19. du Bois A, Reuss A, Pujade-Lauraine E, et al. J Clin Oncol 2019;37:Suppl:5505-5505. abstract. Colombo N, Sessa C, du Bois A, et al. The most common adverse events leading to discontinuation of olaparib were anemia and nausea (Table S7). 11. Perren TJ, Swart AM, Pfisterer J, et al. PARP inhibitors trap PARP on DNA at sites of single-strand breaks, preventing the repair of these breaks and generating double-strand breaks that cannot be repaired accurately in tumors with homologous-recombination deficiency (HRD).9 HRD is not limited to tumors with BRCA mutations and is present in approximately 50% of high-grade serous ovarian tumors.10 Indeed, in platinum-sensitive relapsed ovarian cancer,11-13 PARP inhibitors are active as maintenance monotherapy in patients who have tumors without BRCA mutations, although the magnitude of benefit appears lower than in patients with BRCA-mutated tumors. ), 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. ), and Institut Curie, Hpital Ren Huguenin, Saint Cloud (C.D.)
Patients were eligible regardless of surgical outcome or BRCA mutation status. Contextual synthetic lethality of cancer cell kill based on the tumor microenvironment. The mean global health statusquality of life score at baseline was 68.6 in the olaparib group and 67.1 in the placebo group. 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. 22. 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. 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). ), German Society of Gynecologic Oncology (AGO) (J.S., U.C., F.M., N.G., P.B., A.B., P.H. 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. 10. The data include patients with thrombocytopenia, decreased platelet production, a decreased platelet count, or a decreased plateletcrit. Int J Gynecol Cancer 2010;20:476-478. Among the patients with a tumor BRCA mutation (prespecified subgroup analysis) (Panel A), the KaplanMeier estimate of the percentage of patients who were free from disease progression and death at 24 months was 76% in the olaparib-plus-bevacizumab group and 39% in the placebo-plus-bevacizumab group. ), Milan, and Fondazione Policlinico Universitario A. Gemelli IRCCS, Universit Cattolica, and MITO, Rome (G.S.) Tumor HRD status was determined with the use of the myChoice HRD Plus assay (Myriad Genetic Laboratories). Integrated genomic analyses of ovarian carcinoma. ), Innsbruck, and Medical University of Vienna, Vienna (A.R.) *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. The randomized, double-blind, placebo-controlled PAOLA-1 trial was conducted in 11 countries. The change from baseline in the global health statusquality of life score was assessed with the use of a mixed model for repeated measures.21 Adverse events were analyzed descriptively; an interim safety analysis was planned and conducted. ), University of MilanBicocca and European Institute of Oncology IRCCS, and Mario Negri Gynecologic Oncology Group (MANGO) (N.C.), and Fondazione IRCCS Istituto Nazionale Tumori and MITO (D.L. S5). 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). Lancet Oncol 2014;15:1207-1214. This article was updated on February 19, 2020, at NEJM.org. N Engl J Med 2018;379:2495-2505.
Subgroup Analysis of Progression-free Survival. all in Madrid; Medical University of Innsbruck, University Clinic for Gynecology and Obstetrics (R.B. 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. Clin Cancer Res 2018;24:777-783. ), Hpital Europen Georges Pompidou (P.C. Herzog TJ, Armstrong DK, Brady MF, et al. 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. Details of BRCA testing and full eligibility criteria are provided in the Supplementary Appendix. 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. 13. NA denotes not available. S3C). Neither trial group had a clinically significant change in health-related quality of life. 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. 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. ), Centre Eugne Marquis, Rennes (C.L.-P.), Centre Catherine de Sienne Hpital Priv du Confluent, Nantes (A.L. A total of 30% of the patients had a deleterious tumor BRCA mutation. Patients were randomly assigned in a 2:1 ratio to receive olaparib (300 mg twice daily) or placebo at least 3 weeks and no more than 9 weeks after the last dose of chemotherapy. 18. All subgroups presented here were predefined, except for two post hoc subgroups: homologous-recombination deficiency (HRD) negative or unknown and HRD unknown. 8. 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. Patients with other nonmucinous epithelial ovarian cancers were eligible, provided they had a deleterious germline BRCA1 or BRCA2 mutation. Patients were randomly assigned in a 2:1 ratio to receive olaparib tablets (300 mg twice daily) or placebo for up to 24 months; all the patients received bevacizumab at a dose of 15 mg per kilogram of body weight every 3 weeks for up to 15 months in total. Norquist BM, Brady MF, Harrell MI, et al. Adverse events occurring only in the time period when bevacizumab was being administered as maintenance therapy are summarized in Table S8. 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. 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. Although HRD subgroup analyses were prespecified, they were not part of the multiple-testing procedure for this trial. Patients were eligible irrespective of previous surgical outcome (residual macroscopic disease or no residual macroscopic disease after upfront or interval surgery). Shown are KaplanMeier estimates of the rate of freedom from disease progression, as assessed by investigators, and from death. 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).
Coleman RL, Oza AM, Lorusso D, et al. Olaparib has shown significant clinical benefit as maintenance therapy in women with newly diagnosed advanced ovarian cancer with a BRCA mutation. 20.
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%). ), Health Services and Performance Research Lab (EA 7425 HESPER), University Claude Bernard Lyon 1 (I.R.-C.), and Centre Hospitalier Lyon-Sud (B.Y. 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). 21. 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). S1). Stat Med 1997;16:2349-2380.
La et Napolon Bullukian, Lyon 69008, France, or at [emailprotected]. 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. All the patients provided written informed consent. (Details of serious and fatal adverse events are provided in the Supplementary Appendix.). Unknown was defined as an inconclusive, missing, or failed test. 1. 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. 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. ), Essen, Universittsklinikum Carl Gustav Carus, Technische Universitt Dresden, Dresden (U.C. Adverse Events with Olaparib or Placebo in Patients Also Receiving Bevacizumab. ), Institut Curie, Hpital Claudius Rgaud (M.R. (Funded by ARCAGY Research and others; PAOLA-1 ClinicalTrials.gov number, NCT02477644. 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). 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. The authorized source of trusted medical research and education for the Chinese-language medical community. Karam A, Ledermann JA, Kim JW, et al. all in Japan; University Hospital Leuven, Leuven Cancer Institute, and Belgium and Luxembourg Gynecologic Oncology Group (BGOG) both in Leuven, Belgium (I.V. 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. 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. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. 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). Burger RA, Brady MF, Bookman MA, et al. The baseline characteristics were well balanced between the trial groups (Table 1 and Tables S2 through S4). ); the Nordic Society of Gynecologic Oncology (NSGO), Copenhagen (J.M. ), and Association de Recherche Cancers Gyncologiques (ARCAGY) (E.P.-L.), Paris, Gustave Roussy, Villejuif (P.P. Among the patients with HRD-positive tumors without a BRCA mutation (prespecified subgroup analysis) (Panel D), the KaplanMeier estimate of the percentage of patients who were free from disease progression and death at 24 months was 52% in the olaparib-plus-bevacizumab group and 26% in the placebo-plus-bevacizumab group. 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). Mirza MR, Avall-Lundqvist E, Birrer MJ, et al. 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. Eastern Cooperative Oncology Group (ECOG) performance status ranges from 0 to 5, with higher values reflecting greater disability. **Partial response was defined as radiologic evidence of disease, an abnormal CA-125 level, or both. 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.
DOI: 10.1056/NEJMoa1911361, Tap into groundbreaking research and clinically relevant insights. (Data for patients whose tumor HRD status was unknown are shown in Fig. Liu JF, Barry WT, Birrer M, et al. The statistical analysis plan is available with the protocol at NEJM.org. Lancet Oncol 2017;18:1274-1284. 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. For the hazard ratios, the size of the circle is proportional to the number of events. The most advanced way to teach, practice, and assess clinical reasoning skills. ), and Arbeitsgemeinschaft Gynkologische Onkologie Study Group (AGO)Austria (R.B., A.R. Mirza MR, Monk BJ, Herrstedt J, et al. Lancet Oncol 2014;15:852-861. The adjusted mean change from baseline was 1.33 points (95% CI, 2.47 to 0.19) in the olaparib group (498 patients) and 2.89 points (95% CI, 4.52 to 1.26) in the placebo group (246 patients) (Fig. From July 2015 through September 2017, a total of 806 patients underwent randomization. Details of trial end points and analyses are provided in the Supplementary Appendix. Supported by Association de Recherche Cancers Gyncologiques (ARCAGY) Research, AstraZeneca, Merck Sharp & Dohme (a subsidiary of Merck), and F. HoffmannLa Roche. 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. ), Universittsklinikum Ulm, Ulm (N.G. Lancet Oncol 2016;17:1579-1589. Overall survival data are immature. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were having a response after first-line platinumtaxane chemotherapy plus bevacizumab. Moore K, Colombo N, Scambia G, et al. 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. The trial met its primary objective by showing a significant progression-free survival benefit in the intention-to-treat population. Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup: first-line interventions.
Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Mol Cell 2015;60:547-560. We conducted a randomized, double-blind, international phase 3 trial. 17.
The trial was designed by the European Network for Gynecological Oncological Trial Groups (ENGOT) lead group, Groupe dInvestigateurs Nationaux pour lEtude des Cancers Ovariens, and sponsored by Association de Recherche Cancers Gyncologiques (ARCAGY) Research, according to the ENGOT model A (academic sponsor; details of this research model are provided in the Supplementary Appendix).18,19 ARCAGY Research was responsible for overseeing the collection, analysis, and interpretation of the data. Liu JF, Barry WT, Birrer M, et al. 14.
The trial met its primary objective by showing a significant progression-free survival benefit in the intention-to-treat population. 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! 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 (. all in Germany. Details of discontinuation criteria and methods for unblinding are provided in the Supplementary Appendix. ), Universittsklinikum Essen (P.B. Administering maintenance olaparib in addition to bevacizumab to patients with newly diagnosed advanced ovarian cancer who were receiving standard treatment including bevacizumab resulted in a significant progression-free survival benefit, with a substantial benefit in patients with HRD-positive tumors. Final overall survival of a randomized trial of bevacizumab for primary treatment of ovarian cancer.
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. Adverse events were graded with the use of the CTCAE, version 4.03. N Engl J Med 2011;365:2473-2483. Eur J Cancer 2012;48:1713-1721. Nature 2011;474:609-615. 25. 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 data include patients with leukopenia or a decreased white-cell count. After discontinuation of the intervention, patients could receive other treatments at the investigators discretion. 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). 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. OConnor MJ.
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