); Kliniken Essen Mitte, Essen (P.H. Parmar MK, Ledermann JA, Colombo N, et al. J Clin Oncol 2010;28:2512-2519, 25. Patients continued the assigned study treatment until objective disease progression, as defined by RECIST guidelines, provided that they did not meet any criteria for discontinuation (any grade 3 or 4 adverse event that did not resolve completely or to grade 1 within 28 days after onset, according to the National Cancer Institute's Common Terminology Criteria for Adverse Events [CTCAE], version 3.0) (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf). An interim analysis of overall survival was performed after 101 deaths had been recorded. Perren TJ, Swart AM, Pfisterer J, et al. J Clin Oncol 2011;29:3798-3804. Data collection and analysis were performed by the sponsor, and all the authors had full access to the data. The study design is shown in Figure 1. 0000041044 00000 n
0000037237 00000 n
Moynahan ME, Chiu JW, Koller BH, Jasin M. BRCA1 controls homology-directed DNA repair. 0000044133 00000 n
Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. 0000054600 00000 n
0000025452 00000 n
], 2. M9C0. Int J Gynecol Cancer 2011;21:419-423, 29. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. Analyses of efficacy and patient-reported outcomes included all patients who were randomly assigned to a study group, and safety analyses included all patients who received at least one dose of the assigned study medication. }x0P: 0000040403 00000 n
0000004905 00000 n
At the time that the study was designed, there were no reported data from trials of maintenance treatment in patients with a relapse of platinum-responsive ovarian cancer, which would have provided a basis for estimating progression-free survival in the placebo group. 0000004251 00000 n
N Engl J Med 2011;365:2473-2483, 9. Farmer H, McCabe N, Lord CJ, et al. 0000006077 00000 n
Lancet 2010;376:235-244, 32. Incorporation of bevacizumab in the primary treatment of ovarian cancer. Proc Natl Acad Sci U S A 2011;108:3406-3411, 18. 0000024287 00000 n
We followed patients until progression of disease, regardless of whether the treatment was discontinued or delayed or whether there were deviations from the protocol (i.e., the ongoing study group). Patients were eligible if they were 18 years of age or older and had recurrent ovarian or fallopian-tube cancer or primary peritoneal cancer with high-grade (grade 2 or 3) serous features or a serous component, which was platinum-sensitive (defined by an objective response to a previous platinum-based therapy for more than 6 months). Ledermann JA, Hackshaw A, Kaye S, et al. Kaye SB, Fehrenbacher L, Holloway R, et al. Study treatment was blinded with the use of unique identifiers generated during randomization. Markman M, Liu PY, Moon J, et al. At the time of the data-cutoff point for progression-free survival, too few deaths had occurred for a survival analysis to be performed. 0000054091 00000 n
Disease-related symptoms and health-related quality of life as reported by the patients were also measured (for details, see the Supplementary Appendix). J Clin Oncol 2010;28:3323-3329, 6. 0000030946 00000 n
DOI: 10.1056/NEJMoa1105535, Tap into groundbreaking research and clinically relevant insights. Only the 1000 most recent citing articles are listed here. Microarray studies in serous epithelial ovarian cancer have identified a BRCAness gene-expression profile that appears to correlate with responsiveness to both platinum-based chemotherapy and poly(adenosine diphosphate [ADP]ribose) polymerase (PARP) inhibitors.15,16, PARP plays an essential part in the repair of single-stranded DNA breaks, through the base-excision-repair pathway, and it has been proposed that PARP keeps low-fidelity nonhomologous-end-joining DNA repair machinery in check.17 Thus, PARP inhibition leads to the formation of double-stranded DNA breaks that cannot be accurately repaired in tumors with homologous recombination deficiency,18,19 owing to aberrant activation of low-fidelity repair mediated by nonhomologous end joining,17 a concept known as synthetic lethality.20 Olaparib (AZD2281) is a potent oral PARP inhibitor that induces synthetic lethality in BRCA1/2-deficient tumor cells.21,22 Antitumor activity at doses that were not unacceptably toxic was observed in phase 1 and phase 2 monotherapy studies involving patients with ovarian cancer who had BRCA1/2 germline mutations.23-25 In addition, a phase 2 study of olaparib monotherapy in patients with high-grade serous ovarian cancer with or without BRCA1/2 mutations showed objective response rates of 41% for patients with BRCA1/2 mutations and 24% for those without such mutations.26. 0000002793 00000 n
0000025214 00000 n
The identification of biomarkers for homologous-recombination deficiency may provide an opportunity to target PARP inhibitors to the appropriate population. There were no significant between-group differences in disease-related symptoms or rates of improvement in health-related quality of life, as measured by scores on the Functional Assessment of Cancer Therapy (FACT)Ovarian questionnaire, the FACTNational Comprehensive Cancer Network Ovarian Symptom Index, and the Trial Outcome Index (Table 3 in the Supplementary Appendix).29 The time to worsening of each of these end points was shorter with olaparib than with placebo; however, the difference was not significant (Table 4 in the Supplementary Appendix). Fung-Kee-Fung M, Oliver T, Elit L, Oza A, Hirte HW, Bryson P. Optimal chemotherapy treatment for women with recurrent ovarian cancer. Of 265 patients who underwent randomization, 136 were assigned to the olaparib group and 129 to the placebo group. April 12, 2012N Engl J Med 2012; 366:1382-1392
At the time of the data-cutoff point, the median duration of exposure to the treatment was 206.5 days (range, 3 to 469) for olaparib and 141 days (range, 34 to 413) for placebo, and the mean rate of adherence to the assigned study treatment was 85% and 96%, respectively. 0000054921 00000 n
All the authors vouch for the completeness and accuracy of the data and analyses and the fidelity of the study to the protocol. trailer
The toxicity profile of olaparib in this patient population was consistent with that reported in previous clinical studies.24,25,31 The majority of adverse events were grade 1 or 2 and did not require interruptions of the treatment. 0000002584 00000 n
CA Cancer J Clin 2011;61:69-90[Erratum, CA Cancer J Clin 2011;61:134. Pfisterer J, Plante M, Vergote I, et al. The secondary end points of change in tumor size, combined response rate according to RECIST guidelines and CA-125 measurement (Table 2 in the Supplementary Appendix), and disease-control rate are reported in the Supplementary Appendix. ), and Royal Melbourne Hospital, Parkville, NSW (C.S.) 0l ?D0}*L)mZ [BBc01c\I7mrqE4{,0AEA?6QP)-ci[bB1DPD(TP The subgroups of patients who did not have the BRCA mutation or who were Jewish were not included in the subgroup analysis because there were fewer than 20 events in those subgroups. BMC Cancer 2008;8:17-17, 15. hTRn0{LH$Cj,)R1C,mxw'i]q"TxiDNl $6N]C-`/F0|any56A{*CYoRqJtLjZ-dP*'VqDpB3!i \~V 2W-HK!4 'a3aVo8e,ck"HJdaDg9;A"DLTBi*).(3Hhs~Wkk>S F There is a need to identify biomarkers to select patients for this therapy. Clin Cancer Res 2010;16:2344-2351, 31. Tutt A, Robson M, Garber JE, et al. 0000052775 00000 n
Response rates and rates of improvement in patient-reported outcomes were analyzed with the use of logistic regression, and the percentage change in tumor size was assessed with the use of analysis of covariance; both these analyses were adjusted for the stratification factors at randomization. 2hpp{@I]a`? -b`8HKs(|L8r98( V
An analysis performed after 153 progression events had occurred (in 57.7% of patients) showed that progression-free survival was significantly longer in the olaparib group than in the placebo group. Cella DF, Tulsky DS, Gray G, et al. ]YQWYR},a'XBy+0v"v#Whv}3w{N
;: gD In this randomized, double-blind, phase 2 study, eligible patients were stratified according to the interval between disease progression and completion of their penultimate platinum-based regimen (from 6 to 12 months vs. more than 12 months), objective response to their most recent regimen (complete response vs. partial response), and ancestry (Jewish vs. non-Jewish), to help balance the distribution of BRCA1/2 germline mutations (which are found more frequently in Jewish populations). With the use of an interactive voice response system, patients were randomly assigned in a 1:1 ratio to receive olaparib capsules, at a dose of 400 mg twice daily (the monotherapy dose shown to be the maximum dose associated with acceptable adverse-event rates),23 or matching placebo within 8 weeks after completion of the last dose of platinum-based chemotherapy (Figure 1). 0000054736 00000 n
Valuable tools for building a rewarding career in health care. However, the observed benefit with respect to progression-free survival did not translate into an overall survival benefit at the time of the interim analysis of overall survival. Our data cannot address differences that might exist between patients with BRCA germline mutations and those with a BRCAness phenotype; it will be important to address these questions at the final analysis of overall survival. Clin Cancer Res 2008;14:3916-3925, 22. 0000054214 00000 n
0
0000054043 00000 n
0000001936 00000 n
0000007501 00000 n
The primary end point was progression-free survival, as assessed by the site investigator and defined as the time from randomization (on completion of chemotherapy) until objective assessment of disease progression according to RECIST guidelines27 or death (from any cause in the absence of progression of disease). 3EQy|},
; 2(8vG&( 4LjKp Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. The incidence of grade 3 or 4 adverse events was 35.3% in the olaparib group and 20.3% in the placebo group (Table 2). Ashworth A. NWV.*N"BIU'orH"WY'2$e40A=FKS BRCA1/2 mutation status was not required. 0000013500 00000 n
The study was designed by the first author, in collaboration with the last author and the study sponsor, AstraZeneca. No predictive factors were identified (global treatment-by-subgroup interaction test, P=0.15). Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. 60 82
both in Australia; University of Leuven, Leuven, Belgium (I.V. Stay connected to what's important in medical research and clinical practice, Subscribe to the most trusted and influential source ofmedical knowledge. xb```b`Hd`c` @1v#@(!Gtm6Q>e The most trusted, influential source of new medical knowledge and clinical best practices in the world. The decision to submit the manuscript for publication was made by all the authors and the sponsor. 0000045212 00000 n
O;I FBxLv{*g9PJ:/4(_h= If the event did not resolve within 4 weeks after treatment or if two previous treatment interruptions had occurred, the patient was withdrawn from the study. We conducted a randomized, double-blind, placebo-controlled, phase 2 study to evaluate maintenance treatment with olaparib in patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer who had received two or more platinum-based regimens and had had a partial or complete response to their most recent platinum-based regimen. Mol Cell 2001;7:263-272, 14. 0000043552 00000 n
Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. ), and AstraZeneca, Macclesfield (E.M., C.W., J.C.) both in the United Kingdom; Chaim Sheba Medical Center, Tel Hashomer (R.S.-F.), and Tel Aviv Sourasky Medical Center, Tel Aviv (T.S.) 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, Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults, Case 23-2022: A 49-Year-Old Man with Hypoglycemia, http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf, 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. J Clin Oncol 2008;26:3785-3790, 20. ), and Evangelisches Krankenhaus, Dsseldorf (W.M.) Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). Lancet 2003;361:2099-2106, 4. The most common adverse events that resulted in interruptions or reductions in the dose of olaparib were vomiting, nausea, and fatigue. 0000025289 00000 n
startxref
Management of platinum-sensitive recurrent ovarian cancer. Panel A shows KaplanMeier curves for progression-free survival in the randomized population. 0000055074 00000 n
Adverse events more commonly reported in the olaparib group than in the placebo group (by more than 10% of patients) were nausea (68% vs. 35%), fatigue (49% vs. 38%), vomiting (32% vs. 14%), and anemia (17% vs. 5%); the majority of adverse events were grade 1 or 2. Therasse P, Arbuck SG, Eisenhauer EA, et al. TxDgG%G`FoCoR4U(hwwT()H At the data-cutoff point (June 30, 2010), 68 patients (50%) in the olaparib group and 21 (16%) in the placebo group were still receiving the study treatment. Safety was assessed throughout the study by monitoring for adverse events, biochemical laboratory tests, assessment of vital signs, and physical examination. The majority of patients (246 of 264) had one or more adverse events, most of which were grade 1 or 2 (Table 2). Moynahan ME, Pierce AJ, Jasin M. BRCA2 is required for homology-directed repair of chromosomal breaks. A recent study showed that the formation of Rad51 foci correlated with an in vitro response to PARP inhibition in primary epithelial ovarian-cancer cells.30 Rad51 is involved in homologous recombination repair; it is relocalized to the nucleus in response to DNA damage to form distinct foci that are thought to be assemblages of proteins required for homologous recombination repair. Eligible patients had completed at least two courses of platinum-based chemotherapy, and their most recent regimen induced an objective response as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, version 1.0,27 or a cancer antigen 125 (CA-125) response, according to Gynecological Cancer InterGroup criteria28 (see the Supplementary Appendix, available with the full text of this article at NEJM.org). A significant benefit in the secondary end points of time to progression, as assessed by means of RECIST guidelines or CA-125 level, whichever showed earlier progression, and change in tumor size at 24 weeks was also observed in patients receiving olaparib. 0000008331 00000 n
K3=yg`D}\%-o00 Nature 2005;434:917-921, 19. A phase 3 trial of bevacizumab in ovarian cancer. The size of the circles is proportional to the number of events. Konstantinopoulos PA, Spentzos D, Karlan BY, et al. endstream
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Fong PC, Boss DS, Yap TA, et al. 0000053816 00000 n
There were no unexpected changes in biochemical laboratory measurements, vital signs, or findings on physical examination in either group. 0000037431 00000 n
Gynecol Oncol 2009;114:195-198, 8. Ovarian cancer is the leading cause of death from gynecologic tumors in the Western world.1 Approximately 80% of patients with newly diagnosed ovarian cancer have a response to platinum-based chemotherapy. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. LQX#|w ~S`etECQ{n
UkuO`||ayc`lYnoyr]tdNUx]%EEJq
%uI]T=XJqC69Z'@@w`&?SIzF@OQ0b$slvv]!%PHL}f}__J c1UDdt^Jd&4s}mQX:-V |avlwA[-
iPa8GOk1MIRJ`oP@D\c0iFi15%'j*p40"G9[9"oRm/Pz`{]P,PAWn| -l0KMyddLTJWS Impact on survival of 12 versus 3 monthly cycles of paclitaxel (175 mg/m2) administered to patients with advanced ovarian cancer who attained a complete response to primary platinum-paclitaxel: follow-up of a Southwest Oncology Group and Gynecologic Oncology Group phase 3 trial. At the time of the interim analysis of overall survival, 29 patients were still receiving olaparib after a period of at least 21 months, and 4 patients were still receiving placebo. Of the 265 patients who met the eligibility criteria, 136 were randomly assigned to receive olaparib, at a dose of 400 mg twice daily, and 129 to receive placebo (Figure 1). Mol Cell 1999;4:511-518, 13. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Sz0|{{ZPCL.U(TY 0jA}oJ]fL#RZE Lancet Oncol 2011;12:852-861, 27. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
0000054874 00000 n
Demographic and Baseline Characteristics of the Patients. Risch HA, McLaughlin JR, Cole DE, et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. Subgroup analyses of progression-free survival showed that, regardless of subgroup, patients in the olaparib group had a lower risk of progression. No significant difference in overall survival was observed (hazard ratio for death in the olaparib group, 0.94; 95% CI, 0.63 to 1.39; P=0.75). In both groups, nausea, fatigue, and vomiting were intermittent and did not require discontinuation of the study treatment. Dose modifications were more common in the olaparib group; however, discontinuations due to adverse events were infrequent, and adherence to therapy was high. 0000025531 00000 n
Mukhopadhyay A, Elattar A, Cerbinskaite A, et al. The primary end point was progression-free survival according to the Response Evaluation Criteria in Solid Tumors guidelines. The most effective and engaging way for clinicians to learn, improve their practice, and prepare for board exams. both in Israel; Indiana University School of Medicine, Indianapolis (D.M. ], 10. The identical hazard ratios for the primary end point of progression-free survival, according to RECIST guidelines, and for the secondary progression end point that also incorporated objective CA-125 measurements further support the validity of the significant improvement in progression-free survival. Demographic and baseline characteristics of the patients (Table 1) and any protocol deviations with the potential to affect the primary analysis (Table 1 in the Supplementary Appendix) were well balanced between the two study groups. Olaparib as maintenance treatment significantly improved progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer. Sporadic epithelial ovarian cancer: clinical relevance of BRCA1 inhibition in the DNA damage and repair pathway. 1. p@l{[\Cp:&cS$Pn`j_i)I@d[=}^h4[I6.T?f/g]VN Y~b,9bwE5gMti2UuKAWFRs9o]~L]rr~*n/:G L &Ts&^]0@Cq2I@/Pny>37TP M39N 0000053768 00000 n
More patients in the olaparib group had dose interruptions or reductions (27.9% and 22.8%, respectively) as a result of adverse events, as compared with the placebo group (8.6% and 4.7%). The gray band represents 95% confidence intervals for the overall population. 0000053498 00000 n
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5BCEPZZ ih(z]\E;\)H3}^'A&5'S:kq;X{)@T!AQgM0F,P-1g>0Y!{OJG53z]N}#)cVG However, at the interim analysis, this did not translate into an overall survival benefit. Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin. A blinded, independent, central review of the data also showed consistent results (hazard ratio, 0.39; 95% CI, 0.27 to 0.55; P<0.001). A complete response (vs. partial response) to the final platinum-based therapy before study entry was a significant prognostic factor for longer progression-free survival, regardless of study group (hazard ratio, 0.46; P<0.001). endstream
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We thank Claire Routley, Ph.D. (Mudskipper Bioscience), for editorial assistance, funded by AstraZeneca. However, the observed value of 4.8 months is consistent with recently published data from studies of maintenance treatment in similar patient populations (5.8 months and 2.8 months),32,33 suggesting that progression-free survival in the placebo group in our study was in line with that expected. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. 0000003231 00000 n
Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. Women with germline mutations in BRCA1, BRCA2, or both (BRCA1/2) have an increased risk of ovarian cancer, particularly the most common type, invasive high-grade serous carcinoma.11 About 15% of epithelial ovarian cancers are deficient in homologous recombination repair, owing to mutations in BRCA1/2.12,13 In up to 50% of patients with high-grade serous tumors, the tumor cells may be deficient in homologous recombination as a result of germline or somatically acquired BRCA1/2 mutations, epigenetic inactivation of BRCA1, or defects in the homologous recombination pathway that are independent of BRCA1/2.14 The silencing or dysfunction of genes in BRCA1/2-related pathways gives rise to a BRCAness phenotype similar to that resulting from inherent mutations in BRCA1/2. KaplanMeier Estimates and Subgroup Analysis of Progression-free Survival. N Engl J Med 2011;365:2484-2496[Erratum, N Engl J Med 2012;366:284. 0000025371 00000 n
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f|Dse In conclusion, the results from this randomized, phase 2 study show that maintenance treatment with olaparib was associated with a significant improvement in progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. 0000053672 00000 n
Secondary efficacy end points were time to progression, according to RECIST guidelines or CA-125 level, whichever showed earlier progression (with the CA-125 level assessed according to Gynecological Cancer InterGroup criteria; see the Supplementary Appendix)28; objective response rate, as determined according to RECIST guidelines or a combination of RECIST guidelines and CA-125 level; disease-control rate, according to RECIST guidelines (i.e., the percentage of patients who had confirmed complete response, partial response, stable disease, or no evidence of disease for at least 23 weeks); percentage change from baseline in the size of the target tumor lesion at weeks 12 and 24; and overall survival. Olaparib (AZD2281) is an oral poly(adenosine diphosphate [ADP]ribose) polymerase inhibitor that has shown antitumor activity in patients with high-grade serous ovarian cancer with or without BRCA1 or BRCA2 germline mutations. J Natl Cancer Inst 2006;98:1694-1706, 12. 0000053955 00000 n
The manuscript was written by the first author, with editorial assistance funded by the sponsor, and was reviewed by all authors and the sponsor. Progression events were observed in 60 patients (44.1%) in the olaparib group and 93 (72.1%) in the placebo group. Subgroup analyses of progression-free survival showed that, regardless of subgroup, patients in the olaparib group had a lower risk of progression than those in the placebo group (Figure 2B). We evaluated the efficacy of olaparib monotherapy as maintenance treatment in patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer who had had a response to their most recent platinum-based chemotherapy.
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