paola-1 clinicaltrials gov

N Engl J Med 2011;365:2484-2496. 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. 1. 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. The PAOLA-1 population was representative of the majority of patients with advanced ovarian cancer because patient selection was not restricted on the basis of surgical outcome or, 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, Case Records of the Massachusetts General Hospital, Monkeypox Virus Infection in Humans across 16 Countries AprilJune 2022, Protection Associated with Previous SARS-CoV-2 Infection in Nicaragua, Nirmatrelvir for Nonhospitalized Adults with Covid-19, Efficacy of Antibodies and Antiviral Drugs against Omicron BA.2.12.1, BA.4, and BA.5 Subvariants, Effectiveness of BNT162b2 Vaccine against Omicron in Children 5 to 11 Years of Age, Evidence for Step Therapy in Diabetic Macular Edema, Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults, Case 23-2022: A 49-Year-Old Man with Hypoglycemia, Trial of Anti-BDCA2 Antibody Litifilimab for Cutaneous Lupus Erythematosus, Overall Survival with Brentuximab Vedotin in Stage III or IV Hodgkins Lymphoma, NEJM Catalyst Innovations in Care Delivery. ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease. all in France; the Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, and Multicenter Italian Trials in Ovarian Cancer and Gynecologic Malignancies (MITO), Naples (S.P. ), and Institut Curie, Hpital Ren Huguenin, Saint Cloud (C.D.) In this trial, the progression-free survival benefit seen with olaparib plus bevacizumab in patients with BRCA-mutated tumors (hazard ratio for disease progression or death, 0.31; 95% CI, 0.20 to 0.47) is consistent with that observed in the SOLO1 trial (hazard ratio, 0.30; 95% CI, 0.23 to 0.41),8 despite the improved outcome of the control group in our trial (median progression-free survival, 21.7 months with placebo plus bevacizumab in the PAOLA-1 trial and 13.8 months with placebo in the SOLO1 trial), which may be due to the addition of bevacizumab or to differences in patient selection.22 Caution is needed when comparing outcomes between patients in the SOLO1 trial and patients with BRCA-mutated tumors in the PAOLA-1 trial because of differences between the two trials, including in baseline characteristics (Table S3). 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). HRD negative was defined as an HRD score of less than 42. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. A total of 30% of the patients had a deleterious tumor. 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. After discontinuation of the intervention, patients could receive other treatments at the investigators discretion. Eur J Cancer 2012;48:1713-1721. AstraZeneca, Merck Sharp & Dohme (a subsidiary of Merck), and F. HoffmannLa Roche were given the opportunity to review drafts of the manuscripts but were not asked to approve the final content because this was an academic-sponsored trial. 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. ), and Klinikum der Universitt Mnchen, Munich (A.B.) Analyses of secondary efficacy end points used a method similar to that used in the progression-free survival analysis. Details of discontinuation criteria and methods for unblinding are provided in the Supplementary Appendix. Tewari KS, Burger RA, Enserro D, et al. *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. 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. Lancet Oncol 2017;18:1274-1284. 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). Lancet Oncol 2016;17:1579-1589. Peer-reviewed journal featuring in-depth articles to accelerate the transformation of health care delivery. CA-125 denotes cancer antigen 125, and HRD homologous-recombination deficiency. S1). The gray band represents the 95% confidence interval for the overall population, and the dashed line indicates the point of no effect. S3B.). 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. The randomization of 762 patients would result in data being mature once approximately 60% of the patients had had disease progression or had died; an additional 24 patients underwent randomization in Japan. DOI: 10.1056/NEJMoa1911361, Tap into groundbreaking research and clinically relevant insights. Previously defined toxic effects of olaparib and bevacizumab were noted, and rare serious hematologic and mild-to-moderate pulmonary toxic effects also occurred. The data include patients with thrombocytopenia, decreased platelet production, a decreased platelet count, or a decreased plateletcrit. The addition of olaparib to bevacizumab did not increase the known toxic effects associated with bevacizumab. ), Centre Eugne Marquis, Rennes (C.L.-P.), Centre Catherine de Sienne Hpital Priv du Confluent, Nantes (A.L. 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 CharitMedical University of Berlin (Campus Virchow Klinikum), Berlin (J.S. The median duration of treatment with bevacizumab since randomization was 11.0 months (range, 0.7 to 21.4) in the olaparib group and 10.6 months (range, 0.7 to 17.1) in the placebo group. Stay connected to what's important in medical research and clinical practice, Subscribe to the most trusted and influential source ofmedical knowledge. According to preclinical data, hypoxia that is induced by an antiangiogenic treatment can induce, or at least increase, HRD,23 which means that bevacizumab may increase the activity of olaparib in patients with HRD-positive tumors and, in particular, patients with HRD-positive tumors without a BRCA mutation; this hypothesis requires further exploration. Lancet Oncol 2015;16:928-936. A total of 30% of the patients had a deleterious tumor BRCA mutation. Liu JF, Barry WT, Birrer M, et al. From July 2015 through September 2017, a total of 806 patients underwent randomization. The primary end point was the time from randomization until investigator-assessed disease progression or death. Although HRD subgroup analyses were prespecified, they were not part of the multiple-testing procedure for this trial. Valuable tools for building a rewarding career in health care. No evidence of disease was defined as no measurable or assessable disease after cytoreductive surgery plus no radiologic evidence of disease and a normal CA-125 level after chemotherapy. All the major toxic effects that were associated with chemotherapy had to have resolved to grade 1 (according to the National Cancer Institute Common Terminology Criteria for Adverse Events [CTCAE], version 4.03) or had to have resolved completely (except alopecia and peripheral neuropathy). Ledermann JA, Harter P, Gourley C, et al. NEW! The PAOLA-1 population was representative of the majority of patients with advanced ovarian cancer because patient selection was not restricted on the basis of surgical outcome or BRCA mutation status. Ann Oncol 2017;28:711-717. NEW! There was no evidence of a meaningful difference in health-related quality of life between the trial groups. 15. Anderson Cancer Center Madrid (A.G.-M.), Grupo Espaol de Investigacin en Cncer de Ovario (GEICO) (A.G.-M., E.M.G.A. December 19, 2019N Engl J Med 2019; 381:2416-2428 9. Final overall survival of a randomized trial of bevacizumab for primary treatment of ovarian cancer. S4). **Partial response was defined as radiologic evidence of disease, an abnormal CA-125 level, or both. 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). The most common serious adverse event that occurred at a higher incidence with placebo plus bevacizumab than with olaparib plus bevacizumab was hypertension (35 patients [13%] in the placebo group and 48 patients [9%] in the olaparib group). No other potential conflict of interest relevant to this article was reported. Int J Gynecol Cancer 2010;20:476-478. all in Madrid; Medical University of Innsbruck, University Clinic for Gynecology and Obstetrics (R.B. Evidence-based guidelines for interpreting change scores for the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30.

Gynecol Oncol 2014;132:8-17. In order to show consistency of the treatment effect in prespecified subgroups, a preplanned progression-free survival analysis was performed in which the hazard ratio and 95% confidence interval were calculated with the use of an unstratified Cox model. The content of this site is intended for health care professionals. 23.

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. Prepare to become a physician, build your knowledge, lead a health care organization, and advance your career with NEJM Group information and services. In patients with tumors positive for HRD (tumor score of 42 on the myChoice HRD Plus assay or tumor BRCA mutation), the median progression-free survival was 37.2 months in the olaparib group and 17.7 months in the placebo group (hazard ratio for disease progression or death, 0.33; 95% CI, 0.25 to 0.45) (Figure 3C). Details of BRCA testing and full eligibility criteria are provided in the Supplementary Appendix. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial. 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 most effective and engaging way for clinicians to learn, improve their practice, and prepare for board exams. 25. ), Universittsklinikum Ulm, Ulm (N.G. Mirza MR, Monk BJ, Herrstedt J, et al. 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. 2. ), and Kliniken Essen Mitte (P.H. 5. Adverse events occurring only in the time period when bevacizumab was being administered as maintenance therapy are summarized in Table S8. 14. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. The safety profile of the olaparib group in the PAOLA-1 trial was generally consistent with that reported for olaparib in the SOLO1 trial8 and in patients with relapsed disease (phase 3 SOLO2 trial),24 with the notable exception of hypertension, a frequent toxic effect of bevacizumab, which was more common in the PAOLA-1 trial. After a median follow-up of 22.9 months, the median progression-free survival was 22.1 months with olaparib plus bevacizumab and 16.6 months with placebo plus bevacizumab (hazard ratio for disease progression or death, 0.59; 95% confidence interval [CI], 0.49 to 0.72; P<0.001). Shown are KaplanMeier estimates of the rate of freedom from disease progression, as assessed by investigators, and from death. Of the 806 patients who underwent randomization, 537 were assigned to receive olaparib and 269 to receive placebo. *Percentages may not total 100 because of rounding. KaplanMeier Estimates of Investigator-Assessed Progression-free Survival, According to Tumor, In patients with tumors positive for HRD (tumor score of 42 on the myChoice HRD Plus assay or tumor. S2) were consistent with the results of the primary analysis (median, 26.1 months in the olaparib group and 18.3 months in the placebo group; hazard ratio for disease progression or death, 0.63; 95% CI, 0.51 to 0.77). ), 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. Details of the statistical analyses are provided in the Supplementary Appendix. All the patients provided written informed consent. Subgroup analyses of progression-free survival and a blinded independent central review of progression-free survival were performed. Information, resources, and support needed to approach rotations - and life as a resident. 7. The most common adverse events leading to discontinuation of olaparib were anemia and nausea (Table S7). Pujade-Lauraine E, Ledermann JA, Selle F, et al. Serious adverse events occurred in 31% of the patients in both trial groups (Table S6). Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. J Clin Oncol 2019;37:Suppl:5505-5505. abstract. The effect of combining maintenance olaparib and bevacizumab in patients regardless of BRCA mutation status is unknown. Ann Oncol 2019;30:672-705. 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. ), Innsbruck, and Medical University of Vienna, Vienna (A.R.) The data include patients with neutropenia, febrile neutropenia, neutropenic sepsis, neutropenic infection, a decreased neutrophil count, idiopathic neutropenia, granulocytopenia, a decreased granulocyte count, or agranulocytosis. New primary cancers occurred in 7 of 535 patients (1%) in the olaparib group and in 3 of 267 patients (1%) in the placebo group. The trial met its primary objective by showing a significant progression-free survival benefit in the intention-to-treat population. The trial met its primary objective by showing a significant progression-free survival benefit in the intention-to-treat population. Lancet Oncol 2014;15:852-861. Norquist BM, Brady MF, Harrell MI, et al. Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup: first-line interventions. ), Universittsklinikum Essen (P.B. From Centre Lon Brard (I.R.-C., D.P. The most trusted, influential source of new medical knowledge and clinical best practices in the world. According to KaplanMeier estimates, the percentage of patients in the olaparib-plus-bevacizumab group and the placebo-plus-bevacizumab group who were free from disease progression and death was 78% and 66%, respectively, at 12 months; 62% and 46%, respectively, at 18 months; and 46% and 28%, respectively, at 24 months. Results of the analysis of progression-free survival as assessed by blinded independent review (Fig. 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. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. 16. The most common adverse events leading to discontinuation of olaparib were anemia and nausea (Table S7). Burger RA, Brady MF, Bookman MA, et al. 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. Concise summaries and expert physician commentary that busy clinicians need to enhance patient care. Karam A, Ledermann JA, Kim JW, et al. This article was updated on February 19, 2020, at NEJM.org. A total of 30% of the patients had stage IV disease, and most patients had no evidence of disease owing to complete cytoreduction or were having a complete response after first-line treatment. 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. 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.

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