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). 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). 0000043944 00000 n 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 0000055121 00000 n J Natl Cancer Inst 2000;92:205-216, 28. Objective response was not an informative end point because there were limited opportunities for further responses. The secondary end point of time to progression according to the RECIST guidelines or CA-125 level, whichever showed earlier progression, was also significantly longer in the olaparib group than in the placebo group (median, 8.3 months vs. 3.7 months; hazard ratio for progression, 0.35; 95% CI, 0.25 to 0.47; P<0.001). Rustin GJ, Vergote I, Eisenhauer E, et al. 0000054600 00000 n 0000053768 00000 n Demographic and Baseline Characteristics of the Patients. ;`5*sko\6#mmXp?m9rv6;Enl4m'3Wp-9P2tS(U([PYS&ToR&UUEYpG;6EmVXA~ 0000043552 00000 n There were no unexpected changes in biochemical laboratory measurements, vital signs, or findings on physical examination in either group. The content of this site is intended for health care professionals. Address reprint requests to Dr. Ledermann at the University College London (UCL) Cancer Institute, UCL & UCL Hospitals Comprehensive Biomedical Research Centre, 90 Tottenham Court Rd., London W1T 4TJ, United Kingdom, or at [emailprotected]. 0000053907 00000 n 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). Time-to-event variables (i.e., progression-free survival, overall survival, and time to worsening of disease-related symptoms and health-related quality of life) were analyzed with the use of a Cox proportional-hazards model that included covariates that were used as stratification factors at randomization. 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. Gelmon KA, Tischkowitz M, Mackay H, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. 0000053955 00000 n 60 82 High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. The final analysis of overall survival will be performed at 60% maturity (i.e., when 60% of the patients have died). CA Cancer J Clin 2011;61:69-90[Erratum, CA Cancer J Clin 2011;61:134. 0000036519 00000 n Proc Natl Acad Sci U S A 2011;108:3406-3411, 18. 0000025371 00000 n Because only patients with a response to chemotherapy were enrolled in the study, just 40% had measurable disease at entry. At the time of the data-cutoff point for progression-free survival, too few deaths had occurred for a survival analysis to be performed. ); Mount Vernon Hospital, Northwood (G.R. M9C0. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. The identification of biomarkers for homologous-recombination deficiency may provide an opportunity to target PARP inhibitors to the appropriate population. The most common adverse events that resulted in interruptions or reductions in the dose of olaparib were vomiting, nausea, and fatigue. J Clin Oncol 1993;11:570-579, 30. Press JZ, De Luca A, Boyd N, et al. GCIG denotes Gynecologic Cancer InterGroup. New guidelines to evaluate the response to treatment in solid tumors. 0000053418 00000 n 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. Pfisterer J, Ledermann JA. J Clin Oncol 2010;28:3555-3561[Erratum, J Clin Oncol 2010;28:4868. Mukhopadhyay A, Elattar A, Cerbinskaite A, et al. A supportive analysis of progression-free survival with the use of the log-rank test was performed (stratified by randomization factors). However, at the interim analysis, this did not translate into an overall survival benefit. April 12, 2012N Engl J Med 2012; 366:1382-1392 A stratified log-rank test of progression-free survival supported the primary analysis (hazard ratio, 0.37; 95% CI, 0.26 to 0.51; P<0.001). Stay connected to what's important in medical research and clinical practice, Subscribe to the most trusted and influential source ofmedical knowledge. 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). 0000048139 00000 n All patients provided written informed consent. ); Kliniken Essen Mitte, Essen (P.H. The majority of patients (246 of 264) had one or more adverse events, most of which were grade 1 or 2 (Table 2). Markman M, Liu PY, Moon J, et al. ); and DanaFarber Cancer Institute, Boston (U.M.). Semin Oncol 2006;33:Suppl:S12-S16, 5. Treatment was interrupted for any event of CTCAE grade 3 or 4 that was considered to be related to treatment. Fong PC, Yap TA, Boss DS, et al. 1. Int J Gynecol Cancer 2011;21:419-423, 29. Median progression-free survival was 8.4 months in the olaparib group versus 4.8 months in the placebo group (hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.25 to 0.49; P<0.001) (Figure 2A). Evers B, Drost R, Schut E, et al. Safety was assessed throughout the study by monitoring for adverse events, biochemical laboratory tests, assessment of vital signs, and physical examination. 0000041044 00000 n The study protocol was approved by the institutional review board or independent ethics committee at each investigational site; the protocol and the statistical analysis plan are available at NEJM.org. Konstantinopoulos PA, Spentzos D, Karlan BY, et al. 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. Concise summaries and expert physician commentary that busy clinicians need to enhance patient care. %%EOF 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. Management of platinum-sensitive recurrent ovarian cancer. 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. `M'/n`W?-r}[tb&Pb00;4}@_z)W GpK.)44 C`OF- uL-~ Enrollment, Randomization, and Treatment. In addition, a blinded independent central review of tumor scans was performed retrospectively. 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. 0l ?D0}*L)mZ [BBc01c\I7mrqE4{,0AEA?6QP)-ci[bB1DPD(TP However, at the interim analysis of overall survival (data-cutoff point, October 31, 2011), 101 patients (38%) had died: 52 in the olaparib group and 49 in the placebo group. both in Israel; Indiana University School of Medicine, Indianapolis (D.M. Peer-reviewed journal featuring in-depth articles to accelerate the transformation of health care delivery. 0000036849 00000 n 0000051012 00000 n 0000024287 00000 n The study was performed in accordance with the Declaration of Helsinki and the guidelines for Good Clinical Practice. All reported P values and confidence intervals are two-sided. 0000019390 00000 n Lancet 2003;361:2099-2106, 4. 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). 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. Assuming that the true hazard ratio for progression or death with olaparib versus placebo was 0.75 (corresponding to a 33% increase in the median duration of progression-free survival, from 9 to 12 months after randomization) and that the overall type 1 error was 20% (one-sided test), we calculated that the analysis would have 80% power to show a significant difference in favor of olaparib (one-sided P<0.20). Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. 0000054214 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. K3=yg`D}\%-o00 0000002793 00000 n 0000014253 00000 n Lancet 2010;376:245-251, 26. Incorporation of bevacizumab in the primary treatment of ovarian cancer. 0 endstream endobj 71 0 obj <> endobj 72 0 obj <>stream Predictive and prognostic factors for progression-free survival were explored with the use of preplanned subgroup analyses, including status with respect to BRCA1/2 germline mutation, age, Jewish or non-Jewish ancestry, response status at baseline, and time to progression from the start of the penultimate platinum-based regimen. 0000055027 00000 n 0000013899 00000 n This article (10.1056/NEJMoa1105535) was published on March 27, 2012, at NEJM.org. J Natl Cancer Inst 2006;98:1694-1706, 12. Proc Natl Acad Sci U S A 2008;105:17079-17084, 23. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin. 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. 60 0 obj <> endobj 0000052439 00000 n 0000043244 00000 n 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. From University College London, London (J.L. ], 16. Nature 2005;434:917-921, 19. Kaye SB, Fehrenbacher L, Holloway R, et al. 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. There were no significant differences between the study groups in the end points for symptoms or health-related quality of life. Sporadic epithelial ovarian cancer: clinical relevance of BRCA1 inhibition in the DNA damage and repair pathway. 6,> Dc,R.2B8:Rv-! 3B6k|]OVkRkI'Iji[AZ DN.x$3WZf2Vkz{[*xX+c9l~=cY KBvIg@hEl?_%J)}DwW(A((hll*,/((,- 5BCEPZZ ih(z]\E;\)H3}^'A&5'S:kq;X{)@T!AQgM0F,P-1g>0Y!{OJG53z]N}#)cVG Dose modifications were more common in the olaparib group; however, discontinuations due to adverse events were infrequent, and adherence to therapy was high. NEW! 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. 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. Interim analysis showed no overall survival benefit. 0000053624 00000 n The most trusted, influential source of new medical knowledge and clinical best practices in the world. 0000025289 00000 n 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.