forward-looking statements contained in this release speak only as of its date. We undertake no obligation to update any forward-looking statements contained in this release to reflect events or circumstances occurring after its date or to reflect the occurrence of unanticipated events. Investor Contact: JTC Team, LLC Jenene Thomas (833) 475-8247 MBRX@jtcir.com Company Codes: NASDAQ-SMALL:MBRX

Results showed an absolute difference of an additional 7.4 months in median overall survival for LYNPARZA® (olaparib) plus abiraterone in this setting vs. abiraterone alone WILMINGTON, Del.--(BUSINESS WIRE)-- Results from the final prespecified overall survival (OS) analysis of the PROpel Phase III trial in metastatic castration-resistant prostate cancer (mCRPC) showed LYNPARZA® (olaparib), jointly developed and commercialized by AstraZeneca Pharmaceuticals LP and Merck & Co., Inc., known as MSD outside the US and Canada in combination with abiraterone and prednisone or prednisolone demonstrated median OS of 42.1 months versus 34.7 months for abiraterone plus placebo. This result represents a 7.4-month absolute difference in median OS versus a standard of care (47.9% maturity, hazard ratio [HR] of 0.81, 95% confidence interval [CI] 0.67-1.00; p=0.0544). While this numerical increase in median OS did not achieve statistical significance, this clinical activity builds on the meaningful survival gains achieved for patients in this setting treated with abiraterone alone, a current standard of care. Results will be presented today in an oral presentation at the 2023 American Society of Clinical Oncology (ASCO) Genitourinary (GU) Cancers Symposium (#LBA16). In the primary analysis presented at ASCO GU 2022, and published in The New England Journal of Medicine Evidence, PROpel met its primary endpoint of radiographic progression-free survival (rPFS), showing that LYNPARZA in combination with abiraterone significantly reduced the risk of disease progression or death by 34% versus abiraterone alone (HR 0.66; 95% CI 0.54-0.81; p<0.0001). Noel Clarke, Urological Surgeon and Professor of Urological Oncology at Manchester’s Christie/Salford Royal Hospitals and Manchester University, and a senior investigator in the PROpel trial, said: “From the primary radiographic progression-free survival analysis presented at ASCO GU last year to the updated overall survival data presented today, the data reinforce the therapeutic potential of olaparib plus abiraterone and prednisone for patients with metastatic castration-resistant prostate cancer in the overall trial population and across subgroups. The results of PROpel are important for patients and the oncology community alike, providing support for this combination as a potential and critically needed new treatment option in metastatic castration-resistant prostate cancer.” Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “Both PARP, the target of LYNPARZA, and the androgen receptor are important for providing DNA repair in prostate cancer. The results in the overall trial population from PROpel illustrate how the combination of LYNPARZA and abiraterone can exploit the dependency of the androgen receptor’s role in DNA repair on PARP to provide greater anticancer activity than abiraterone alone. Based on the totality of the data, it is notable to see this combination delivering a meaningful benefit in a broad population of patients in this setting, which is further underscored by the recent indication approved in the EU.” Dr Eliav Barr, Head, Global Clinical Development and Chief Medical Officer, Merck & Co, Inc. Research Laboratories, said: “Prostate cancer is the second most commonly diagnosed cancer in patients assigned male at birth, and mortality is estimated to almost double over the next 20 years. With limited treatment options for these patients, we recognize the critical need for therapies that can delay disease progression. We are proud of our collaboration with AstraZeneca as we work together to advance pending regulatory reviews and bring a new treatment option to the prostate cancer community.” Summary of results on key secondary OS endpoint across subgroups LYNPARZA + abiraterone Placebo + abiraterone ITT Number of patients (n) 399 397 Median OS in months 42.1 34.7 HR (95% CI) 0.81 (0.67, 1.00) HRRm Number of patients (n) 111 115 Median OS in months NR 28.5 HR (95% CI) 0.66 (0.45, 0.95) Non-HRRm Number of patients (n) 279 273 Median OS in months 42.1 38.9 HR (95% CI) 0.89 (0.70, 1.14) BRCAm Number of patients (n) 47 38 Median OS in months NR 23.0 HR (95% CI) 0.29 (0.14, 0.56) Non-BRCAm Number of patients (n) 343 350 Median OS in months 39.6 38.0 HR (95% CI) 0.91 (0.73, 1.13) *18 patients with unknown HRRm status were excluded from subgroup analysis. NR, not reached The safety and tolerability of LYNPARZA plus abiraterone was in line with that observed in prior clinical trials and the known profiles of the individual medicines. At the time of this updated analysis, there were no new long-term safety issues identified. The most common adverse events (AEs) in the LYNPARZA plus abiraterone arm (greater than or equal to 20% of patients) were anemia (49.7%), fatigue (38.7%), nausea (30.7%), back pain (21.6%) and diarrhea (20.6%). Approximately 83% of patients treated with LYNPARZA plus abiraterone who experienced AEs remained on treatment at the time of data cut-off. LYNPARZA in combination with abiraterone was approved by the European Commission in December 2022 for the treatment of mCRPC in adult men for whom chemotherapy is not clinically indicated and is currently undergoing regulatory review in other countries. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS There are no contraindications for LYNPARZA. WARNINGS AND PRECAUTIONS Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in approximately 1.5% of patients exposed to LYNPARZA monotherapy, and the majority of events had a fatal outcome. The median duration of therapy in patients who developed MDS/AML was 2 years (range: <6 months to >10 years). All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy. Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood count weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA if MDS/AML is confirmed. Pneumonitis: Occurred in 0.8% of patients exposed to LYNPARZA monotherapy, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt LYNPARZA treatment and initiate prompt investigation. Discontinue LYNPARZA if pneumonitis is confirmed and treat patient appropriately. Venous Thromboembolic Events (VTE): Including severe or fatal pulmonary embolism (PE) occurred in patients treated with LYNPARZA. VTE occurred in 7% of patients with metastatic castration-resistant prostate cancer who received LYNPARZA plus androgen deprivation therapy (ADT) compared to 3.1% of patients receiving enzalutamide or abiraterone plus ADT in the PROfound study. Patients receiving LYNPARZA and ADT had a 6% incidence of pulmonary embolism compared to 0.8% of patients treated with ADT plus either enzalutamide or abiraterone. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism, and treat as medically appropriate, which may include long-term anticoagulation as clinically indicated. Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, LYNPARZA can cause fetal harm. A pregnancy test is recommended for females of reproductive potential prior to initiating treatment. Females Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose. Males Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of LYNPARZA and to not donate sperm during this time. ADVERSE REACTIONS—First-Line Maintenance BRCAm Advanced Ovarian Cancer Most common adverse reactions (Grades 1-4) in ≥10% of patients who received LYNPARZA in the first-line maintenance setting for SOLO-1 were: nausea (77%), fatigue (67%), abdominal pain (45%), vomiting (40%), anemia (38%), diarrhea (37%), constipation (28%), upper respiratory tract infection/influenza/nasopharyngitis/bronchitis (28%), dysgeusia (26%), decreased appetite (20%), dizziness (20%), neutropenia (17%), dyspepsia (17%), dyspnea (15%), leukopenia (13%), urinary tract infection (13%), thrombocytopenia (11%), and stomatitis (11%). Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients who received LYNPARZA in the first-line maintenance setting for SOLO-1 were: decrease in hemoglobin (87%), increase in mean corpuscular volume (87%), decrease in leukocytes (70%), decrease in lymphocytes (67%), decrease in absolute neutrophil count (51%), decrease in platelets (35%), and increase in serum creatinine (34%). ADVERSE REACTIONS—First-Line Maintenance Advanced Ovarian Cancer in Combination with Bevacizumab Most common adverse reactions (Grades 1-4) in ≥10% of patients treated with LYNPARZA/bevacizumab and at a ≥5% frequency compared to placebo/bevacizumab in the first-line maintenance setting for PAOLA-1 were: nausea (53%), fatigue (including asthenia) (53%), anemia (41%), lymphopenia (24%), vomiting (22%), and leukopenia (18%). In addition, the most common adverse reactions (≥10%) for patients receiving LYNPARZA/bevacizumab irrespective of the frequency compared with the placebo/bevacizumab arm were: diarrhea (18%), neutropenia (18%), urinary tract infection (15%), and headache (14%). In addition, venous thromboembolic events occurred more commonly in patients receiving LYNPARZA/bevacizumab (5%) than in those receiving placebo/bevacizumab (1.9%). Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients for LYNPARZA in combination with bevacizumab in the first-line maintenance setting for PAOLA-1 were: decrease in hemoglobin (79%), decrease in lymphocytes (63%), increase in serum creatinine (61%), decrease in leukocytes (59%), decrease in absolute neutrophil count (35%), and decrease in platelets (35%). ADVERSE REACTIONS—Maintenance Recurrent Ovarian Cancer Most common adverse reactions (Grades 1-4) in ≥20% of patients who received LYNPARZA in the maintenance setting for SOLO-2 were: nausea (76%), fatigue (including asthenia) (66%), anemia (44%), vomiting (37%), nasopharyngitis/upper respiratory tract infection (URI)/influenza (36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%), headache (26%), decreased appetite (22%), and stomatitis (20%). Study 19: nausea (71%), fatigue (including asthenia) (63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory tract infection (22%), constipation (22%), headache (21%), decreased appetite (21%), and dyspepsia (20%). Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients who received LYNPARZA in the maintenance setting (SOLO-2/Study 19) were: increase in mean corpuscular volume (89%/82%), decrease in hemoglobin (83%/82%), decrease in leukocytes (69%/58%), decrease in lymphocytes (67%/52%), decrease in absolute neutrophil count (51%/47%), increase in serum creatinine (44%/45%), and decrease in platelets (42%/36%). ADVERSE REACTIONS—Adjuvant Treatment of gBRCAm, HER2-Negative, High-Risk Early Breast Cancer Most common adverse reactions (Grades 1-4) in ≥10% of patients who received LYNPARZA in the adjuvant setting for OlympiA were: nausea (57%), fatigue (including asthenia) (42%), anemia (24%), vomiting (23%), headache (20%), diarrhea (18%), leukopenia (17%), neutropenia (16%), decreased appetite (13%), dysgeusia (12%), dizziness (11%), and stomatitis (10%). Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients who received LYNPARZA in the adjuvant setting for OlympiA were: decrease in lymphocytes (77%), increase in mean corpuscular volume (67%), decrease in hemoglobin (65%), decrease in leukocytes (64%), and decrease in absolute neutrophil count (39%). ADVERSE REACTIONS—gBRCAm, HER2-Negative Metastatic Breast Cancer Most common adverse reactions (Grades 1-4) in ≥20% of patients who received LYNPARZA in the metastatic setting for OlympiAD were: nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%). Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients who received LYNPARZA in the metastatic setting for OlympiAD were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%). ADVERSE REACTIONS—First-Line Maintenance gBRCAm Metastatic Pancreatic Adenocarcinoma Most common adverse reactions (Grades 1-4) in ≥10% of patients who received LYNPARZA in the first-line maintenance setting for POLO were: fatigue (60%), nausea (45%), abdominal pain (34%), diarrhea (29%), anemia (27%), decreased appetite (25%), constipation (23%), vomiting (20%), back pain (19%), arthralgia (15%), rash (15%), thrombocytopenia (14%), dyspnea (13%), neutropenia (12%), nasopharyngitis (12%), dysgeusia (11%), and stomatitis (10%). Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients who received LYNPARZA in the first-line maintenance setting for POLO were: increase in serum creatinine (99%), decrease in hemoglobin (86%), increase in mean corpuscular volume (71%), decrease in lymphocytes (61%), decrease in platelets (56%), decrease in leukocytes (50%), and decrease in absolute neutrophil count (25%). ADVERSE REACTIONS—HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer Most common adverse reactions (Grades 1-4) in ≥10% of patients who received LYNPARZA for PROfound were: anemia (46%), fatigue (including asthenia) (41%), nausea (41%), decreased appetite (30%), diarrhea (21%), vomiting (18%), thrombocytopenia (12%), cough (11%), and dyspnea (10%). Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients who received LYNPARZA for PROfound were: decrease in hemoglobin (98%), decrease in lymphocytes (62%), decrease in leukocytes (53%), and decrease in absolute neutrophil count (34%). DRUG INTERACTIONS Anticancer Agents: Clinical studies of LYNPARZA with other myelosuppressive anticancer agents, including DNA-damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity. CYP3A Inhibitors: Avoid coadministration of strong or moderate CYP3A inhibitors when using LYNPARZA. If a strong or moderate CYP3A inhibitor must be coadministered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA treatment. CYP3A Inducers: Avoid coadministration of strong or moderate CYP3A inducers when using LYNPARZA. USE IN SPECIFIC POPULATIONS Lactation: No data are available regarding the presence of olaparib in human milk, its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with LYNPARZA and for 1 month after receiving the final dose. Pediatric Use: The safety and efficacy of LYNPARZA have not been established in pediatric patients. Hepatic Impairment: No adjustment to the starting dose is required in patients with mild or moderate hepatic impairment (Child-Pugh classification A and B). There are no data in patients with severe hepatic impairment (Child-Pugh classification C). Renal Impairment: No dosage modification is recommended in patients with mild renal impairment (CLcr 51-80 mL/min estimated by Cockcroft-Gault). In patients with moderate renal impairment (CLcr 31-50 mL/min), reduce the dose of LYNPARZA to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min). INDICATIONS LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated: First-Line Maintenance BRCAm Advanced Ovarian Cancer For the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA. First-Line Maintenance HRD-Positive Advanced Ovarian Cancer in Combination with Bevacizumab In combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either: a deleterious or suspected deleterious BRCA mutation, and/or genomic instability Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA. Maintenance Recurrent Ovarian Cancer For the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy. Adjuvant Treatment of gBRCAm, HER2-Negative, High-Risk Early Breast Cancer For the adjuvant treatment of adult patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative high-risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA. gBRCAm, HER2-Negative Metastatic Breast Cancer For the treatment of adult patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA. First-Line Maintenance gBRCAm Metastatic Pancreatic Cancer For the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA. HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer For the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA. Please see complete Prescribing Information, including Medication Guide. Notes Prostate cancer Prostate cancer is the second most commonly diagnosed cancer in men and the fifth leading cause of cancer death in men globally, with an incidence of 1.4 million and 375,000 deaths in 2020.1,2,3 In the United States, it is estimated that there were 268,490 new cases and 34,500 deaths in 2022.4,5 Overall survival for patients with mCRPC is approximately three years in clinical trial settings, and even shorter in the real-world.6 Approximately half of patients with mCRPC may receive only one line of active treatment, with diminishing benefit of subsequent therapies.7-12 Metastatic castration-resistant prostate cancer Metastatic prostate cancer is associated with a significant mortality rate.14 Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone.15 In patients with mCRPC, their prostate cancer grows and spreads to other parts of the body despite the use of androgen-deprivation therapy to block the action of male sex hormones.16 Approximately 10-20% of men with advanced prostate cancer will develop castration-resistant prostate cancer (CRPC) within five years, and at least 84% of these men will have metastases at the time of CRPC diagnosis.16 Of patients with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.16 Despite the advances in mCRPC treatment in the past decade with taxane and new hormonal agent (NHA) treatment, there is high unmet need in this population.16-19 PROpel PROpel is a randomized, double-blind, multi-center Phase III trial testing the efficacy, safety, and tolerability of LYNPARZA versus placebo when given in addition to abiraterone, as well as prednisone or prednisolone, in men with mCRPC who had not received prior chemotherapy or NHAs in the mCRPC setting. The primary endpoint is rPFS and secondary endpoints include overall survival, time to secondary progression or death, and time to first subsequent therapy. In the PROpel Phase III trial, LYNPARZA is combined with abiraterone, an NHA which targets the androgen receptor (AR) pathway. AR signaling engages a transcriptional program that is critical for tumor cell growth and survival in prostate cancer.20,21 In addition, the AR also plays a role in repairing DNA damage in prostate cancer cells, including damage not normally repaired by HRR. Preclinical models have suggested a number of potential mechanisms that could account for increased combination efficacy in both HRR deficient and HRR proficient prostate cancer. 22,23,24,26,27 Recent data provides evidence that PARP facilitates AR-DNA binding in the presence of DNA damage (AZ internal data on file) and that combined inhibition of PARP with LYNPARZA and AR activity with an NHA results in enhanced DNA damage and anti-tumor activity in non-HRRm prostate cancer models.22,24 For more information about the trial please visit ClinicalTrials.gov. LYNPARZA LYNPARZA® (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumors harboring a deficiency in HRR, such as those with mutations in BRCA1 and/or BRCA2, or those where deficiency is induced by other agents (such as NHAs). Inhibition of PARP with LYNPARZA leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. LYNPARZA is currently approved in a number of countries across multiple tumor types including maintenance treatment of platinum-sensitive relapsed ovarian cancer and as both monotherapy and in combination with bevacizumab for the 1st-line maintenance treatment of BRCA-mutated (BRCAm) and homologous recombination repair deficient (HRD)-positive advanced ovarian cancer, respectively; for gBRCAm, HER2-negative metastatic breast cancer (in the EU and Japan this includes locally advanced breast cancer); for gBRCAm, HER2-negative high-risk early breast cancer (in Japan this includes all BRCAm HER2-negative high-risk early breast cancer); for gBRCAm metastatic pancreatic cancer; and HRR gene-mutated metastatic castration-resistant prostate cancer (BRCAm only in the EU and Japan). In China, LYNPARZA is approved for the treatment of BRCA-mutated metastatic castration-resistant prostate cancer as well as a 1st-line maintenance therapy in BRCA-mutated advanced ovarian cancer. LYNPARZA, which is being jointly developed and commercialized by AstraZeneca and Merck, has been used to treat over 75,000 patients worldwide. LYNPARZA has a broad clinical trial development program, and AstraZeneca and Merck & Co, Inc. are working together to understand how it may affect multiple PARP-dependent tumors as a monotherapy and in combination across multiple cancer types. LYNPARZA is the foundation of AstraZeneca's industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells. The AstraZeneca and Merck strategic oncology collaboration In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the US and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialize LYNPARZA, the world’s first PARP inhibitor, and selumetinib, a mitogen-activated protein kinase (MEK) inhibitor, for multiple cancer types. Working together, the companies will develop LYNPARZA and selumetinib and other potential new medicines as monotherapies and as combinations. The companies will also develop LYNPARZA and selumetinib in combination with their respective PD-L1 and PD-1 medicines independently. AstraZeneca in oncology AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients. The Company's focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience. AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death. About AstraZeneca AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialization of prescription medicines in Oncology, Rare Diseases, and Biopharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit and follow the Company on Twitter @AstraZenecaUS. References Cancer.Net. Prostate Cancer: Statistics. Available at . Accessed January 2023. 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Eur Urol. 2018;74(1):37-45 Hussein M, et al. Prostate-Specific Antigen Progression Predicts Overall Survival in Patients with Metastatic Prostate Cancer: Data from Southwest Oncology Group Trials 9346 (Intergroup Study 0162) and 9916. J Clin Oncol. 2009;27(15):2450. de Wit, R, et al. Real-World Evidence of Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Cabazitaxel: Comparison with the Randomized Clinical Study CARD. Prostate Cancer Prostatic Dis. 2022;2660. Ryan C, et al. Abiraterone Acetate Plus Prednisone Versus Placebo Plus Prednisone in Chemotherapy-Naive Men with Metastatic Castration-Resistant Prostate Cancer (COU-AA-302): Final Overall Survival Analysis of a Randomised, Double-Blind, Placebo-Controlled Phase 3 Study. Lancet Oncol. 2015;16(2):152-60. Miller K, et al. The Phase 3 COU-AA-302 Study of Abiraterone Acetate Plus Prednisone in Men with Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer: Stratified Analysis Based on Pain, Prostate-Specific Antigen, and Gleason Score. Eur Urol. 2018;74(1):17-23. AstraZeneca.com. Lynparza plus abiraterone reduced risk of disease progression by 34% vs. standard-of-care in 1st-line metastatic-castration resistant prostate cancer. Available at . Accessed January 2023. Chowdhury S, et al. Real-World Outcomes in First-Line Treatment of Metastatic Castration-Resistant Prostate Cancer: The Prostate Cancer Registry. Target Oncol. 2020;15(3):301-315. Cancer.Net. Treatment of metastatic castration-resistant prostate cancer. Available at Accessed: January 2023. Kirby M, et al. Characterising the Castration-Resistant Prostate Cancer Population: Systematic Review. Int J of Clin Pract. 2021;65(11):1180-1192. UroToday. What is Changing in Advanced Prostate Cancer? Available at . Accessed January 2023. Liu J, et al. Second-Line Hormonal Therapy for the Management of Metastatic Castration-Resistant Prostate Cancer: a Real-World Data Study Using a Claims Database. Sci Rep. 2020;10(1):4240. UroToday. Beyond First-line Treatment of Metastatic Castrate-resistant Prostate Cancer. Available at . Accessed January 2023. Schiewer MJ, et al. Dual roles of PARP-1 promote cancer growth and progression. Cancer Discov. 2012;2(12):1134-1149. Schiewer MJ & Knudsen KE. AMPed Up To Treat Prostate Cancer: Novel AMPK Activators Emerge for Cancer Therapy. EMBO Mol Med. 2014;6(4):439-441. Li L, et al. Androgen Receptor Inhibitor–Induced “BRCAness” and PARP Inhibition are Synthetically Lethal for Castration-Resistant Prostate Cancer. Sci Signal. 2017; 10(480):eaam7479. Polkinghorn WR, et al. Androgen Receptor Signaling Regulates DNA Repair in Prostate Cancers. Cancer Discov. 2013;3(11):1245-1253. Asim M, et al. Synthetic Lethality Between Androgen Receptor Signalling and the PARP Pathway in Prostate Cancer. Nat Commun. 2017;8(1):374. Ju B-G, et al. A Topoisomerase IIbeta-Mediated dsDNA Break Required for Regulated Transcription. Science. 2006;312(5781):1798-1802. Goodwin JF, et al. A Hormone-DNA Repair Circuit Governs the Response to Genotoxic Insult. Cancer Discov. 2013;3(11):1254-1271. Tarish FL, et al. Castration Radiosensitizes Prostate Cancer Tissue by Impairing DNA Double-Strand Break Repair. Sci Transl Med. 2015;7(312):312re11. US-72847 Last Updated 02/23