Susan M Domchek1, Sophie Postel-Vinay2, Seock-Ah Im3, Yeon Hee Park4, Jean-Pierre Delord5, Antoine Italiano6, Jerome Alexandre7, Benoit You8, Sara Bastian9, Matthew G Krebs10, Ding Wang11, Saiama N Waqar12, Mark Lanasa13, Joon Rhee13, Haiyan Gao14, Vidalba Rocher-Ros14, Emma V Jones14, Sakshi Gulati14, Anna Coenen-Stass14, Iwanka Kozarewa14, Zhongwu Lai13, Helen K Angell14, Laura Opincar13, Pia Herbolsheimer13, Bella Kaufman15. 1. Basser Center for BRCA, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: susan.domchek@pennmedicine.upenn.edu. 2. ATIP -Avenir group, Inserm Unit U981, Villejuif, France; Faculté de Médicine, Le Kremlin Bicêtre, Université Paris Saclay, Université Paris-Sud, Villejuif, France; Department of Drug Development, Gustave Roussy, Villejuif, France. 3. Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of South Korea. 4. Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of South Korea. 5. Institut Universitaire du Cancer de Toulouse, Toulouse, France. 6. Institut Bergonié, Bordeaux, France. 7. Hôpital Cochin, Paris, France. 8. Medical Oncology, Institut de Cancérologie des Hospices Civils de Lyon, Centre d'Investigation de Therapeutiques en Oncologie et H ematologie de Lyon, Centre Hospitalier Lyon-Sud, Lyon, France; Faculté de Médecine Lyon-Sud, Univ Lyon, Université Claude Bernard Lyon 1, EMR UCBL/HCL 3738, Lyon, France; Groupe des Investigateurs Nationaux pour les Cancers de l Ovaire et du sein-GINEGEPS, Paris, France. 9. Kantonsspital Graubuenden, Chur, Switzerland. 10. Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester and The Christie NHS Foundation Trust, Manchester, UK; Manchester Academic Health Science Centre, Manchester, UK. 11. Henry Ford Medical Center, Detroit, MI, USA. 12. Washington University School of Medicine, Saint Louis, MO, USA. 13. AstraZeneca, Gaithersburg, MD, USA. 14. AstraZeneca, Cambridge, UK. 15. Chaim Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Abstract
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.
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.
Authors: Roman M Chabanon; Mathieu Rouanne; Christopher J Lord; Jean-Charles Soria; Philippe Pasero; Sophie Postel-Vinay Journal: Nat Rev Cancer Date: 2021-08-10 Impact factor: 60.716
Authors: Hannah Dabagian; Tahereh Taghvaee; Paul Martorano; Daniel Martinez; Minu Samanta; Carolyn M Watkins; Richard Chai; Adam Mansfield; Thomas J Graham; John M Maris; Daniel A Pryma; Robert H Mach; Mehran Makvandi Journal: ACS Pharmacol Transl Sci Date: 2021-01-26