Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study

Domchek, Susan M.; Postel-Vinay, Sophie; Im, Seock Ah; Park, Yeon Hee; Delord, Jean Pierre; Italiano, Antoîne; Alexandre, Jérôme; You, Benoît; Bastian, Sara; Krebs, Matthew; Wang, Ding; Waqar, Saiama N.; Lanasa, Mark C.; Rhee, Joon Haeng; Gao, Haiyan; Rocher-Ros, Vidalba; Jones, Emma V.; Gulati, Sakshi; Coenen-Stass, Anna M.L.; Kozarewa, Iwanka; Lai, Zhongwu; Angell, Helen K.; Opincar, Laura; Herbolsheimer, Pia; Kaufman, Bella

doi:10.1016/s1470-2045(20)30324-7

Cited by 319 publications

(231 citation statements)

References 24 publications

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“…Supporting data come from phase II trials combining olaparib with durvalumab (anti-PD-L1), showing tolerable toxicity and promising disease control rates in patients with breast and prostate cancer. 120 121 In general, immunotherapy in PDAC appears to be restricted to cases with specific mutations leading to neoantigen expression. As in an unselected population with metastatic PDAC, ORR was far below expectations.…”

Section: Therapeutic Interference With the Ddr In Pancreatic Cancermentioning

confidence: 99%

DNA damage repair as a target in pancreatic cancer: state-of-the-art and future perspectives

Perkhofer

Gout

Roger

et al. 2020

Gut

129

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Complex rearrangement patterns and mitotic errors are hallmarks of most pancreatic ductal adenocarcinomas (PDAC), a disease with dismal prognosis despite some therapeutic advances in recent years. DNA double-strand breaks (DSB) bear the greatest risk of provoking genomic instability, and DNA damage repair (DDR) pathways are crucial in preserving genomic integrity following a plethora of damage types. Two major repair pathways dominate DSB repair for safeguarding the genome integrity: non-homologous end joining and homologous recombination (HR). Defective HR, but also alterations in other DDR pathways, such as BRCA1, BRCA2, ATM and PALB2, occur frequently in both inherited and sporadic PDAC. Personalised treatment of pancreatic cancer is still in its infancy and predictive biomarkers are lacking. DDR deficiency might render a PDAC vulnerable to a potential new therapeutic intervention that increases the DNA damage load beyond a tolerable threshold, as for example, induced by poly (ADP-ribose) polymerase inhibitors. The Pancreas Cancer Olaparib Ongoing (POLO) trial, in which olaparib as a maintenance treatment improved progression-free survival compared with placebo after platinum-based induction chemotherapy in patients with PDAC and germline BRCA1/2 mutations, raised great hopes of a substantially improved outcome for this patient subgroup. This review summarises the relationship between DDR and PDAC, the prevalence and characteristics of DNA repair mutations and options for the clinical management of patients with PDAC and DNA repair deficiency.

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Section: Therapeutic Interference With the Ddr In Pancreatic Cancermentioning

confidence: 99%

DNA damage repair as a target in pancreatic cancer: state-of-the-art and future perspectives

Perkhofer

Gout

Roger

et al. 2020

Gut

129

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“…In line with this, Pantelidou et al have shown PARPi efficacy in BRCA mutant mouse models is dependent upon the STING pathway immune response 128 . Additionally, early phase clinical work in the MEDIOLA basket trial has demonstrated anti‐tumor activity for the combination of olaparib and durvulumab (a PD‐L1 inhibitor) in germline BRCA ‐mutated advanced breast cancer 129 . Furthermore, in the I‐SPY 2 trial the use of this combination, together with paclitaxel, followed by doxorubicin/cyclophosphamide in the neoadjuvant setting in both high risk ER‐ and ER+ early breast cancer resulted in an estimated pCR rate of 37%, compared with 20% in patients receiving paclitaxel‐adriamycin/cyclophosphamide chemotherapy alone 130 …”

Section: Hr Defects and Cancer Treatmentmentioning

confidence: 87%

Homologous recombination deficiency in breast cancer: Implications for risk, cancer development, and therapy

Ali

McIntosh

Savage

2020

Genes Chromosomes & Cancer

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An underlying cause of breast cancers has been largely attributed to defects in the DNA damage response (DDR) pathway. In particular, the homologous recombination (HR) pathway repairs double‐stranded breaks (DSBs) in DNA, ultimately protecting the cell from genomic instability and thus preventing the accumulation of transforming mutations. In line with this, mutations in a number of genes encoding HR proteins are a well‐studied cause of HR deficiency (HRD), and, at the germline level, can confer risk to breast cancer but also occur somatically, contributing to sporadic breast cancer development, progression and response to therapy. Our understanding of the biological processes involved in HR and how these become compromised during breast cancer development has led to a better understanding of how HRD cells can be targeted with specific DNA damaging agents and/or with synthetic lethal targeting approaches such as PARP inhibition. Additionally, in vitro and preclinical modeling has supported the development of clinical trials to assess targeted therapies such as PARP inhibitors (PARPis), ultimately leading to development of therapies with greater clinical benefit. A number of challenges have been encountered, including resistance to therapy; however, addressing these challenges head‐on and continually driving scientific research and clinical trials with innovative therapies will contribute to our ability to target HRD in breast cancers. Ongoing research efforts into HRD in breast cancer development are therefore essential, even in the era of targeted therapies, to provide innovative strategies for improved tumor responses.

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“…141,142 A recent phase Ⅰ/Ⅱ study found that olaparib combined with durvalumab showed promising antitumor effects in patients with germline BRCA-mutated metastatic breast cancer. 143 Understanding the immunomodulatory activity of these new pathways will help to develop novel combinations of molecular targeted therapy and immunotherapy and optimize synergistic antitumor effects through the use of nanomaterials.…”

mentioning

confidence: 99%

Nanomaterials Enhance the Immunomodulatory Effect of Molecular Targeted Therapy

Li¹,

Liu²,

Fang³

et al. 2021

IJN

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Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study

Cited by 319 publications

References 24 publications

DNA damage repair as a target in pancreatic cancer: state-of-the-art and future perspectives

DNA damage repair as a target in pancreatic cancer: state-of-the-art and future perspectives

Homologous recombination deficiency in breast cancer: Implications for risk, cancer development, and therapy

Nanomaterials Enhance the Immunomodulatory Effect of Molecular Targeted Therapy

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