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Front-Line Maintenance Therapy in Advanced Ovarian Cancer-Current Advances and Perspectives.

ABSTRACT: Ovarian tumor is the gynecological cancer associated with the highest mortality. Most diseases are diagnosed at an advanced stage, which impairs the chances of prolonged complete remission. The standard front-line treatment of advanced stages combines surgery in an expert center with platinum-based chemotherapy. Most patients experience a relapse in the years following the initial treatment. During the last decade, anti-angiogenic agents used in the maintenance setting improved progression free survival (PFS) over chemotherapy alone. More recently, PARP inhibitors demonstrated substantial efficacy, mainly in patients with germinal or somatic BRCA mutations or other homologous recombination deficiencies (HRD), all involved in double strand DNA Damage Repair (DDR). Other therapeutic paradigms are currently being explored, including combinations of immune-checkpoints inhibitors, chemotherapy, bevacizumab and PARP inhibitors. In addition to these clinical advances, molecular characterization of the tumors and their correlations with drugs efficacy are needed to better understand which patient will benefit the most from the various treatments available to date.

SUBMITTER: Reverdy T

PROVIDER: S-EPMC7564452 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Front-Line Maintenance Therapy in Advanced Ovarian Cancer-Current Advances and Perspectives.

Reverdy Thibaut T Sajous Christophe C Péron Julien J Glehen Olivier O Bakrin Naoual N Gertych Witold W Lopez Jonathan J You Benoit B Freyer Gilles G

Cancers 20200825 9

Ovarian tumor is the gynecological cancer associated with the highest mortality. Most diseases are diagnosed at an advanced stage, which impairs the chances of prolonged complete remission. The standard front-line treatment of advanced stages combines surgery in an expert center with platinum-based chemotherapy. Most patients experience a relapse in the years following the initial treatment. During the last decade, anti-angiogenic agents used in the maintenance setting improved progression free ...[more]

PMID: 32854393

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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:BackgroundData 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.MethodsIn 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.ResultsA 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.ConclusionsAcross 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.).

Dataset Information

Front-Line Maintenance Therapy in Advanced Ovarian Cancer-Current Advances and Perspectives.

Publications

Front-Line Maintenance Therapy in Advanced Ovarian Cancer-Current Advances and Perspectives.

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