(For details on the FIGO staging system, see Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org.) ), Universittsklinikum Heidelberg, Heidelberg (F.M. Tumor assessment scans (computed tomography or magnetic resonance imaging) were performed at baseline and then every 24 weeks (or at planned visits every 12 weeks if there was evidence of clinical progression or progression according to the serum level of cancer antigen 125) up to month 42 or until the date of data cutoff. 8. all in Madrid; Medical University of Innsbruck, University Clinic for Gynecology and Obstetrics (R.B. ), Milan, and Fondazione Policlinico Universitario A. Gemelli IRCCS, Universit Cattolica, and MITO, Rome (G.S.) 16. In patients with HRD-negative tumors (277 patients), the median progression-free survival was 16.6 months in the olaparib group and 16.2 months in the placebo group (hazard ratio for disease progression or death, 1.00; 95% CI, 0.75 to 1.35) (Fig. The adjusted mean change from baseline was 1.33 points (95% CI, 2.47 to 0.19) in the olaparib group (498 patients) and 2.89 points (95% CI, 4.52 to 1.26) in the placebo group (246 patients) (Fig. The hazard ratio and associated 95% confidence interval were calculated with the use of a stratified Cox proportional-hazards model. Ovarian cancer clinical trial endpoints: Society of Gynecologic Oncology white paper. NEW! Grade 1 or 2 pneumonitis, interstitial lung disease, or bronchiolitis occurred in 6 patients (1%) in the olaparib group and no patients in the placebo group. Nature 2011;474:609-615. Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer, In patients with advanced ovarian cancer receiving first-line standard therapy including bevacizumab, the addition of maintenance olaparib provided a significant progression-free survival benefit, which was substantial in patients with HRD-positive tumors, including those without a. Characteristics of the Patients at Baseline. The content of this site is intended for health care professionals. The primary analysis of investigator-assessed progression-free survival was performed after 474 of 806 patients had had disease progression or had died (data maturity, 59%) (data cutoff, March 22, 2019). Burger RA, Brady MF, Bookman MA, et al. Among the patients with HRD-positive tumors, as defined by a tumor HRD score of 42 or higher or a tumor BRCA mutation (prespecified subgroup analysis) (Panel C), the KaplanMeier estimate of the percentage of patients who were free from disease progression and death at 24 months was 66% in the olaparib-plus-bevacizumab group and 29% in the placebo-plus-bevacizumab group. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. Cancer Genome Atlas Research Network. In patients with HRD-positive tumors that did not have BRCA mutations, the median progression-free survival was 28.1 months in the olaparib group and 16.6 months in the placebo group (hazard ratio for disease progression or death, 0.43; 95% CI, 0.28 to 0.66) (Figure 3D). NA denotes not available. The data include patients with leukopenia or a decreased white-cell count. Fatal adverse events occurred during the trial intervention or up to 30 days after discontinuation of the intervention in 1 of 535 patients (<1%) in the olaparib group and in 4 of 267 patients (1%) in the placebo group. Adverse Events with Olaparib or Placebo in Patients Also Receiving Bevacizumab. We thank the investigators and the staff of the nine groups that make up the European Network for Gynecological Oncological Trial Groups (see the Supplementary Appendix) who contributed to this trial; Sbastien Armanet, Sylvie Mijonnet, Christine Montoto-Grillot, Aurlie Morvan, Kardiatou Thiam-Kieffer, and Bndicte Votan from ARCAGY for assistance with coordinating the trial; Sophie Perrin Brutto and Aude Lasfargues from Ascopharm Groupe Novasco for monitoring and data management; the staff of Centre de Ressources Biologiques dARCAGYGINECO (Institut Curie), the staff of the screening platforms from Institut Curie, Gustave Roussy, Assistance PubliqueHpitaux de Paris, and Institut Bergoni, Centre Franois Baclesse, the French National Cancer Institute, and Sylvie Chabaud, Claire Cropet, and Laure Montan from Centre Lon Brard for statistical analyses; Amlie Anota for assistance with the quality-of-life analyses; the members of the independent data monitoring committee: Jan Vermorken, Stan Kaye, and Gregory Pond; Gillian Keating from Mudskipper for medical writing assistance with an earlier version of the manuscript; and all the women who participated in this trial and their families. In patients with HRD-negative tumors or whose tumor HRD status was unknown (total, 419 patients), the median progression-free survival was 16.9 months in the olaparib group and 16.0 months in the placebo group (hazard ratio for disease progression or death, 0.92; 95% CI, 0.72 to 1.17) (Fig. KaplanMeier Estimates of Investigator-Assessed Progression-free Survival. ), Universittsklinikum Essen (P.B. Administering maintenance olaparib in addition to bevacizumab to patients with newly diagnosed advanced ovarian cancer who were receiving standard treatment including bevacizumab resulted in a significant progression-free survival benefit, with a substantial benefit in patients with HRD-positive tumors. Ledermann JA, Harter P, Gourley C, et al. Analyses of secondary efficacy end points used a method similar to that used in the progression-free survival analysis. Concise summaries and expert physician commentary that busy clinicians need to enhance patient care. S4). The hazard ratio (olaparib group vs. placebo group) for disease progression or death was 0.33 (95% CI, 0.25 to 0.45) in patients with tumors positive for homologous-recombination deficiency (HRD), including tumors that had BRCA mutations (median progression-free survival, 37.2 vs. 17.7 months), and 0.43 (95% CI, 0.28 to 0.66) in patients with HRD-positive tumors that did not have BRCA mutations (median progression-free survival, 28.1 vs. 16.6 months). The most common adverse events (all grades) that occurred at a higher incidence among patients receiving olaparib plus bevacizumab than among those receiving placebo plus bevacizumab were fatigue, nausea, and anemia (. All efficacy data were summarized and analyzed in the intention-to-treat population, which included all the patients who had undergone randomization, regardless of the intervention received. 13. However, owing to late diagnosis with advanced-stage disease, the vast majority of patients have a relapse (after a median of 10 to 18 months),1,2 despite being treated with cytoreductive surgery and platinum-based chemotherapy.3, The addition of the antiangiogenic agent bevacizumab to carboplatin plus paclitaxel, followed by bevacizumab alone, is a standard option in patients with newly diagnosed advanced ovarian cancer.1,2,4-7 Recently, in the phase 3 SOLO1 trial, the poly(adenosine diphosphateribose) polymerase (PARP) inhibitor olaparib provided a substantial progression-free survival benefit as maintenance monotherapy in patients with newly diagnosed advanced ovarian cancer whose tumors had a BRCA1 or BRCA2 mutation (BRCA mutation) and who had a complete or partial clinical response after platinum-based chemotherapy (hazard ratio for disease progression or death, 0.30; 95% confidence interval [CI], 0.23 to 0.41; P<0.001).8. Eligible patients were 18 years of age or older and had newly diagnosed advanced (International Federation of Gynecology and Obstetrics [FIGO] stage III or IV), high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian-tube cancer. Cocks K, King MT, Velikova G, et al. ), Institut Curie, Hpital Claudius Rgaud (M.R. Evidence-based guidelines for interpreting change scores for the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30. OConnor MJ. 6. Lancet Oncol 2014;15:1207-1214. The trial was designed by the European Network for Gynecological Oncological Trial Groups (ENGOT) lead group, Groupe dInvestigateurs Nationaux pour lEtude des Cancers Ovariens, and sponsored by Association de Recherche Cancers Gyncologiques (ARCAGY) Research, according to the ENGOT model A (academic sponsor; details of this research model are provided in the Supplementary Appendix).18,19 ARCAGY Research was responsible for overseeing the collection, analysis, and interpretation of the data. The statistical analysis plan is available with the protocol at NEJM.org. Among the patients without a tumor BRCA mutation (prespecified subgroup analysis) (Panel B), the KaplanMeier estimate of the percentage of patients who were free from disease progression and death at 24 months was 33% in the olaparib-plus-bevacizumab group and 23% in the placebo-plus-bevacizumab group. The KaplanMeier method was used to estimate progression-free survival, with the stratified log-rank test used to assess the difference between the olaparib group and the placebo group. Herzog TJ, Armstrong DK, Brady MF, et al. Eur J Cancer 2012;48:1713-1721. We conducted a randomized, double-blind, international phase 3 trial. Overall survival data are immature. The lack of a maintenance olaparib monotherapy comparator group is a limitation of the PAOLA-1 trial, making it difficult to conclude whether the progression-free survival benefit seen in patients with HRD-positive tumors without BRCA mutations (who were not included in the SOLO1 trial) was due largely to the addition of olaparib or whether a synergistic effect occurred with olaparib and bevacizumab. Results of subgroup analyses of progression-free survival showed a benefit in the majority of predefined subgroups (Figure 2). Peer-reviewed journal featuring in-depth articles to accelerate the transformation of health care delivery. After first-line treatment with platinumtaxane chemotherapy plus bevacizumab, patients were required to have no evidence of disease or to have had a clinical complete or partial response (definitions in Table 1). N Engl J Med 2011;365:2484-2496. Colombo N, Sessa C, du Bois A, et al. 20. In this analysis, we used the electronic case-report form data set, except for the prespecified HRD analysis, which used the Myriad myChoice Plus HRD test. 5. Anderson Cancer Center Madrid (A.G.-M.), Grupo Espaol de Investigacin en Cncer de Ovario (GEICO) (A.G.-M., E.M.G.A. A benefit was also seen in patients whose tumor HRD status was unknown, such as those with failed tests or insufficient tumor samples. A total of 535 of the 537 patients assigned to olaparib plus bevacizumab (olaparib group) and 267 of the 269 patients assigned to placebo plus bevacizumab (placebo group) received the trial intervention; 2 patients in each group withdrew before receiving the trial intervention (Fig. Clinical complete response was defined as the disappearance of all measurable or assessable disease and normalization of CA-125 levels. Patients were eligible regardless of surgical outcome or BRCA mutation status. The most common adverse event (all grades) that occurred at a higher incidence among patients receiving placebo plus bevacizumab than among those receiving olaparib plus bevacizumab was hypertension (Table 2). Stay connected to what's important in medical research and clinical practice, Subscribe to the most trusted and influential source ofmedical knowledge. ), and Kliniken Essen Mitte (P.H. Contextual synthetic lethality of cancer cell kill based on the tumor microenvironment. *Percentages may not total 100 because of rounding. ), Hpital Europen Georges Pompidou (P.C. ), Essen, Universittsklinikum Carl Gustav Carus, Technische Universitt Dresden, Dresden (U.C. Ledermann J, Harter P, Gourley C, et al. Although HRD subgroup analyses were prespecified, they were not part of the multiple-testing procedure for this trial. Tumor HRD status was determined for 82% of the tumor samples. (Funded by ARCAGY Research and others; PAOLA-1 ClinicalTrials.gov number, NCT02477644. Thrombocytopenia occurred in less than 10% of the patients in each trial group, but the data are provided to complete the profile of hematologic toxic effects. Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer. 3. J Clin Oncol 2019;37:2317-2328. Information and tools for librarians about site license offerings. Details of discontinuation criteria and methods for unblinding are provided in the Supplementary Appendix. Details of trial end points and analyses are provided in the Supplementary Appendix. The estimated between-group difference was 1.56 points (95% CI, 0.42 to 3.55). Tewari KS, Burger RA, Enserro D, et al. Liu JF, Barry WT, Birrer M, et al. Mol Cell 2015;60:547-560. The primary end point was the time from randomization until investigator-assessed disease progression or death. Adverse events were usually managed by dose modification rather than discontinuation (Table 2). The trial met its primary objective by showing a significant progression-free survival benefit in the intention-to-treat population. Ann Oncol 2017;28:711-717. A phase 3 trial of bevacizumab in ovarian cancer. Final overall survival of a randomized trial of bevacizumab for primary treatment of ovarian cancer. 2. In patients without a tumor BRCA mutation, the median progression-free survival was 18.9 months in the olaparib group and 16.0 months in the placebo group (hazard ratio for disease progression or death, 0.71; 95% CI, 0.58 to 0.88) (Figure 3B). In the phase 3 PAOLA-1 trial, we evaluated maintenance therapy with the PARP inhibitor olaparib as compared with placebo in patients with newly diagnosed advanced ovarian cancer who were receiving chemotherapy and bevacizumab followed by bevacizumab. Patients were randomly assigned in a 2:1 ratio to receive olaparib (300 mg twice daily) or placebo at least 3 weeks and no more than 9 weeks after the last dose of chemotherapy. The most common adverse events leading to discontinuation of olaparib were anemia and nausea (Table S7). S3B.). ), Lyon, Groupe dInvestigateurs Nationaux pour lEtude des Cancers Ovariens (GINECO) (I.R.-C., P.P., F.S., C.L.-P., A.L., P.C., M.R., C.D., B.Y., E.P.-L.), Groupe Hospitalier Diaconesses Croix Saint-Simon (F.S. ), University of MilanBicocca and European Institute of Oncology IRCCS, and Mario Negri Gynecologic Oncology Group (MANGO) (N.C.), and Fondazione IRCCS Istituto Nazionale Tumori and MITO (D.L. all in Germany. all in Italy; M.D. 22. Ledermann JA, Raja FA, Fotopoulou C, Gonzalez-Martin A, Colombo N, Sessa C. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24:Suppl 6:vi24-vi32. Mutations in homologous recombination genes and outcomes in ovarian carcinoma patients in GOG 218: an NRG Oncology/Gynecologic Oncology Group study. Serious adverse events occurred in 31% of the patients in both trial groups (Table S6). As part of the intervention, intravenous bevacizumab was initiated in combination with chemotherapy and was continued after randomization as maintenance therapy at a dose of 15 mg per kilogram of body weight every 3 weeks for a total duration of up to 15 months. all in Japan; University Hospital Leuven, Leuven Cancer Institute, and Belgium and Luxembourg Gynecologic Oncology Group (BGOG) both in Leuven, Belgium (I.V. European Network of Gynaecological Oncological Trial Groups requirements for trials between academic groups and pharmaceutical companies. Myelodysplastic syndromes, acute myeloid leukemia, or aplastic anemia occurred in 6 of 535 patients (1%) receiving olaparib plus bevacizumab and in 1 of 267 patients (<1%) receiving placebo plus bevacizumab. ), and Hyogo Cancer Center, Akashi (S.N.) 24. Mirza MR, Monk BJ, Herrstedt J, et al. Lancet Oncol 2016;17:1579-1589. ); the Nordic Society of Gynecologic Oncology (NSGO), Copenhagen (J.M. Clin Cancer Res 2018;24:777-783. Lancet Oncol 2017;18:1274-1284. N Engl J Med 2011;365:2473-2483. Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer: a randomized controlled chemotherapy-free study NSGO-AVANOVA2/ENGOT-OV24. Randomization was performed centrally with the use of a block design with stratification according to the outcome of first-line treatment at screening and tumor BRCA status (see the Supplementary Appendix). *Data are shown for adverse events that occurred in at least 10% of the patients in either trial group (except where noted) during the trial intervention or up to 30 days after discontinuation of the intervention. Administration of olaparib or placebo continued for up to 24 months from randomization or until disease progression (according to investigators assessment of imaging based on the modified Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1) or unacceptable toxic effects, whichever occurred first, as long as the patient had a benefit and did not meet other discontinuation criteria. A hierarchical-testing procedure was used to control for type I error at 5% for progression-free survival, second progressionfree survival, and overall survival, in that order. The most common adverse events and the incidence of associated grade 3 or higher adverse events for the entire maintenance treatment period are shown in Table 2 and Table S5. CA-125 denotes cancer antigen 125, and HRD homologous-recombination deficiency. S3C). Subgroup Analysis of Progression-free Survival. 23. December 19, 2019N Engl J Med 2019; 381:2416-2428 A total of 30% of the patients had a deleterious tumor BRCA mutation. The adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. CA-125 denotes cancer antigen 125, CR complete response, ECOG Eastern Cooperative Oncology Group, FIGO International Federation of Gynecology and Obstetrics, NED no evidence of disease, PR partial response, and ULN upper limit of the normal range. The baseline characteristics were well balanced between the trial groups (Table 1 and Tables S2 through S4). Details on the International Federation of Gynecology and Obstetrics (FIGO) staging system are provided in Table S1 in the Supplementary Appendix. Address reprint requests to Dr. Ray-Coquard at Centre Lon Brard, 28 Prom. The data include patients with anemia, a decreased hemoglobin level, a decreased hematocrit, a decreased red-cell count, erythropenia, macrocytic anemia, normochromic anemia, normochromic normocytic anemia, or normocytic anemia. The most common adverse events (all grades) that occurred at a higher incidence among patients receiving olaparib plus bevacizumab than among those receiving placebo plus bevacizumab were fatigue, nausea, and anemia (Table 2). 18. 19. du Bois A, Reuss A, Pujade-Lauraine E, et al. Vergote I, Pujade-Lauraine E, Pignata S, et al. Analyses of health-related quality of life used an imputation-based approach for missing questionnaires. Supported by Association de Recherche Cancers Gyncologiques (ARCAGY) Research, AstraZeneca, Merck Sharp & Dohme (a subsidiary of Merck), and F. HoffmannLa Roche. Patients with other nonmucinous epithelial ovarian cancers were eligible, provided they had a deleterious germline BRCA1 or BRCA2 mutation. Patients were randomly assigned in a 2:1 ratio to receive olaparib tablets (300 mg twice daily) or placebo for up to 24 months; all the patients received bevacizumab at a dose of 15 mg per kilogram of body weight every 3 weeks for up to 15 months in total. The median duration of follow-up for the primary analysis was 22.7 months (range, 18.0 to 27.7) in the olaparib group and 24.0 months (range, 18.7 to 27.7) in the placebo group; the median duration of follow-up in the combined groups was 22.9 months.
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