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

Summary

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.

Introduction

BRCA1 and BRCA2 are tumour suppressor genes closely linked to breast cancer susceptibility. Pathogenic germline variants of BRCA1 and BRCA2 occur in approximately 5% of patients with breast cancer1, 2 and are associated with high risk of cancer.³ BRCA proteins help repair DNA double-strand breaks via the homologous recombination repair pathway.⁴ Poly (ADP-ribose) polymerases (PARPs) are a family of enzymes involved in the repair of single-strand DNA breaks through base excision repair.

In the OlympiAD study, olaparib showed a significant benefit over standard chemotherapy in patients with germline BRCA1-mutated or BRCA2-mutated metastatic breast cancer. Among 205 patients randomised to olaparib, the objective response rate was 60% versus 29% of 97 patients assigned to chemotherapy; the median progression-free survival was 7·0 months versus 4·2 months (hazard ratio [HR] 0·58, p<0·001); median duration of response was 6·4 months versus 7·1 months; and median overall survival 19·3 months versus 17·1 months.5, 6 Subgroup analysis of patients receiving olaparib in the first-line setting (n=59, 29%) showed an improvement in median overall survival compared with chemotherapy (n=28, 29%) of 22·6 months versus 14·7 months (HR 0·51, 95% CI 0·29–0·90).⁶

Research in context

Evidence before this study

We searched PubMed, Embase, MEDLINE, and oncology congress websites for clinical trials of combinations of poly (ADP-ribose) polymerase (PARP) inhibitors and anti-PD-L1 or anti-PD-1 antibodies used to treat patients with breast cancer published between Jan 1, 2000, and Dec 31, 2015. The search terms used were “poly (ADP-ribose) polymerase inhibitors”, “nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor”, “antineoplastic agents”, “immunological/antineoplastic monoclonal antibody”, “breast neoplasms”, and “breast tumor”. No language preferences were specified. At the time of the initial protocol approval (Sept 9, 2015), there were no published reports of a clinical trial combining a PARP inhibitor with an immune checkpoint inhibitor for treatment of patients with breast cancer. Previous studies had shown that in germline BRCA-mutated tumours, PARP inhibition results in an accumulation of DNA damage, causing genomic instability and ultimately cell death. An interaction between DNA damage induced by the PARP inhibitor, olaparib, and the immune system has previously been shown. Furthermore, preclinical data indicated that PARP inhibition upregulates PD-L1 expression and elicits an antitumour immune response through a stimulator of interferon genes pathway in BRCA1-deficient mice. These data provided the rationale for combining olaparib with durvalumab, an inhibitor of PD-L1, in patients with germline BRCA1-mutated or BRCA2-mutated metastatic breast cancer.

Added value of this study

To our knowledge, the MEDIOLA study of a PARP inhibitor combined with immunotherapy in the treatment of BRCA1-mutated or BRCA2-mutated breast cancer is the first study to report results for hormone receptor positive disease to date. Combining olaparib with durvalumab showed no new safety signals for either drug administered at full doses and promising antitumour activity.

Implications of all the available evidence

Our research suggests the addition of a PD-L1 inhibitor (durvalumab) to olaparib has potential for the treatment of patients with metastatic breast cancer whose tumours harbour a germline BRCA mutation. Further research in a randomised setting is justified to determine whether there are subsets of patients with metastatic breast cancer who could benefit from the addition of durvalumab to olaparib. Understanding mechanisms of innate and acquired resistance to PARP inhibitors will lead to new insights into targeting the DNA damage response in cancers, and because resistance to PARP inhibitors represents an emerging population with unmet medical need, new therapeutic options for these patients are required.

Durvalumab is a human IgG1 κ monoclonal antibody that inhibits binding of PD-L1 to its receptors PD-1 and CD80. Durvalumab is approved for the treatment of urothelial carcinoma⁷ and unresectable stage 3 non-small-cell lung cancer.⁸ Atezolizumab, another immune checkpoint inhibitor, in combination with nab-paclitaxel is approved for PD-L1-positive metastatic triple-negative breast cancer based on data on median progression-free survival.⁹

Immunotherapies combined with chemotherapy or a PARP inhibitor are being explored in various studies.10, 11, 12 In the TOPACIO trial,¹¹ a combination of niraparib and pembrolizumab in patients with advanced or metastatic triple-negative breast cancer showed promising efficacy, particularly in those with a tumour BRCA mutation (n=15; objective response rate 47% [90% CI 24–70] and a disease control rate 80% [56–94]). Increasing evidence shows an interaction between olaparib-induced DNA damage and the immune system.¹³ Preclinical data suggest that PARP inhibitors might elicit an antitumour immune response14, 15 and provide the rationale for investigating olaparib in combination with durvalumab in germline BRCA1-mutated and BRCA2-mutated metastatic breast cancer.13, 14 The dosing schedule of this combination has been previously tested in six patients in a phase 1 study.¹² In this study, we aimed to further evaluate the safety profile and antitumour activity of this combination.