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. 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. *Percentages may not total 100 because of rounding. 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. 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. The most trusted, influential source of new medical knowledge and clinical best practices in the world. 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. Crossover between the trial groups was not planned. Subgroup analyses of progression-free survival and a blinded independent central review of progression-free survival were performed. La et Napolon Bullukian, Lyon 69008, France, or at [emailprotected]. 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. The data include patients with thrombocytopenia, decreased platelet production, a decreased platelet count, or a decreased plateletcrit. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study.
Adverse events occurring only in the time period when bevacizumab was being administered as maintenance therapy are summarized in Table S8. J Clin Oncol 2019;37:Suppl:5505-5505. abstract.
None of these changes were considered to be clinically significant. 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.
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. 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. 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). 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. 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). The primary end point was the time from randomization until investigator-assessed disease progression or death. all in Madrid; Medical University of Innsbruck, University Clinic for Gynecology and Obstetrics (R.B. 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). There was no evidence of a meaningful difference in health-related quality of life between the trial groups.
The estimated between-group difference was 1.56 points (95% CI, 0.42 to 3.55). Tumor HRD status was determined with the use of the myChoice HRD Plus assay (Myriad Genetic Laboratories). Tewari KS, Burger RA, Enserro D, et al. Ann Oncol 2019;30:672-705. Prespecified subgroup analyses showed a progression-free survival benefit with olaparib in patients with BRCA-mutated and HRD-positive tumors. ), and Association de Recherche Cancers Gyncologiques (ARCAGY) (E.P.-L.), Paris, Gustave Roussy, Villejuif (P.P. The dashed horizontal line indicates the median value. 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. 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. Cancer Genome Atlas Research Network. Cnaan A, Laird NM, Slasor P. Using the general linear mixed model to analyse unbalanced repeated measures and longitudinal data. 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 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. ), Universittsklinikum Ulm, Ulm (N.G. Lancet 2017;390:1949-1961. 23. 25. 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. 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). 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).
From July 2015 through September 2017, a total of 806 patients underwent randomization. (Details of serious and fatal adverse events are provided in the Supplementary Appendix.). ); and CharitMedical University of Berlin (Campus Virchow Klinikum), Berlin (J.S. ), Innsbruck, and Medical University of Vienna, Vienna (A.R.) 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. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. After discontinuation of the intervention, patients could receive other treatments at the investigators discretion. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. 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. 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. 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 a tumor BRCA mutation, the median progression-free survival was 37.2 months in the olaparib group and 21.7 months in the placebo group (hazard ratio for disease progression or death, 0.31; 95% CI, 0.20 to 0.47) (Figure 3A). 2. ), German Society of Gynecologic Oncology (AGO) (J.S., U.C., F.M., N.G., P.B., A.B., P.H.
(Funded by ARCAGY Research and others; PAOLA-1 ClinicalTrials.gov number, NCT02477644. ), and Institut Curie, Hpital Ren Huguenin, Saint Cloud (C.D.) Int J Gynecol Cancer 2010;20:476-478. 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.
(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.) Subgroup Analysis of Progression-free Survival. Lancet Oncol 2014;15:852-861. Coleman RL, Oza AM, Lorusso D, et al. Ann Oncol 2013;24:Suppl 6:vi24-vi32.
Eastern Cooperative Oncology Group (ECOG) performance status ranges from 0 to 5, with higher values reflecting greater disability. Incorporation of bevacizumab in the primary treatment of ovarian cancer. Liu JF, Barry WT, Birrer M, et al.
Clinical complete response was defined as the disappearance of all measurable or assessable disease and normalization of CA-125 levels.
13. 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. Although HRD subgroup analyses were prespecified, they were not part of the multiple-testing procedure for this trial. ), Milan, and Fondazione Policlinico Universitario A. Gemelli IRCCS, Universit Cattolica, and MITO, Rome (G.S.) All subgroups presented here were predefined, except for two post hoc subgroups: homologous-recombination deficiency (HRD) negative or unknown and HRD unknown. 4. J Clin Oncol 2019;37:2317-2328. 12. A total of 30% of the patients had a deleterious tumor. A list of the PAOLA-1 principal investigators is provided in the Supplementary Appendix, available at NEJM.org. For the hazard ratios, the size of the circle is proportional to the number of events. ), Hpital Europen Georges Pompidou (P.C. The most effective and engaging way for clinicians to learn, improve their practice, and prepare for board exams. The authorized source of trusted medical research and education for the Chinese-language medical community. ), 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. Adverse events of special interest for bevacizumab (e.g., hypertension) are shown in Table S9.
Clin Cancer Res 2018;24:777-783. The statistical analysis plan is available with the protocol at NEJM.org. Overall survival data are immature. S4). 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. The randomized, double-blind, placebo-controlled PAOLA-1 trial was conducted in 11 countries. 10. Lancet Oncol 2015;16:928-936. HRD negative was defined as an HRD score of less than 42. The most common adverse events leading to discontinuation of olaparib were anemia and nausea (Table S7). Concise summaries and expert physician commentary that busy clinicians need to enhance patient care. No other potential conflict of interest relevant to this article was reported. 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. 15. The baseline characteristics were well balanced between the trial groups (Table 1 and Tables S2 through 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). Mirza MR, Monk BJ, Herrstedt J, et al. Patients were assigned to olaparib tablets or matching placebo tablets with the use of an interactive Web or voice response system. 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. Perren TJ, Swart AM, Pfisterer J, 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. 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). 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. Int J Gynecol Cancer 2015;25:1328-1330. Shown are KaplanMeier estimates of the rate of freedom from disease progression, as assessed by investigators, and from death. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Patients were eligible irrespective of previous surgical outcome (residual macroscopic disease or no residual macroscopic disease after upfront or interval surgery). The effect of combining maintenance olaparib and bevacizumab in patients regardless of BRCA mutation status is unknown. The gray band represents the 95% confidence interval for the overall population, and the dashed line indicates the point of no effect. Mutations in homologous recombination genes and outcomes in ovarian carcinoma patients in GOG 218: an NRG Oncology/Gynecologic Oncology Group study. 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 addition of olaparib to bevacizumab did not increase the known toxic effects associated with bevacizumab. 24. The adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. Serious adverse events occurred in 31% of the patients in both trial groups (Table S6). Oza AM, Cook AD, Pfisterer J, et al. 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. 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). 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. 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. Information and tools for librarians about site license offerings. European Network of Gynaecological Oncological Trial Groups requirements for trials between academic groups and pharmaceutical companies. The most advanced way to teach, practice, and assess clinical reasoning skills. all in Austria; Saitama Medical University International Medical Center, Hidaka (K.F. 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. Lancet Oncol 2017;18:1274-1284. N Engl J Med 2011;365:2473-2483. ); Tampere University and University Hospital, Tampere, Finland (J.M. 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. Herzog TJ, Armstrong DK, Brady MF, et al. 6. Lancet Oncol 2014;15:1207-1214. Integrated genomic analyses of ovarian carcinoma. The authors wrote the manuscript, with medical writing assistance funded by ARCAGY Research, AstraZeneca, and Merck Sharp & Dohme. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. **Partial response was defined as radiologic evidence of disease, an abnormal CA-125 level, or both. ), Centre Eugne Marquis, Rennes (C.L.-P.), Centre Catherine de Sienne Hpital Priv du Confluent, Nantes (A.L. Colombo N, Sessa C, du Bois A, et al.
16. ); the Nordic Society of Gynecologic Oncology (NSGO), Copenhagen (J.M. Details on the International Federation of Gynecology and Obstetrics (FIGO) staging system are provided in Table S1 in the Supplementary Appendix. Mirza MR, Avall-Lundqvist E, Birrer MJ, et al. Details of trial end points and analyses are provided in the Supplementary Appendix. The data include patients with leukopenia or a decreased white-cell count. Information, resources, and support needed to approach rotations - and life as a resident. A total of 30% of the patients had a deleterious tumor BRCA mutation. The content of this site is intended for health care professionals. 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). ), and Kliniken Essen Mitte (P.H. Analyses of health-related quality of life used an imputation-based approach for missing questionnaires. 21. The trial met its primary objective by showing a significant progression-free survival benefit in the intention-to-treat population. 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). Stat Med 1997;16:2349-2380. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were having a response after first-line platinumtaxane chemotherapy plus bevacizumab.
), Health Services and Performance Research Lab (EA 7425 HESPER), University Claude Bernard Lyon 1 (I.R.-C.), and Centre Hospitalier Lyon-Sud (B.Y.
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. 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. The primary end point was the time from randomization until investigator-assessed disease progression or death. Contextual synthetic lethality of cancer cell kill based on the tumor microenvironment. 5. 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. Details of BRCA testing and full eligibility criteria are provided in the Supplementary Appendix. 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). 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. 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). 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.
Adverse events occurring only in the time period when bevacizumab was being administered as maintenance therapy are summarized in Table S8. J Clin Oncol 2019;37:Suppl:5505-5505. abstract.
None of these changes were considered to be clinically significant. 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.
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. 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. 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). 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. 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). The primary end point was the time from randomization until investigator-assessed disease progression or death. all in Madrid; Medical University of Innsbruck, University Clinic for Gynecology and Obstetrics (R.B. 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). There was no evidence of a meaningful difference in health-related quality of life between the trial groups.
The estimated between-group difference was 1.56 points (95% CI, 0.42 to 3.55). Tumor HRD status was determined with the use of the myChoice HRD Plus assay (Myriad Genetic Laboratories). Tewari KS, Burger RA, Enserro D, et al. Ann Oncol 2019;30:672-705. Prespecified subgroup analyses showed a progression-free survival benefit with olaparib in patients with BRCA-mutated and HRD-positive tumors. ), and Association de Recherche Cancers Gyncologiques (ARCAGY) (E.P.-L.), Paris, Gustave Roussy, Villejuif (P.P. The dashed horizontal line indicates the median value. 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. 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. Cancer Genome Atlas Research Network. Cnaan A, Laird NM, Slasor P. Using the general linear mixed model to analyse unbalanced repeated measures and longitudinal data. 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 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. ), Universittsklinikum Ulm, Ulm (N.G. Lancet 2017;390:1949-1961. 23. 25. 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. 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). 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).
From July 2015 through September 2017, a total of 806 patients underwent randomization. (Details of serious and fatal adverse events are provided in the Supplementary Appendix.). ); and CharitMedical University of Berlin (Campus Virchow Klinikum), Berlin (J.S. ), Innsbruck, and Medical University of Vienna, Vienna (A.R.) 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. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. After discontinuation of the intervention, patients could receive other treatments at the investigators discretion. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. 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. 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. 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 a tumor BRCA mutation, the median progression-free survival was 37.2 months in the olaparib group and 21.7 months in the placebo group (hazard ratio for disease progression or death, 0.31; 95% CI, 0.20 to 0.47) (Figure 3A). 2. ), German Society of Gynecologic Oncology (AGO) (J.S., U.C., F.M., N.G., P.B., A.B., P.H.
(Funded by ARCAGY Research and others; PAOLA-1 ClinicalTrials.gov number, NCT02477644. ), and Institut Curie, Hpital Ren Huguenin, Saint Cloud (C.D.) Int J Gynecol Cancer 2010;20:476-478. 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.
(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.) Subgroup Analysis of Progression-free Survival. Lancet Oncol 2014;15:852-861. Coleman RL, Oza AM, Lorusso D, et al. Ann Oncol 2013;24:Suppl 6:vi24-vi32.
Eastern Cooperative Oncology Group (ECOG) performance status ranges from 0 to 5, with higher values reflecting greater disability. Incorporation of bevacizumab in the primary treatment of ovarian cancer. Liu JF, Barry WT, Birrer M, et al.
Clinical complete response was defined as the disappearance of all measurable or assessable disease and normalization of CA-125 levels.
13. 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. Although HRD subgroup analyses were prespecified, they were not part of the multiple-testing procedure for this trial. ), Milan, and Fondazione Policlinico Universitario A. Gemelli IRCCS, Universit Cattolica, and MITO, Rome (G.S.) All subgroups presented here were predefined, except for two post hoc subgroups: homologous-recombination deficiency (HRD) negative or unknown and HRD unknown. 4. J Clin Oncol 2019;37:2317-2328. 12. A total of 30% of the patients had a deleterious tumor. A list of the PAOLA-1 principal investigators is provided in the Supplementary Appendix, available at NEJM.org. For the hazard ratios, the size of the circle is proportional to the number of events. ), Hpital Europen Georges Pompidou (P.C. The most effective and engaging way for clinicians to learn, improve their practice, and prepare for board exams. The authorized source of trusted medical research and education for the Chinese-language medical community. ), 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. Adverse events of special interest for bevacizumab (e.g., hypertension) are shown in Table S9.
Clin Cancer Res 2018;24:777-783. The statistical analysis plan is available with the protocol at NEJM.org. Overall survival data are immature. S4). 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. The randomized, double-blind, placebo-controlled PAOLA-1 trial was conducted in 11 countries. 10. Lancet Oncol 2015;16:928-936. HRD negative was defined as an HRD score of less than 42. The most common adverse events leading to discontinuation of olaparib were anemia and nausea (Table S7). Concise summaries and expert physician commentary that busy clinicians need to enhance patient care. No other potential conflict of interest relevant to this article was reported. 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. 15. The baseline characteristics were well balanced between the trial groups (Table 1 and Tables S2 through 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). Mirza MR, Monk BJ, Herrstedt J, et al. Patients were assigned to olaparib tablets or matching placebo tablets with the use of an interactive Web or voice response system. 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. Perren TJ, Swart AM, Pfisterer J, 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. 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). 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. Int J Gynecol Cancer 2015;25:1328-1330. Shown are KaplanMeier estimates of the rate of freedom from disease progression, as assessed by investigators, and from death. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Patients were eligible irrespective of previous surgical outcome (residual macroscopic disease or no residual macroscopic disease after upfront or interval surgery). The effect of combining maintenance olaparib and bevacizumab in patients regardless of BRCA mutation status is unknown. The gray band represents the 95% confidence interval for the overall population, and the dashed line indicates the point of no effect. Mutations in homologous recombination genes and outcomes in ovarian carcinoma patients in GOG 218: an NRG Oncology/Gynecologic Oncology Group study. 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 addition of olaparib to bevacizumab did not increase the known toxic effects associated with bevacizumab. 24. The adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. Serious adverse events occurred in 31% of the patients in both trial groups (Table S6). Oza AM, Cook AD, Pfisterer J, et al. 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. 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). 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. 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. Information and tools for librarians about site license offerings. European Network of Gynaecological Oncological Trial Groups requirements for trials between academic groups and pharmaceutical companies. The most advanced way to teach, practice, and assess clinical reasoning skills. all in Austria; Saitama Medical University International Medical Center, Hidaka (K.F. 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. Lancet Oncol 2017;18:1274-1284. N Engl J Med 2011;365:2473-2483. ); Tampere University and University Hospital, Tampere, Finland (J.M. 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. Herzog TJ, Armstrong DK, Brady MF, et al. 6. Lancet Oncol 2014;15:1207-1214. Integrated genomic analyses of ovarian carcinoma. The authors wrote the manuscript, with medical writing assistance funded by ARCAGY Research, AstraZeneca, and Merck Sharp & Dohme. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. **Partial response was defined as radiologic evidence of disease, an abnormal CA-125 level, or both. ), Centre Eugne Marquis, Rennes (C.L.-P.), Centre Catherine de Sienne Hpital Priv du Confluent, Nantes (A.L. Colombo N, Sessa C, du Bois A, et al.
16. ); the Nordic Society of Gynecologic Oncology (NSGO), Copenhagen (J.M. Details on the International Federation of Gynecology and Obstetrics (FIGO) staging system are provided in Table S1 in the Supplementary Appendix. Mirza MR, Avall-Lundqvist E, Birrer MJ, et al. Details of trial end points and analyses are provided in the Supplementary Appendix. The data include patients with leukopenia or a decreased white-cell count. Information, resources, and support needed to approach rotations - and life as a resident. A total of 30% of the patients had a deleterious tumor BRCA mutation. The content of this site is intended for health care professionals. 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). ), and Kliniken Essen Mitte (P.H. Analyses of health-related quality of life used an imputation-based approach for missing questionnaires. 21. The trial met its primary objective by showing a significant progression-free survival benefit in the intention-to-treat population. 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). Stat Med 1997;16:2349-2380. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were having a response after first-line platinumtaxane chemotherapy plus bevacizumab.
), Health Services and Performance Research Lab (EA 7425 HESPER), University Claude Bernard Lyon 1 (I.R.-C.), and Centre Hospitalier Lyon-Sud (B.Y.
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. 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. The primary end point was the time from randomization until investigator-assessed disease progression or death. Contextual synthetic lethality of cancer cell kill based on the tumor microenvironment. 5. 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. Details of BRCA testing and full eligibility criteria are provided in the Supplementary Appendix. 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). 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. 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). 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.