study 19 olaparib lancet

0000001936 00000 n

As of this writing, 21% of the patients were still receiving olaparib (and 3% were still receiving placebo), which indicates that the disease is controlled for a prolonged period in some patients. Olaparib as maintenance treatment significantly improved progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer. There is a need to identify biomarkers to select patients for this therapy. If the toxicity resolved entirely or to a grade 1 level, treatment was restarted with a reduction in the dose to 200 mg or 100 mg twice daily. 0000002584 00000 n Progression-free survival was assessed with the use of computed tomographic scans obtained every 12 weeks and was calculated on the basis of measurements of target and nontarget lesions and assessment for new lesions that were recorded by the investigators. J Clin Oncol 2010;28:3323-3329, 6. 0 0000040403 00000 n O;I FBxLv{*g9PJ:/4(_h= 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. 0000024287 00000 n 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. 0000036519 00000 n 0000007932 00000 n TxDgG%G`FoCoR4U(hwwT()H 0000006077 00000 n

Evers B, Drost R, Schut E, et al. 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. 0000013899 00000 n In addition, a blinded independent central review of tumor scans was performed retrospectively. Clin Cancer Res 2010;16:2344-2351, 31. 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. 0000033104 00000 n 0000054647 00000 n Treatment was interrupted for any event of CTCAE grade 3 or 4 that was considered to be related to treatment. Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer. 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. 0000003231 00000 n Patients could continue receiving olaparib or placebo until disease progression or as long as they were benefitting from the treatment and did not meet any criteria for discontinuation (i.e., the ongoing-treatment group). Only the 1000 most recent citing articles are listed here. ), 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.) 0000008331 00000 n Data collection and analysis were performed by the sponsor, and all the authors had full access to the data. 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). Management of platinum-sensitive recurrent ovarian cancer. 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. Stay connected to what's important in medical research and clinical practice, Subscribe to the most trusted and influential source ofmedical knowledge. Burger RA, Brady MF, Bookman MA, et al. The median overall survival was similar in the two study groups (29.7 months in the olaparib group and 29.9 months in the placebo group). 0000055121 00000 n Rottenberg S, Jaspers JE, Kersbergen A, et al.

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. April 12, 2012N Engl J Med 2012; 366:1382-1392 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.

0000053955 00000 n 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). 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. xref At study entry, 40% of the overall study population had measurable disease and could be assessed for an objective response according to RECIST guidelines; the response rate was 12% (7 of 57 patients with measurable disease at study entry) in the olaparib group, as compared with 4% (2 of 48) in the placebo group (odds ratio, 3.36; 95% CI, 0.75 to 23.72; P=0.12). 0000049608 00000 n xb```b`Hd`c` @1v#@(!Gtm6Q>e A phase 3 trial of bevacizumab in ovarian cancer. 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 The decision to submit the manuscript for publication was made by all the authors and the sponsor. Dose modifications were more common in the olaparib group; however, discontinuations due to adverse events were infrequent, and adherence to therapy was high. trailer 0000054214 00000 n Enrollment, Randomization, and Treatment. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. BMC Cancer 2008;8:17-17, 15. Rustin GJ, Vergote I, Eisenhauer E, et al. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. An interim analysis of overall survival (38% maturity, meaning that 38% of the patients had died) showed no significant difference between groups (hazard ratio with olaparib, 0.94; 95% CI, 0.63 to 1.39; P=0.75). N Engl J Med 2011;365:2473-2483, 9. 0000053418 00000 n Between August 28, 2008, and February 9, 2010, we screened 326 patients at 82 investigational sites in 16 countries. Demographic and Baseline Characteristics of the Patients. hW XqZkqF#eE7Ph A"l# -Ep5yY&5w^ 7LSP J Clin Oncol 2010;28:3555-3561[Erratum, J Clin Oncol 2010;28:4868. 0000054921 00000 n 0000051012 00000 n A supportive analysis of progression-free survival with the use of the log-rank test was performed (stratified by randomization factors). Lancet 2010;376:245-251, 26. endstream endobj 71 0 obj <> endobj 72 0 obj <>stream 0000020900 00000 n 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). Interim analysis showed no overall survival benefit. Markman M, Liu PY, Moon J, et al. Panel A shows KaplanMeier curves for progression-free survival in the randomized population. Y@bS*S$3OS_6kfYN L5oxBgr both in Germany; University of Edinburgh Cancer Research U.K. Centre, Edinburgh (C.G. 141 0 obj <>stream 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 total enrollment of 250 patients was planned for the study, and the primary analysis was to be performed when at least 137 progression-free survival events had occurred. Adverse events that led to the permanent discontinuation of treatment occurred in three patients receiving olaparib (one each with palpitations and myalgia, erythematous rash, and nausea and obstruction in the small intestine) and in one patient receiving placebo (nausea); all these adverse events were grade 2 and were considered by the investigator to be related to treatment, except for the grade 4 obstruction in the small intestine. Incorporation of bevacizumab in the primary treatment of ovarian cancer. The final analysis of overall survival will be performed at 60% maturity (i.e., when 60% of the patients have died). Semin Oncol 2006;33:Suppl:S12-S16, 5. 0000036849 00000 n Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer. 0000020418 00000 n 0000053816 00000 n The study design is shown in Figure 1. 0000053672 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. }x0P: 0000054874 00000 n Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT00753545.).

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. 0000054311 00000 n 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. Curr Oncol 2007;14:195-208, 3. 0000053546 00000 n 0000004251 00000 n <<241AA167470147488D06DE51829A8373>]>> 60 82 Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). 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. The study was designed by the first author, in collaboration with the last author and the study sponsor, AstraZeneca. 0000024625 00000 n Progression-free survival was significantly longer with olaparib than with placebo (median, 8.4 months vs. 4.8 months from randomization on completion of chemotherapy; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.25 to 0.49; P<0.001). 0000043552 00000 n The toxicity profile of olaparib in this population was consistent with that in previous studies. K3=yg`D}\%-o00 Subgroup analyses of progression-free survival showed that, regardless of subgroup, patients in the olaparib group had a lower risk of progression. DOI: 10.1056/NEJMoa1105535, Tap into groundbreaking research and clinically relevant insights.

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). Ashworth A. 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).

Patients were randomly assigned to receive olaparib, at a dose of 400 mg twice daily, or placebo. Weberpals JI, Clark-Knowles KV, Vanderhyden BC. 0000025214 00000 n J Natl Cancer Inst 2006;98:1694-1706, 12. Nature 2005;434:917-921, 19. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. Information and tools for librarians about site license offerings. Mol Cell 2001;7:263-272, 14. The content of this site is intended for health care professionals. 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. 0000046595 00000 n 0000054736 00000 n 0000025289 00000 n 0000054358 00000 n However, most patients have relapses, and responses to subsequent therapies are generally short-lived.2-6 Maintenance chemotherapy as part of first-line treatment has been shown to prolong control of ovarian cancer,7 and disease control has also been prolonged with the combination of bevacizumab and chemotherapy in patients receiving first-line treatment8,9 and in those with platinum-sensitive relapsed ovarian cancer.10 However, new treatments are needed because most patients eventually have a relapse. In both groups, nausea, fatigue, and vomiting were intermittent and did not require discontinuation of the study treatment. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. 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. ], 2. Disease-related symptoms and health-related quality of life as reported by the patients were also measured (for details, see the Supplementary Appendix). 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). Fung-Kee-Fung M, Oliver T, Elit L, Oza A, Hirte HW, Bryson P. Optimal chemotherapy treatment for women with recurrent ovarian cancer. Tutt A, Robson M, Garber JE, et al. Because only patients with a response to chemotherapy were enrolled in the study, just 40% had measurable disease at entry. 0000052922 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.

Safety was assessed throughout the study by monitoring for adverse events, biochemical laboratory tests, assessment of vital signs, and physical examination. New guidelines to evaluate the response to treatment in solid tumors. ;`5*sko\6#mmXp?m9rv6;Enl4m'3Wp-9P2tS(U([PYS&ToR&UUEYpG;6EmVXA~ 0000007501 00000 n The size of the circles is proportional to the number of events. Response rates were low in both study groups, and some patients in the placebo group had a reduction in tumor size. 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. Of 265 patients who underwent randomization, 136 were assigned to the olaparib group and 129 to the placebo group. Gynecol Oncol 2009;114:195-198, 8. both in Israel; Indiana University School of Medicine, Indianapolis (D.M. We thank Claire Routley, Ph.D. (Mudskipper Bioscience), for editorial assistance, funded by AstraZeneca. J Clin Oncol 2011;29:3798-3804.

Valuable tools for building a rewarding career in health care. A digital journal for innovative original research and fresh, bold ideas in clinical trial design and clinical decision-making. Mukhopadhyay A, Elattar A, Cerbinskaite A, et al. 0000054091 00000 n ], 16. Pujade-Lauraine E, Wagner U, Avall-Lundqvist E, et al.

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study 19 olaparib lancet