20. N Engl J Med 2018;379:2495-2505. 3. Mirza MR, Monk BJ, Herrstedt J, et al. European Network of Gynaecological Oncological Trial Groups requirements for trials between academic groups and industry partners first update 2015. 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. all in Madrid; Medical University of Innsbruck, University Clinic for Gynecology and Obstetrics (R.B. Mirza MR, Avall-Lundqvist E, Birrer MJ, et al. Prespecified subgroup analyses showed a progression-free survival benefit with olaparib in patients with BRCA-mutated and HRD-positive tumors. Karam A, Ledermann JA, Kim JW, et al. 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). Eastern Cooperative Oncology Group (ECOG) performance status ranges from 0 to 5, with higher values reflecting greater disability. The most common adverse events leading to discontinuation of olaparib were anemia and nausea (Table S7). 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). Prepare to become a physician, build your knowledge, lead a health care organization, and advance your career with NEJM Group information and services. 10. Stay connected to what's important in medical research and clinical practice, Subscribe to the most trusted and influential source ofmedical knowledge. All the patients provided written informed consent. 7. 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). 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 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). Unknown was defined as an inconclusive, missing, or failed test. The data include patients with thrombocytopenia, decreased platelet production, a decreased platelet count, or a decreased plateletcrit. Adverse events were graded with the use of the CTCAE, version 4.03. 16. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were having a response after first-line platinumtaxane chemotherapy plus bevacizumab. The outcome of first-line treatment at screening was determined according to the electronic case-report form. 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. ), Centre Eugne Marquis, Rennes (C.L.-P.), Centre Catherine de Sienne Hpital Priv du Confluent, Nantes (A.L. Dr. Ray-Coquard reports receiving consulting fees and travel support from Roche and AstraZeneca, consulting fees from PharmaMar, Genmab, Pfizer, Tesaro, and Clovis Oncology, and grant support and consulting fees from Merck Sharp & Dohme; Dr. Pautier, receiving advisory board fees from AstraZeneca; Dr. Pignata, receiving honoraria from AstraZeneca, Roche, Merck Sharp & Dohme, Pfizer, Tesaro, Clovis Oncology, and PharmaMar; Dr. Prol, receiving fees for training and advisory fees from Roche, fees for training, advisory fees, and travel support from AstraZeneca, and grant support from MSDAVENIR; Dr. Gonzlez-Martn, receiving consulting fees, lecture fees, and travel support from AstraZeneca and PharmaMar, grant support, consulting fees, lecture fees, and travel support from Tesaro and Roche, and consulting fees from Clovis Oncology, Merck Sharp & Dohme, Pfizer, ImmunoGen, Genmab, and Novartis; Dr. Berger, receiving travel support from Roche, Merck, Biocad, Clovis Oncology, and Advaxis, lecture fees and travel support from AstraZeneca, and advisory board fees from PharmaMar; Dr. Fujiwara, receiving grant support from Kaken Pharmaceutical, Shionogi, GlaxoSmithKline, Eli Lilly, ImmunoGen, OncoTherapy Science, and Regeneron Pharmaceuticals, grant support and consulting fees from Pfizer, Eisai, and Taiho, grant support, consulting fees, and honoraria from Merck Sharp & Dohme, grant support and honoraria from Zeria Pharmaceutical, and honoraria from Nippon Kayaku, Kyowa Hakko Kirin, Janssen, Daiichi Sankyo, and Mochida Pharmaceutical; Dr. Vergote, receiving consulting fees, paid to his institution, from Advaxis, Eisai, Merck Sharp & Dohme Belgium, F. HoffmannLa Roche, Millennium Pharmaceuticals, Oncoinvent, and Sotio, consulting fees, paid to his institution, and travel support from Roche, Genmab, PharmaMar, Clovis Oncology, AstraZeneca, Tesaro, and ImmunoGen, grant support, paid to his institution, from Amgen, Stichting tegen Kanker, and Roche, research support from Oncoinvent and Genmab, and travel support from Takeda Oncology; Dr. Colombo, receiving advisory board fees from Roche, Clovis Oncology, Pfizer, Merck Sharp & Dohme, Biocad, ImmunoGen, and Takeda and advisory board fees and lecture fees from AstraZeneca, Tesaro, and PharmaMar; Dr. Menp, receiving consulting fees from AstraZeneca, Clovis Oncology, Merck Sharp & Dohme, and Orion Pharma and consulting fees and travel support from Roche and Tesaro; Dr. Selle, receiving consulting fees, lecture fees, fees for serving on a speakers bureau, and travel support from Roche, lecture fees, fees for serving on a speakers bureau, and travel support from AstraZeneca, Tesaro, and PharmaMar, lecture fees from Clovis Oncology, and lecture fees and travel support from Merck Sharp & Dohme; Dr. Sehouli, receiving advisory board fees and travel support from AstraZeneca and grant support, advisory board fees, and travel support from Clovis Oncology, Tesaro, and Roche; Dr. Lorusso, receiving grant support and advisory board fees from ImmunoGen, Genmab, PharmaMar, Clovis Oncology, Tesaro, Merck, and AstraZeneca; Dr. Guerra Ala, receiving consulting fees, advisory board fees, and travel support from Roche, consulting fees and advisory board fees from Clovis Oncology, Tesaro, PharmaMar, AstraZeneca, Merck Sharp & Dohme, and GlaxoSmithKline, and travel support from Baxter and GlaxoSmithKline/Tesaro; Dr. Reinthaller, receiving grant support, lecture fees, advisory board fees, and travel support from Roche, lecture fees, advisory board fees, and travel support from Amgen, AstraZeneca, PharmaMar, and Tesaro, and lecture fees and advisory board fees from Merck Sharp & Dohme and Vifor Pharma; Dr. Nagao, receiving grant support from PFDeNA, Tosoh, and Toray and lecture fees from Chugai, AstraZeneca, Mochida Pharmaceutical, and Asahi Kasei Medical; Dr. Lefeuvre-Plesse, receiving advisory board fees from AstraZeneca and participating in a medical congress for Novartis, Pfizer, Roche, and Pierre Fabre; Dr. Canzler, receiving honoraria from AstraZeneca, Roche, and Eli Lilly; Dr. Scambia, receiving honoraria from AstraZeneca, Tesaro, and Roche; Dr. Lortholary, receiving advisory board fees from AstraZeneca and participating in a medical congress for Novartis, Pfizer, and Roche; Dr. Marm, receiving fees for serving as principal investigator of a clinical trial, advisory board fees, and lecture fees from Pfizer, Tesaro, and Novartis, advisory board fees and lecture fees from Amgen, PharmaMar, Genomic Health, Eisai, and Celgene, advisory board fees from CureVac and Janssen-Cilag, and advisory board fees, paid to his institution, from Immunomedics; Dr. de Gregorio, receiving advisory fees from Roche, PharmaMar, and Amgen and advisory fees and travel support from AstraZeneca and Tesaro; Dr. Rodrigues, receiving travel support from F. HoffmannLa Roche, advisory board fees and lecture fees from AstraZeneca, advisory board fees and travel support from Tesaro, and grant support from Bristol-Myers Squibb and Merck; Dr. Buderath, receiving advisory board fees and travel support from Roche and travel support from PharmaMar; Dr. Burges, receiving consulting fees and lecture fees from AstraZeneca, Tesaro, and Roche; Dr. You, receiving consulting fees, advisory board fees, and travel support from and participating in a medical congress for AstraZeneca, Merck Sharp & Dohme, and Bayer and receiving consulting fees and advisory board fees from Tesaro, Clovis Oncology, Amgen, Novartis, Roche, and ECS Progastrin; Dr. Pujade-Lauraine, receiving lecture fees, fees for serving on a speakers bureau, and travel support from AstraZeneca, Tesaro, and Roche, receiving lecture fees from Clovis Oncology, Incyte, and Pfizer, and being employed by ARCAGY Research; and Dr. Harter, receiving consulting fees from Sotio, Merck Sharp & Dohme, Clovis Oncology, and ImmunoGen, grant support, consulting fees, and lecture fees from Tesaro, AstraZeneca, and Roche, lecture fees from Stryker and Zai Lab, and grant support from GlaxoSmithKline, Boehringer Ingelheim, Medac, Genmab, and Deutsche Forschungsgemeinschaft. 23. 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. 17. Serious adverse events occurred in 31% of the patients in both trial groups (Table S6). 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. 19. du Bois A, Reuss A, Pujade-Lauraine E, et al. Information, resources, and support needed to approach rotations - and life as a resident. 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. A list of the PAOLA-1 principal investigators is provided in the Supplementary Appendix, available at NEJM.org. 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. ), and Kliniken Essen Mitte (P.H. 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. Tumor HRD status was determined with the use of the myChoice HRD Plus assay (Myriad Genetic Laboratories). Lancet Oncol 2017;18:1274-1284. Adverse events occurring only in the time period when bevacizumab was being administered as maintenance therapy are summarized in Table S8.

HRD positive was defined as a tumor BRCA mutation or an HRD score of 42 or higher on the myChoice HRD Plus assay (Myriad Genetic Laboratories). S1). The most trusted, influential source of new medical knowledge and clinical best practices in the world. A phase 3 trial of bevacizumab in ovarian cancer. Supported by Association de Recherche Cancers Gyncologiques (ARCAGY) Research, AstraZeneca, Merck Sharp & Dohme (a subsidiary of Merck), and F. HoffmannLa Roche. Overall survival data are immature. ), and Association de Recherche Cancers Gyncologiques (ARCAGY) (E.P.-L.), Paris, Gustave Roussy, Villejuif (P.P. The data include patients with a decreased lymphocyte count, lymphopenia, a decreased B-lymphocyte count, or a decreased T-lymphocyte count. 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. Vergote I, Pujade-Lauraine E, Pignata S, et al. 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. NEW! Details on the International Federation of Gynecology and Obstetrics (FIGO) staging system are provided in Table S1 in the Supplementary Appendix. 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. The results in patients with HRD-positive tumors without a BRCA mutation (comprising nearly 20% of the PAOLA-1 population, which is broadly consistent with expectations)10 identify another patient population who had a substantial clinical benefit from olaparib. Olaparib has shown significant clinical benefit as maintenance therapy in women with newly diagnosed advanced ovarian cancer with a BRCA mutation. The estimated between-group difference was 1.56 points (95% CI, 0.42 to 3.55). Adverse Events with Olaparib or Placebo in Patients Also Receiving Bevacizumab. 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. ), Institut Curie, Hpital Claudius Rgaud (M.R. The incidence of myelodysplastic syndromes, acute myeloid leukemia, or aplastic anemia among patients with newly diagnosed disease in the PAOLA-1 trial (1% in the olaparib group and <1% in the placebo group) was similar to that reported in the SOLO1 trial8 and in trials involving patients with relapsed disease.12,13,24,25 Greater understanding and prospective registries are needed to determine the characteristics of patients at risk for these rare, but potentially fatal, hematologic disturbances. Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup: first-line interventions. The most advanced way to teach, practice, and assess clinical reasoning skills. 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. Patients were eligible irrespective of previous surgical outcome (residual macroscopic disease or no residual macroscopic disease after upfront or interval surgery).

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. 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). 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).

), Newly diagnosed advanced ovarian cancer is treated with curative intent. The primary end point was the time from randomization until investigator-assessed disease progression or death. Patients with other nonmucinous epithelial ovarian cancers were eligible, provided they had a deleterious germline BRCA1 or BRCA2 mutation. ), Innsbruck, and Medical University of Vienna, Vienna (A.R.) 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 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. From Centre Lon Brard (I.R.-C., D.P. Patients had an Eastern Cooperative Oncology Group performance status of 0 or 1 (on a 5-point scale in which higher numbers reflect greater disability), and a tumor sample had to be available for central testing to determine BRCA mutation status. Other was defined as clear-cell (in 2 patients assigned to olaparib plus bevacizumab), undifferentiated (in 1 patient assigned to olaparib plus bevacizumab and 6 patients assigned to placebo plus bevacizumab), or other (in 3 patients assigned to olaparib plus bevacizumab and 2 patients assigned to placebo plus bevacizumab). all in Germany. Colombo N, Sessa C, du Bois A, et al. 15. Adverse events were consistent with the established safety profiles of olaparib and bevacizumab. 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. The trial met its primary objective by showing a significant progression-free survival benefit in the intention-to-treat population. Coleman RL, Oza AM, Lorusso D, et al. N Engl J Med 2016;375:2154-2164. Pujade-Lauraine E, Ledermann JA, Selle F, et al. HRD negative was defined as an HRD score of less than 42. The trial was designed to detect a treatment effect (hazard ratio for disease progression or death) of 0.75, translating to an improvement in median progression-free survival from 15.8 months in the placebo group to 21.1 months in the olaparib group20; 458 primary end-point events (disease progression or death) would give the trial more than 80% power at a two-sided significance level of 5% to show a significant difference in progression-free survival between the olaparib group and the placebo group. This article was updated on February 19, 2020, at NEJM.org. 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). NEW! The content of this site is intended for health care professionals. The trial met its primary objective by showing a significant progression-free survival benefit in the intention-to-treat population.

), Universittsklinikum Essen (P.B. 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. all in Austria; Saitama Medical University International Medical Center, Hidaka (K.F. The trial was performed in accordance with the provisions of the Declaration of Helsinki and Good Clinical Practice guidelines under the auspices of an independent data monitoring committee. Norquist BM, Brady MF, Harrell MI, et al. 18. The most common serious adverse event that occurred at a higher incidence with olaparib plus bevacizumab than with placebo plus bevacizumab was anemia (34 patients [6%] in the olaparib group and 1 patient [<1%] in the placebo group). all in Italy; M.D. The duration of investigator-assessed progression-free survival was significantly longer in the olaparib group than in the placebo group (median, 22.1 months vs. 16.6 months; hazard ratio for disease progression or death, 0.59; 95% CI, 0.49 to 0.72; P<0.001) (Figure 1). Patients in the PAOLA-1 trial had a higher disease burden, with a lower percentage of patients undergoing upfront cytoreductive surgery (51%, vs. 63% in the SOLO1 trial) and a higher percentage of patients having residual macroscopic disease after cytoreductive surgery (35% vs. 22%) and stage IV disease (30% vs. 17%). Integrated genomic analyses of ovarian carcinoma. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. The baseline characteristics were well balanced between the trial groups (Table 1 and Tables S2 through S4). Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. 1. Chan N, Pires IM, Bencokova Z, et al. Int J Gynecol Cancer 2015;25:1328-1330. An HRD score of 42 or higher indicated a positive test, and an HRD score of less than 42 indicated a negative test. 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). The median time until the first subsequent treatment for all patients was 24.8 months in the olaparib group and 18.5 months in the placebo group (hazard ratio, 0.59; 95% CI, 0.49 to 0.71). Lancet Oncol 2016;17:1579-1589. Details of BRCA testing and full eligibility criteria are provided in the Supplementary Appendix. A total of 30% of the patients had a deleterious tumor. Subgroup Analysis of Progression-free Survival. Eur J Cancer 2012;48:1713-1721. All subgroups presented here were predefined, except for two post hoc subgroups: homologous-recombination deficiency (HRD) negative or unknown and HRD unknown. Patients were eligible irrespective of previous surgical outcome (residual macroscopic disease or no residual macroscopic disease after upfront or interval surgery).

Nature 2011;474:609-615. Results of subgroup analyses of progression-free survival showed a benefit in the majority of predefined subgroups (Figure 2). The most common adverse events leading to discontinuation of olaparib were anemia and nausea (Table S7). Cocks K, King MT, Velikova G, et al. Moore K, Colombo N, Scambia G, et al. Ledermann J, Harter P, Gourley C, et al. Subgroup analyses of progression-free survival and a blinded independent central review of progression-free survival were performed. ); Tampere University and University Hospital, Tampere, Finland (J.M. The primary end point was the time from randomization until investigator-assessed disease progression or death.

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