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Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer.

ABSTRACT: BACKGROUND:Data are limited regarding the use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors, such as veliparib, in combination with chemotherapy followed by maintenance as initial treatment in patients with high-grade serous ovarian carcinoma. METHODS:In an international, phase 3, placebo-controlled trial, we assessed the efficacy of veliparib added to first-line induction chemotherapy with carboplatin and paclitaxel and continued as maintenance monotherapy in patients with previously untreated stage III or IV high-grade serous ovarian carcinoma. Patients were randomly assigned in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance (control), chemotherapy plus veliparib followed by placebo maintenance (veliparib combination only), or chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout). Cytoreductive surgery could be performed before initiation or after 3 cycles of trial treatment. Combination chemotherapy was 6 cycles, and maintenance therapy was 30 additional cycles. The primary end point was investigator-assessed progression-free survival in the veliparib-throughout group as compared with the control group, analyzed sequentially in the BRCA-mutation cohort, the cohort with homologous-recombination deficiency (HRD) (which included the BRCA-mutation cohort), and the intention-to-treat population. RESULTS:A total of 1140 patients underwent randomization. In the BRCA-mutation cohort, the median progression-free survival was 34.7 months in the veliparib-throughout group and 22.0 months in the control group (hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.28 to 0.68; P<0.001); in the HRD cohort, it was 31.9 months and 20.5 months, respectively (hazard ratio, 0.57; 95 CI, 0.43 to 0.76; P<0.001); and in the intention-to-treat population, it was 23.5 months and 17.3 months (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P<0.001). Veliparib led to a higher incidence of anemia and thrombocytopenia when combined with chemotherapy as well as of nausea and fatigue overall. CONCLUSIONS:Across all trial populations, a regimen of carboplatin, paclitaxel, and veliparib induction therapy followed by veliparib maintenance therapy led to significantly longer progression-free survival than carboplatin plus paclitaxel induction therapy alone. The independent value of adding veliparib during induction therapy without veliparib maintenance was less clear. (Funded by AbbVie; VELIA/GOG-3005 ClinicalTrials.gov number, NCT02470585.).

SUBMITTER: Coleman RL

PROVIDER: S-EPMC6941439 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer.

Coleman Robert L RL Fleming Gini F GF Brady Mark F MF Swisher Elizabeth M EM Steffensen Karina D KD Friedlander Michael M Okamoto Aikou A Moore Kathleen N KN Efrat Ben-Baruch Noa N Werner Theresa L TL Cloven Noelle G NG Oaknin Ana A DiSilvestro Paul A PA Morgan Mark A MA Nam Joo-Hyun JH Leath Charles A CA Nicum Shibani S Hagemann Andrea R AR Littell Ramey D RD Cella David D Baron-Hay Sally S Garcia-Donas Jesus J Mizuno Mika M Bell-McGuinn Katherine K Sullivan Danielle M DM Bach Bruce A BA Bhattacharya Sudipta S Ratajczak Christine K CK Ansell Peter J PJ Dinh Minh H MH Aghajanian Carol C Bookman Michael A MA

The New England journal of medicine 20190928 25

<h4>Background</h4>Data are limited regarding the use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors, such as veliparib, in combination with chemotherapy followed by maintenance as initial treatment in patients with high-grade serous ovarian carcinoma.<h4>Methods</h4>In an international, phase 3, placebo-controlled trial, we assessed the efficacy of veliparib added to first-line induction chemotherapy with carboplatin and paclitaxel and continued as maintenance monotherapy in ...[more]

PMID: 31562800

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Project description:The incidence and mortality rates of ovarian cancer are increasing globally. Ovarian cancer is diagnosed at an advanced stage in 80% of women. After standard, platinum-based, front-line chemotherapy, poly (ADP-ribose) polymerase (PARP) inhibitors and antiangiogenic agents are successfully employed as maintenance strategies for newly diagnosed, advanced ovarian cancer patients. Landmark clinical studies, including SOLO-1, PAOLA-1, PRIMA, and VELIA, have provided crucial insights on optimizing first-line maintenance treatment using PARP inhibitors. A group of ovarian cancer experts, primarily from low- and middle-income countries, met in September 2019 to discuss new developments for the first-line treatment of ovarian cancer and its implications. Key implications of the evolving clinical data included: (1) olaparib or niraparib maintenance therapy appears to be the preferred choice for patients with BRCA1/2 mutations; hence, BRCA testing is beneficial in identifying these patients; (2) niraparib monotherapy and olaparib in combination with bevacizumab have demonstrated significant benefit in progression-free survival (PFS) in homologous recombination deficiency (HRD)-positive patients; (3) bevacizumab, niraparib alone, or observation can be an alternative for HRD-negative patients; (4) further data is warranted to explore the role of PARP inhibitors in treating HRD-negative, ovarian cancer patients to confirm findings of the exploratory analysis of PRIMA; (5) PARP inhibitors may be beneficial for stage IV ovarian cancer patients with inoperable disease and patients with prior neoadjuvant chemotherapy; and (6) there is an urgent need to increase awareness in both clinicians and patients on BRCA and HRD testing for optimizing treatment decision-making and improving clinical outcomes in newly diagnosed, advanced ovarian cancer patients. In clinical medicine, the limited availability of family history (FH) information and the complexity of FH criteria has hampered the implementation of BRCA testing. Moreover, many cancer patients with BRCA mutations are not tested because they do not meet the criteria for FH. Consequently, BRCA testing in many high income countries, including the US and Australia, is underused and used inappropriately, which has resulted in the loss of valuable opportunities for better cancer management and cancer prevention.

Project description:BackgroundEpithelial ovarian cancer accounts for about 90% of all cases of ovarian cancer. Debulking surgery and six courses of platinum-based chemotherapy results in complete clinical remission (CCR) in up to 75% of cases. However, 75% of the responders will relapse within a median time of 18 to 28 months and only 20% to 40% of women will survive beyond five years. It has been suggested that maintenance chemotherapy could assist in prolonging remission. To date, there has not been a systematic review on the impact of maintenance chemotherapy for epithelial ovarian cancer.ObjectivesTo assess the effectiveness and toxicity of maintenance chemotherapy for epithelial ovarian cancer and to evaluate the impact on quality of life (QoL).Search methodsIn the original review we searched the Cochrane Gynaecological Cancer Review Group Specialised Register, The Cochrane Central Register of Controlled Trails (CENTRAL, The Cochrane Library 2009, Issue 1), MEDLINE, EMBASE, PubMed, CBMdisc, CNKI and VIP (to May 2009). We collected information from ongoing trials, checked reference lists of published articles and consulted experts in the field. For this update, the searches were extended to October 2012.Selection criteriaRandomised controlled trials (RCTs) comparing maintenance chemotherapy with no further intervention, maintenance radiotherapy or other maintenance therapy.Data collection and analysisTwo review authors independently assessed trials for eligibility and quality and extracted data. We analysed overall survival (OS) and progression-free survival (PFS) rates as dichotomous variables. Toxicity and QoL data were extracted where present. All analyses were based on intention-to-treat (ITT) on the endpoint of survival. We also analysed data by subgroups of drugs.Main resultsWe included eight trials (1644 women). When all chemotherapy regimens were combined, meta-analysis indicated no significant difference in three-, five- and 10-year OS or PFS. For five-year OS, the combined risk ratio (RR) was 1.03 (95% confidence interval (CI) 0.96 to 1.10) and for the five-year PFS, the combined RR was 1.06 (95% CI 0.97 to 1.17). Results were very similar when trials of different regimens were analysed. Comparing chemotherapy with radiotherapy, only the RR for 10-year PFS in pathological complete remission (PCR) was in favour of whole abdominal radiotherapy 0.51 (95% CI 0.27 to 1.00), while three- and five-year OS rates have no significant difference between the two groups.Authors' conclusionsThere is no evidence to suggest that the use of platinum agents, doxorubicin or paclitaxel used as maintenance chemotherapy is more effective than observation alone. Further investigations regarding the effect of paclitaxel used as maintenance chemotherapy are required.

Project description:Ovarian cancer is the worst prognostic gynaecological cancer and represents a grave clinical and social problem. Therefore, the study aimed to assess female patients' emotional, cognitive, physical, and social quality of life. The study included 100 patients diagnosed with ovarian cancer and treated with chemotherapy in a day hospital setting at the Department of Radiotherapy and Gynaecological Oncology at the Wielkopolska Oncology Centre in Poznań. The patients were given a standard treatment regimen: paclitaxel 175 mg/m2 in a 3 h infusion and carboplatin at an AUC of 6 (5-7) following Calvert as a 1 h infusion for six cycles administered every 21 days. In addition, standardised questionnaires of the Polish version of the EORTC QLQ-C30 and QLQOV28 were used. The analysis of the collected material shows that the patients reported the highest level of general health and quality of life at the study's first stage, i.e., before chemotherapy (mean value of 59.67 points). In contrast, the patients' lowest level of general health and quality of life was observed in the fourth stage of the study (mean value of 45.04 points). The problem of side effects, such as nausea and vomiting, affected the entire study group and was more troublesome in the final stage of treatment for all patients. In the study's first stage, the mean score on the nausea and vomiting symptom scale was 16 points; in the fourth stage, the mean score was 40.07. Of the clinical factors, the symptom of fatigue was the most severe health problem for the subjects. The mean score of the fatigue scale in the study's first stage was 37.11 points, while a score of 70.33 was obtained in the fourth stage of the research. The multivariate linear regression model showed that the lack of professional activity lowers quality of life, especially combined with other side effects of chemotherapy, including hair loss in Stage IV of the study. This study shows that women with ovarian cancer undergoing chemotherapy need exceptional support from psychologists, nurses, dieticians, and physiotherapists.

Dataset Information

Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer.

Publications

Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer.

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