TY - JOUR
T1 - Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA)
T2 - an open-label, multicentre, phase 1/2, basket study
AU - Domchek, Susan M.
AU - Postel-Vinay, Sophie
AU - Im, Seock Ah
AU - Park, Yeon Hee
AU - Delord, Jean Pierre
AU - Italiano, Antoine
AU - Alexandre, Jerome
AU - You, Benoit
AU - Bastian, Sara
AU - Krebs, Matthew G.
AU - Wang, Ding
AU - Waqar, Saiama N.
AU - Lanasa, Mark
AU - Rhee, Joon
AU - Gao, Haiyan
AU - Rocher-Ros, Vidalba
AU - Jones, Emma V.
AU - Gulati, Sakshi
AU - Coenen-Stass, Anna
AU - Kozarewa, Iwanka
AU - Lai, Zhongwu
AU - Angell, Helen K.
AU - Opincar, Laura
AU - Herbolsheimer, Pia
AU - Kaufman, Bella
N1 - Funding Information:
SMD has received honoraria from AstraZeneca, Clovis, and Bristol-Myers Squibb; and the University of Pennsylvania research funding from AstraZeneca and Clovis. SP-V, as part of the Drug Development Department (DITEP), is principal or subinvestigator of clinical trials for AbbVie, Adaptimmune, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X BVBA, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, Aveo, Bayer AG, Bbb Technologies BV, Beigene, Bioalliance Pharma, Biontech AG, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol-Myers Squibb, Celgene Corporation, Cephalon, Chugai Pharmaceutical Co, Clovis Oncology, Cullinan-Apollo, Daiichi Sankyo, Debiopharm, Eisai, Eli Lilly, Exelixis, Forma Therapeutics, GamaMabs, Genentech, Gilead Sciences, GlaxoSmithKline, Glenmark Pharmaceuticals, H3 Biomedicine, Hoffmann La Roche AG, Incyte Corporation, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Janssen Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharmaceutical Development, Lilly France, Loxo Oncology, Lytix Biopharma AS, MedImmune, Menarini Ricerche, Merck KGaA, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Molecular Partners AG, Nanobiotix, Nektar Therapeutics, Nerviano Medical Sciences, Novartis Pharma, Octimet Oncology NV, Oncoethix, Oncomed, Oncopeptides, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Ose Pharma, Pfizer, Pharma Mar, Philogen SPA, Pierre Fabre Medicament, Plexxikon, Rigontec GmbH, Roche, Sanofi Aventis, Sierra Oncology, Sotio AS, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Tioma Therapeutics, Wyeth Pharmaceuticals France, Xencor, and Y's Therapeutics. S-AI reports receiving research grants from AstraZeneca, Pfizer, and Roche; personal fees and non-financial support for presenting results of clinical trials from Novartis; and personal fees from AstraZeneca, Hanmi, Pfizer, Eisai, Amgen, MediPacto, Roche, and Lilly, outside the submitted work. YHP reports receiving grants from Pfizer, AstraZeneca, Eisai, Novartis, Merck, and Hanmi; and non-financial support from Pfizer, AstraZeneca, Novartis, Merck, and Roche, all outside the submitted work. AI reports grants from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Merck, Roche, and Pharmamar; and personal fees from Merck, Roche, Springworks, and Daiichi Sankyo. JA reports receiving personal fees from AstraZeneca, GlaxoSmithKline/Tesaro, Pharmamar, Novartis, and Roche; and non-financial support from Novartis and Janssen. MGK has participated in advisory boards or acted as a consultant for Achilles Therapeutics Ltd, Janssen, Octimet Oncology, and Roche; received travel grants from AstraZeneca and BerGenBio; and received research funding from Merck Sharp & Dohme, BerGenBio, and Roche. SNW reports being a junior faculty mentee of a UM1 National Cancer Institute grant outside the submitted work. BK has participated in advisory boards for AstraZeneca. ML, JR, HG, VR-R, EVJ, SG, AC-S, IK, ZL, HKA, LO, and PH are employees of or have stock ownership with AstraZeneca, or both. SB, J-PD, BY, and DW declare no competing interests.
Funding Information:
The funder designed the trial and was responsible for overseeing the data collection, data analysis, and data interpretation. The manuscript was written by the authors with medical writing support, funded by the funder. The corresponding author (SMD) had full access to study data and final responsibility for the decision to submit for publication.
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2020/9
Y1 - 2020/9
N2 - Background: Poly (ADP-ribose) polymerase inhibitors combined with immunotherapy have shown antitumour activity in preclinical studies. We aimed to assess the safety and activity of olaparib in combination with the PD-L1-inhibitor, durvalumab, in patients with germline BRCA1-mutated or BRCA2-mutated metastatic breast cancer. Methods: The MEDIOLA trial is a multicentre, open-label, phase 1/2, basket trial of durvalumab and olaparib in solid tumours. Patients were enrolled into four initial cohorts: germline BRCA-mutated, metastatic breast cancer; germline BRCA-mutated, metastatic ovarian cancer; metastatic gastric cancer; and relapsed small-cell lung cancer. Here, we report on the cohort of patients with breast cancer. Patients who were aged 18 years or older (or aged 19 years or older in South Korea) with germline BRCA1-mutated or BRCA2-mutated or both and histologically confirmed, progressive, HER2-negative, metastatic breast cancer were enrolled from 14 health centres in the UK, the USA, Israel, France, Switzerland, and South Korea. Patients should not have received more than two previous lines of chemotherapy for metastatic breast cancer. Patients received 300 mg olaparib in tablet form orally twice daily for 4 weeks and thereafter a combination of olaparib 300 mg twice daily and durvalumab 1·5 g via intravenous infusion every 4 weeks until disease progression. Primary endpoints were safety and tolerability, and 12-week disease control rate. Safety was analysed in patients who received at least one dose of study treatment, and activity analyses were done in the full-analysis set (patients who received at least one dose of study treatment and were not excluded from the study). Recruitment has completed and the study is ongoing. This trial is registered with ClinicalTrials.gov, NCT02734004. Findings: Between June 14, 2016, and May 2, 2017, 34 patients were enrolled and received both study drugs and were included in the safety analysis. 11 (32%) patients experienced grade 3 or worse adverse events, of which the most common were anaemia (four [12%]), neutropenia (three [9%]), and pancreatitis (two [6%]). Three (9%) patients discontinued due to adverse events and four (12%) patients experienced a total of six serious adverse events. There were no treatment-related deaths. 24 (80%; 90% CI 64·3–90·9) of 30 patients eligible for activity analysis had disease control at 12 weeks. Interpretation: Combination of olaparib and durvalumab showed promising antitumour activity and safety similar to that previously observed in olaparib and durvalumab monotherapy studies. Further research in a randomised setting is needed to determine predictors of therapeutic benefit and whether addition of durvalumab improves long-term clinical outcomes compared with olaparib monotherapy. Funding: AstraZeneca.
AB - Background: Poly (ADP-ribose) polymerase inhibitors combined with immunotherapy have shown antitumour activity in preclinical studies. We aimed to assess the safety and activity of olaparib in combination with the PD-L1-inhibitor, durvalumab, in patients with germline BRCA1-mutated or BRCA2-mutated metastatic breast cancer. Methods: The MEDIOLA trial is a multicentre, open-label, phase 1/2, basket trial of durvalumab and olaparib in solid tumours. Patients were enrolled into four initial cohorts: germline BRCA-mutated, metastatic breast cancer; germline BRCA-mutated, metastatic ovarian cancer; metastatic gastric cancer; and relapsed small-cell lung cancer. Here, we report on the cohort of patients with breast cancer. Patients who were aged 18 years or older (or aged 19 years or older in South Korea) with germline BRCA1-mutated or BRCA2-mutated or both and histologically confirmed, progressive, HER2-negative, metastatic breast cancer were enrolled from 14 health centres in the UK, the USA, Israel, France, Switzerland, and South Korea. Patients should not have received more than two previous lines of chemotherapy for metastatic breast cancer. Patients received 300 mg olaparib in tablet form orally twice daily for 4 weeks and thereafter a combination of olaparib 300 mg twice daily and durvalumab 1·5 g via intravenous infusion every 4 weeks until disease progression. Primary endpoints were safety and tolerability, and 12-week disease control rate. Safety was analysed in patients who received at least one dose of study treatment, and activity analyses were done in the full-analysis set (patients who received at least one dose of study treatment and were not excluded from the study). Recruitment has completed and the study is ongoing. This trial is registered with ClinicalTrials.gov, NCT02734004. Findings: Between June 14, 2016, and May 2, 2017, 34 patients were enrolled and received both study drugs and were included in the safety analysis. 11 (32%) patients experienced grade 3 or worse adverse events, of which the most common were anaemia (four [12%]), neutropenia (three [9%]), and pancreatitis (two [6%]). Three (9%) patients discontinued due to adverse events and four (12%) patients experienced a total of six serious adverse events. There were no treatment-related deaths. 24 (80%; 90% CI 64·3–90·9) of 30 patients eligible for activity analysis had disease control at 12 weeks. Interpretation: Combination of olaparib and durvalumab showed promising antitumour activity and safety similar to that previously observed in olaparib and durvalumab monotherapy studies. Further research in a randomised setting is needed to determine predictors of therapeutic benefit and whether addition of durvalumab improves long-term clinical outcomes compared with olaparib monotherapy. Funding: AstraZeneca.
UR - http://www.scopus.com/inward/record.url?scp=85089967617&partnerID=8YFLogxK
U2 - 10.1016/S1470-2045(20)30324-7
DO - 10.1016/S1470-2045(20)30324-7
M3 - Article
C2 - 32771088
AN - SCOPUS:85089967617
VL - 21
SP - 1155
EP - 1164
JO - The Lancet Oncology
JF - The Lancet Oncology
SN - 1470-2045
IS - 9
ER -