by Susan M Domchek, Sophie Postel-Vinay, Seock-Ah Im, Yeon
Hee Park, Jean-Pierre Delord, Antoine Italiano, Jerome Alexandre, Benoit You,
Sara Bastian, Matthew G Krebs, Ding Wang, Saiama N Waqar, Mark Lanasa, Joon
Rhee, Haiyan Gao, Vidalba Rocher-Ros, Emma V Jones, Sakshi Gulati, Anna
Coenen-Stass, Iwanka Kozarewa, Zhongwu Lai, Helen K Angell, Laura Opincar, Pia
Herbolsheimer, Bella Kaufman
The Lancet Oncology: VOLUME 21,
ISSUE 9, P1155-1164, SEPTEMBER 01, 2020
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.
