Olaparib and durvalumab in patients with germline BRCA-mutated metastatic

breast cancer (MEDIOLA): results from an open-label phase 1/2 basket study

Susan M Domchek (MD), Sophie Postel-Vinay (MD), Seock-Ah Im (MD, Professor),

Yeon Hee Park (MD, Professor), Jean-Pierre Delord (MD, Professor), Antoine Italiano

(MD, Professor), Jerome Alexandre (MD, Professor), Benoit You (MD), Sara Bastian

(MD), Matthew G Krebs (PhD), Ding Wang (MD), Saiama N Waqar (MBBS MSCI), Mark

Lanasa (MD), Joon Rhee (PhD), Haiyan Gao (PhD), Vidalba Rocher-Ros (PhD), Emma

V Jones (PhD), Sakshi Gulati (PhD), Anna Coenen-Stass (PhD), Iwanka Kozarewa

(PhD), Zhongwu Lai (PhD), Helen K Angell (PhD), Laura Opincar (PharmD), Pia

Herbolsheimer (MD), Bella Kaufman (MD, Professor)

Basser Center for BRCA University of Pennsylvania, Philadelphia, USA (S M

Domchek MD); ATIP-Avenir group, Inserm Unit U981, Gustave Roussy, Villejuif,

France and Université Paris Saclay, Université Paris-Sud, Faculté de Médicine, Le

Kremlin Bicêtre, and Department of Drug Development, DITEP, Gustave Roussy,

Villejuif, France (S Postel-Vinay MD); Seoul National University Hospital, Cancer

Research Institute, Seoul National University College of Medicine, Seoul, Republic

of Korea (Prof S-A Im MD); Samsung Medical Center, Sungkyunkwan University

School of Medicine, Seoul, Republic of Korea Prof Y H Park MD); Institut

Universitaire du Cancer de Toulouse, Toulouse, France (Prof J-P Delord MD);

Institut Bergonié, Bordeaux, France (Prof A Italiano MD); Hôpital Cochin, Paris,

France (Prof J Alexandre MD); Medical Oncology; Institut de Cancérologie des

Hospices Civils de Lyon (IC-HCL); CITOHL; Centre Hospitalier Lyon-Sud; GINECO;

Université Claude Bernard Lyon 1; Lyon; France (B You MD); Kantonsspital

Graubuenden, Chur, Switzerland (S Bastian MD); Division of Cancer Sciences,

Faculty of Biology, Medicine and Health, The University of Manchester and The

Christie NHS Foundation Trust, Manchester Academic Health Science Centre,

Manchester, UK (M G Krebs PhD); Henry Ford Medical Center, Detroit, USA (D

Wang MD); Washington University School of Medicine, Saint Louis, USA (S N

Waqar MBBS MSCI); AstraZeneca, Gaithersburg, MD, USA (M Lanasa MD, J Rhee

MD, L Opincar PharmD, P Herbolsheimer MD, Z Lai PhD); AstraZeneca, Cambridge,

UK (H Gao PhD, V Rocher-Ros PhD, E V Jones PhD, S Gulati PhD, A Coenen-Stass

PhD, I Kozarewa PhD, H K Angell PhD); Chaim Sheba Medical Center, Tel

Hashomer, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv,

Israel (Prof B Kaufman MD)

Correspondence to: Professor Susan M Domchek, Basser Center for BRCA University

of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA.

susan.domchek@pennmedicine.upenn.edu

Word count: 3499

References: 30

Summary

Background: PARP inhibitors combined with immunotherapy have shown anti-tumour

activity in preclinical studies. The MEDIOLA trial (ClinicalTrials.gov; NCT02734004), a

multicentre phase 1/2 open-label trial aims to assess the safety and efficacy of olaparib

in combination with PD-L1-inhibitor, durvalumab, in patients with solid tumours.

Methods: In the breast cancer cohort, patients (≥18 years or ≥19 years for South Korea)

with germline BRCA1 and/or BRCA2-mutated (gBRCAm) and histologically confirmed,

progressive, HER2-negative metastatic breast cancer (mBC) were enrolled from 14 sites

in six countries. Patients should not have received >2 prior lines of chemotherapy for

mBC. Patients received 300 mg olaparib (tablet) orally twice-daily (bid) for 4 weeks and

thereafter a combination of olaparib 300 mg bid and durvalumab 1·5 g via IV infusion

every 4 weeks until disease progression. Primary endpoints were safety, tolerability, and

12-week disease control rate (DCR) analysed per protocol. The study is ongoing.

Findings: Between June 14, 2016 and May 2, 2017, 34 patients enrolled, received

study drugs and were included in the safety analysis. Eleven (32%) patients experienced

≥grade 3 adverse events (AEs), of which the most common were anaemia (n=4; 12%),

neutropenia (n=3; 9%) and pancreatitis (n=2; 6%). Three patients discontinued due to

AEs and four patients experienced a total of six serious AEs (SAEs). There were no

treatment related deaths. Among 30 patients eligible for efficacy analysis, 13 (43%) had

hormone receptor positive (HR+) and 17 (57%) had triple-negative disease (TNBC).

DCR was 80% (24/30; 90% CI 64·3–90·9) at 12 weeks.

Interpretation: Combination of olaparib and durvalumab showed promising long-term

safety similar to those previously seen 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 to olaparib monotherapy.

Funding: AstraZeneca

Introduction

BRCA1 and BRCA2 are tumour suppressor genes closely linked to breast cancer

susceptibility. Pathogenic germline variants in BRCA1/2 occur in approximately 5% of

breast cancer patients1,2 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 BRCA1/2 mutated (gBRCAm) metastatic breast

cancer (mBC). Among 205 patients randomised to olaparib and 97 to chemotherapy, the

objective response rate (ORR) was 60% versus 29%, while median progression-free

survival (mPFS) was 7·0 versus 4·2 months (hazard ratio [HR] 0·58, p<0·001),

respectively. Median duration of response (mDOR) was 6·4 versus 7·1 months and

median overall survival (mOS) 19·3 versus 17·1 months, respectively.5,6 Subgroup

analysis of patients receiving olaparib in the first-line setting (n=59, 29%) showed an

improvement in mOS compared to chemotherapy of 22·6 versus 14·7 months (95%

confidence interval [CI] 0·29–0·90; HR 0·51).6

Durvalumab is a human immunoglobulin G1 kappa monoclonal antibody that inhibits

binding of the immune checkpoint ligand programmed cell death ligand-1 (PD-L1) to its

receptors programmed cell death-1 (PD-1) and CD80. Durvalumab is approved for the

treatment of urothelial carcinoma7 and unresectable stage III 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 (TNBC) based on

mPFS.9

Immunotherapies combined with chemotherapy or a PARP inhibitor are currently being

explored in various studies.10-12 In the TOPACIO trial,11 a combination of niraparib and

pembrolizumab in patients with advanced or metastatic TNBC showed promising

efficacy, particularly in patients with a tumour BRCA mutation (n=15) (ORR 47% [90% CI

24–70] and a disease control rate [DCR] of 80% [90% CI 56–94]). Increasing evidence

shows an interaction between olaparib-induced DNA damage and the immune system.13

Preclinical data suggest that PARPi may elicit an anti-tumour immune response 14,15 and

provide the rationale for investigating olaparib in combination with durvalumab in

gBRCAm mBC.13,14 The dosing schedule of this combination has been previously tested

in 6 patients in a phase 1 trial.12 Further safety evaluation of this combination is

warranted.

Methods

Study design and participants

MEDIOLA (NCT02734004) is a phase 1/2 open-label, multicentre basket study

evaluating safety and tolerability, pharmacokinetics (PK) and anti-tumour activity of

durvalumab in combination with olaparib in patients with advanced solid tumours, with

four cohorts: gBRCAm-associated breast, gBRCAm-associated ovarian, gastric, and

relapsed small-cell lung cancer. Results from the other cohorts have been reported

previously.16-18 Here, we present the breast cohort, preliminary results of which have

been disclosed previously.19-21

Eligible patients (≥18 years [≥19 years for South Korea]) had a deleterious gBRCAm

(locally or centrally determined) with histologically confirmed, progressive locally

advanced or metastatic HER2-negative breast cancer, either TNBC or hormone-

receptor–positive (HR+; oestrogen-receptor and/or progesterone-receptor positive).

Hormone receptor status was determined locally. Patients were PARP-inhibitor and

immunotherapy-naive. Patients had to have measurable disease (definition in appendix

p 2) and history of anthracycline and/or taxane therapy. Prior platinum therapy was

allowed if there was no disease progression while receiving treatment and at least 12

months had elapsed since the last dose. Patients with HR+ tumours had to have disease

progression on at least one endocrine therapy or be considered not appropriate for

endocrine therapy. Other inclusion criteria included: Eastern Cooperative Oncology

Group performance status 0–1; life expectancy ≥12 weeks; normal baseline organ and

bone marrow function. Patients could not have received more than two prior lines of

cytotoxic chemotherapy for mBC. Further exclusion criteria are detailed in the protocol

(appendix p 11). All patients provided written informed consent and the institutional

review boards or independent ethics committees of all investigational sites approved the

protocol. The study was done in accordance with the Declaration of Helsinki, Good

Clinical Practice.

Procedures

Patients received olaparib monotherapy of 300 mg (tablet) orally twice-daily (bid) for the

first 4 weeks, after which combination of olaparib 300 mg bid and durvalumab 1 ·5 g

intravenously was administered every 4 weeks (28-day cycle) until disease progression

or intolerable toxicity. Population PK models (AstraZeneca, data on file) have shown that

the fixed durvalumab dose 1.5 g every 4 weeks is equivalent in exposure to weight-

based dosing (10 mg/kg every 2 weeks), but with greater ease of use. This dose was the

recommended Phase 2 dose reached in a Phase 1 dose-escalation study of the

combination.12 Patients were able to withdraw from the study at any time.

Dose modifications were allowed to manage toxicities. Olaparib toxicities were managed

with supportive care, dose interruptions, and/or dose reductions (two levels). Dose re-

escalation was not permitted. Durvalumab toxicities could be managed with supportive

care and/or dose interruptions; dose reductions were not permitted. Guidelines for these

dose modifications are provided in the study protocol (appendix p 11). Prophylaxis for

nausea and vomiting was not mandatory.

Tumours were assessed by investigator review of computed tomography or magnetic

resonance images at baseline, 4 weeks after starting olaparib and every 8 weeks

thereafter using Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. Safety

and tolerability were assessed by recording adverse events (AEs) and serious AEs

(SAEs) as graded by Common Terminology Criteria for Adverse Events v4.03 and by

documenting dose interruptions/ reductions and treatment discontinuations. Safety

assessments comprised measurements of haematology and clinical chemistry (on Days

1, 8, 15, 22, 29, then every 2 weeks until week 9, then every 4 weeks thereafter).

For the biomarker analysis, archival tumour tissue was collected for all patients. Analysis

of tumor cell (TC) and immune cell (IC PD-L1) expression was performed using the

VENTANA PD-L1 (SP263) assay (Roche, Switzerland) and quantified by a pathologist.

PD-L1 TC and IC cut-offs were set at ≥1%. Evaluation of PD-L1 expression was a

secondary endpoint of the study; all other biomarker analyses were exploratory.

Densities (cells/mm2) of CD3+ lymphocytes (clone 2GV6) and CD8+ cytotoxic T cells

(clone C8/144b) were evaluated and quantified using digital image analysis (HALOTM).

Median cohort cut-offs were used to determine low/high tumour-infiltrating lymphocyte

(TIL) densities (CD3 ≥458 cells/mm2 and CD8 ≥140 cells/mm2). PAM50 intrinsic

subtyping was calculated using gene expression data generated by NanoString profiling

(commercial BC360 panel; NanoString Technologies, USA) using RNA extracted from

baseline formalin-fixed paraffin-embedded samples. Tumour mutation burden (TMB)

was provided by Foundation Medicine Inc (FMI) using methods previously described.22

TMB above 20 mut/Mb is considered high, between 6 and 20 medium, and below 6 low.

Outcomes

The primary efficacy endpoint was DCR at 12 weeks, defined as the percentage of

patients who have at least one complete or partial response in the first 12 weeks or have

demonstrated stable disease that is maintained until RECIST 1.1 assessment at

12 weeks. Safety and tolerability were primary safety endpoints. Secondary efficacy

endpoints (defined in appendix p 2) included DCR at 28 weeks, ORR, duration of

response (DoR), PFS, percentage change from baseline in tumour size at 12 and 28

weeks, best percentage change from baseline in tumour size, time to study treatment

discontinuation or death (TDT) and overall survival (OS).

Additional secondary endpoints included serum concentrations of durvalumab and

olaparib at steady state during the monotherapy and combination therapy periods,

presence of anti-drug antibodies ADAs for durvalumab, serum concentration of ADA,

serum PD-L1, and PD-L1 expression in tumour samples. Exploratory analyses

examining predictors of response or progression were performed, including tumour

analyses of CD3 and CD8 density, TMB, and PAM50 subtype analysis.

Deviations from the protocol included the omission of blinded independent central

review, which was not performed due to changes in sponsor strategy. Also, four patients

did not meet predefined eligibility criteria (described below).

Statistical analysis

The safety analyses were conducted in patients who received at least one dose of study

treatment. Efficacy analyses were conducted in the full analysis set (FAS), which

included patients who received at least one dose of study treatment and were not

excluded from the study for administrative reasons. A Bayesian predictive probability

design was applied.23 Using prior data for olaparib monotherapy with mPFS of 5·7

months,24 a target mPFS of 7·5 months was set, equivalent to a target DCR at 12 weeks

of 75%, assuming an exponential distribution of progression times. A DCR of 55% or

less was considered undesirable. These values resulted in a target sample size of 30

patients, the minimum sample size that results in type I and type II error rates under 0 ·10

and 0·20, respectively.

Kaplan–Meier (KM) methods were used to generate time-to-event curves and calculate

medians (95% CIs) and interquartile ranges [IQRs] for TDT, OS, PFS and DoR. 95% CIs

for ORR were calculated using Exact Clopper-Pearson confidence limits for the binomial

proportion. Percentage changes in tumour size were summarised and presented in

medians and IQRs.

Post-hoc subgroup analysis was carried out for DoR, PFS and OS by translational

biomarkers such as PD-L1 in TCs and ICs, CD3 and CD8, and by prior lines of cytotoxic

chemotherapy, hormone receptor status, BRCA status (BRCA1 or BRCA2 mutations),

and lactate dehydrogenase (LDH) level (> upper limit of normal [ULN] or ≤ULN).

SAS® version 9.2 or higher were used for all analyses.

Role of the funding source

AstraZeneca designed the trial and was responsible for overseeing the collection,

analysis, and interpretation of the data. The manuscript was written by the authors with

medical writing support, funded by AstraZeneca. The corresponding author [SMD]

confirms full access to study data and final responsibility for the decision to submit for

publication.

Results

Between June 14, 2016 and May 2, 2017, 34 patients were enrolled from 14 centres in

six countries and received study treatment. Four patients were excluded from the

efficacy analyses because they did not fulfil the predefined eligibility criteria (three

patients had received more than two prior lines of chemotherapy for mBC and one had

non-measurable bone-only disease); thus, the FAS comprised 30 patients (figure 1) and

baseline characteristics are shown in table 1. Data cut-off was March 18, 2019, at which

three patients remained on treatment, with a duration of study treatment of 23·2, 30·4,

and 27·6 months, respectively.

Median treatment duration was 30·8 weeks for olaparib and 26·8 weeks (6·5 cycles) for

durvalumab. Seven (21%) of 34 patients required a dose reduction for olaparib.

Fourteen (41%) of 34 (41%) had a dose delay for durvalumab.

AEs of any grade are summarised in table 2. Eleven (32%) of 34 patients experienced

grade ≥3 AEs (table 2) and six (18%) of 34 had a dose reduction for olaparib resulting

from an AE (including anaemia, influenza and neutropenia). Seven (21%) of 34 had a

dose delay for durvalumab because of AEs (including influenza, anaemia and colitis).

Three patients discontinued one or both study treatments due to AEs (arthralgia,

anaemia, and dyspnoea; n=1 for each), of which arthralgia and anaemia were

considered to be causally related to the study treatment. All grade ≥ 3 AEs considered

by the investigator to be causally-related to study treatment are summarised in the

appendix (p 8). Immune-mediated AEs (table 2) were reported in 12 (35%) of 34

patients. Four patients experienced six SAEs (n=1 each for anaemia, haemolysis,

hypercalcaemia, dyspnoea, pancreatitis, hydronephrosis) of which anaemia was

considered causally related to olaparib and haemolysis and pancreatitis (experienced in

one patient) were considered causally related to durvalumab. Nineteen deaths occurred

during the study, all of which were due to the disease under investigation. There were no

treatment-related deaths.

As shown in table 3, the primary efficacy endpoint of 12-week DCR was 80% (24/30). At

week 28, 50% (15/30) had disease control (secondary endpoint). The majority of

responses were partial responses (n=18), and there was one complete response, for an

ORR of 63% (95% CI 43·9–80·1) and mDoR of 9·2 months (14 events, IQR 5·5–20·3)

(figure 2), mPFS was 8·2 months (95% CI 4·6–11·8) (figure 2; 24 progression events,

80% maturity, median follow-up 6.7 months [IQR 4.6- 13.8]), and mOS was 21·5 months

(95% CI 16·2–25·7) (figure 2; 19 deaths, 63% maturity, median follow-up 19·8 months

[IQR 14.4 -25.5]). Efficacy outcomes for individual patients by hormone receptor status

are shown in figure 3.

Efficacy outcomes for the full cohort and subgroups defined by prior lines of

chemotherapy for mBC (0–1 prior line or 2 prior lines) and HR status (HR+ or TNBC) are

presented in the appendix (p 4). KM curves showing DoR, PFS, and OS in these

subgroups, as well as the FAS, are presented in the appendix (p 5–6).

In the TNBC subgroup, there were two distinct outcome patterns, with a group of

patients having early disease progressions and another group having responses that

were mostly durable (figure 3). mPFS in the TNBC subgroup was 4·9 months (95% CI

2·6–13·8,) and mOS was 20·5 months (95% CI 12·3–not reached,). mPFS in the HR+

subgroup was 9·9 months (95% CI 6·2–21·5,) and mOS was 22·4 months (95% CI

14·4–25·5, ). For patients with 0–1 prior lines of chemotherapy (n=20) mOS was 23·4

months (95% CI 16·3–not reached) and for patients with two lines of prior chemotherapy

(n=10), mOS was 16·9 months (95% CI 4·6–25·5). Results of PAM50 subtyping were

analysed in 18 patients showing no correlation between intrinsic subtypes and clinical

outcomes (figure 3). Nineteen patients had evaluable TMB profiling (5 patients had

medium and 14, low TMB) with no correlation with clinical outcome (figure 3). Efficacy

outcomes for subgroups defined by BRCA status (BRCA1 or BRCA2 mutations) and

LDH level (>ULN or ≤ULN) were similar (data not shown).

Median changes in target lesion size at 12 and 28 weeks, best change in target lesion

size, and median time to treatment discontinuation are summarized in the appendix (p

7). Plasma concentration-time curves demonstrated good overlap between the profile of

olaparib as monotherapy (on Day 1 and at steady state on Day 22) and the combined

therapy period, suggesting no impact of durvalumab on olaparib exposure. Durvalumab

exposure reached steady state at approximately Week 16. Durvalumab exposure in

combination therapy with olaparib was consistent with that observed in durvalumab

monotherapy (data not shown). Among 32 patients with antidrug antibody (ADA)

samples collected and titre statistics, the post-baseline incidence of ADA was zero. The

analysis of soluble PD-L1 indicated near-complete suppression of sPD-L1 by Cycle 1

Day 15.

Expression of PD-L1, CD3 and CD8 in archival tumour tissue specimens and their

correlation with OS are shown in the appendix (p 8–9). PD-L1 positivity (≥1%) was

observed in 10 (33%, TC) of 30 patients and 17 (57%, IC) of 30 with evaluable archival

tumour tissue specimens. For PD-L1 TC–positive patients mOS was 23·9 months (95%

CI 4·6–not reached) and 18·8 months (95% CI 15·6–25·7) for PD-L1 TC-negative

patients. PD-L1 IC-positive patients showed a mOS of 21·5 months (95% CI 16·2–25·5,)

and 16·9 months (95% CI 9·0–not reached) for PD-L1 IC-negative patients. TIL

infiltration above the proposed median cut off (CD3 ≥458 cell/mm2; CD8 ≥140 cell/mm2)

was observed in 13 (43%) of 30 patients’ archival tumour tissues specimens. For

patients with CD3+ TILs high status mOS was 21·5 months (95% CI 14·4–not reached)

and patients with low CD3+ TILs mOS was 19·2 months (95% CI 10·1–23·4). Patients

with CD8+ TILs high status showed a mOS of 23·9 months (95% CI 16·2–not reached)

and patients with low CD3+ TILs a mOS of 18·6 months (95% CI 10·1–25·7).

Discussion

The MEDIOLA trial tested the hypothesis that olaparib efficacy could be further

enhanced by adding a PD-L1 inhibitor durvalumab without compromising safety. Here,

we report the results in a cohort of patients with gBRCAm HER2-negative mBC.

The combination of olaparib and durvalumab was well tolerated over a long follow-up

period. In contrast to recent studies exploring other combinations of PARP inhibitors and

immunotherapy,11 MEDIOLA employed full doses of both agents, based on a phase 1

study that showed the absence of dose-limiting toxicity in a heavily pre-treated

population.12 No new safety signals, including no excess in immune-mediated AEs, were

observed, in line with those previously seen in respective monotherapy studies. This

study of chemotherapy-free combination reported no grade 3 or higher incidences of

nausea, heart failure, or neuropathy. In addition, overall rates of neutropenia were low.

No olaparib AEs of special interest (AESIs) (pneumonitis, myelodysplastic syndromes,

new primary malignancies) were reported; the most commonly reported durvalumab

AESIs were diarrhoea and hypothyroidism. Safety and exposure data from this study is

consistent with prior studies, showing no evidence of drug-drug interactions between

olaparib and durvalumab.13,30 Exposure data confirm that the use of fixed dose

durvalumab at 1·5 g every 4 weeks is equivalent to the use of weight-based dosing at

10 mg/kg every 2 weeks.

The observed primary endpoint of 12-week DCR (80%) exceeded the pre-specified

target (75%); however, this target was based on a phase 2 trial24 of more heavily pre-

treated patients and prior to the OlympiAD results; mOS (21·5 months, 95% CI 16·2–

25·7) and ORR (63.3%, 95% CI 43·9–80·1) were similar to those reported in OlympiAD

(19·3 months and 60%). Of note, there was a slightly higher use of prior platinum-based

therapy in the MEDIOLA study (43%) than in OlympiAD (29·3%), although the

proportions of patients receiving zero, one and two prior lines of chemotherapy were

similar. The mDOR of 9·2 months and mPFS of 8·2 months with the combination of

durvalumab and olaparib were also similar to the mDOR of 6·4 months and mPFS of 7·0

months with olaparib monotherapy.5 Although studies have suggested that adding

immune checkpoint inhibitors to standard of care may lead to improved clinical

outcomes,10 we were not able to confirm this in this study.

Despite the relatively poor mPFS in the TNBC subgroup (4·9 months), which was driven

by several non-responders with early disease progression, responses were mostly

durable. The mDOR of 12·9 months in TNBC patients (n=10 responders) compares

favourably to standard of care chemotherapy with or without the addition of immune

checkpoint inhibitors. OS was also similar between the TNBC (20·5 months) and HR+

(22·4 months) subgroups, despite the poorer prognosis expected for patients with

TNBC.6,25 Three patients (one with TNBC) remained on therapy at the data cut-off with

no evidence of disease progression. The TNBC patient remained on therapy without

progression at 30·4 months. These results may be confounded by the imbalance of

more first-line patients in the TNBC subgroup.

Recognising the small sample size, duration of response was longer in patients with 0–1

prior lines of chemotherapy (mDoR 12·9 months) compared with those who had >1 prior

line of chemotherapy (5·5 months). mOS was longest in patients with 0–1 prior lines of

chemotherapy (23·4 months), suggesting a greater benefit in early-line patients, which is

consistent with previous experience with each compound.5,26 Validation in a larger

population will be required to understand if any of the factors (early vs later line, TNBC

vs HR+, and PD-L1 ≥1% vs PD-L1 <1%) are predictive of treatment benefit.

Greater understanding of the biology of tumours from patients with improved survival is

critical to identifying predictive biomarkers. The KM curves of OS by PD-L1 TC and IC

subgroups were overlapping, suggesting that PD-L1 status is not of treatment benefit in

this study. The KM curves of OS by CD8+ (but not CD3+) TIL subgroups suggest a

modest increase in benefit for patients with high CD8 TIL at the proposed median cut-off

supporting the value of CD8+ TIL as a potential predictive biomarker of clinical benefit in

breast cancer in concordance with other studies.27

Limitations of the MEDIOLA study include that it is a single-arm open-label study with a

small patient population and no comparator arm. The study also enrolled a population

with differing prognoses (HR+ and TNBC; zero, one or two prior lines of chemotherapy),

introducing potential confounders into subgroup analyses. The olaparib run-in reduced

the exposure of some patients to durvalumab and potentially influenced the results. In

the neoadjuvant setting, starting the treatment with durvalumab run-in has been shown

to improve the outcomes.28 PD-L1 inhibitors are typically not as efficacious in later-line

patients, in part due to the impact of disease progression on the immune system.29 The

small sample size, heterogeneity of the population, combined with the use of archival

samples, contribute to challenges in interpretation of the PD-L1 and TIL analyses. It is

known that the immune landscape changes over time with exposure to multiple lines of

anti-cancer therapy. Moreover, 43% (n=13) of enrolled patients had HR+ disease, which

generally has a much lower PD-L1-positivity rate compared to TNBC and a lower rate of

response to PD-L1 inhibition.30 Note that the antibody used here (VENTANA PD-L1

SP263) differs from that used in IMPassion130, making cross-trial comparisons difficult.

In conclusion, findings from the MEDIOLA trial demonstrate that the combination of

olaparib and durvalumab produced promising long-term tolerability and anti-tumour

activity in patients with gBRCAm metastatic breast cancer. Further research is needed to

determine whether there are subsets of patients who benefit from the addition of

durvalumab to olaparib. The potential for improvement in duration of response in TNBC,

particularly in the early-line setting, needs to be further explored in additional

randomised studies.

Panel: Research in context panel

Evidence before this study

PubMed, Embase, MEDLINE, and oncology congress websites were searched from

January 1, 2000 to December 31, 2015 for clinical trials of combinations of PARP

inhibitors and anti-PD-L1 or anti-PD-1 antibodies use to treat patients with breast cancer.

The search terms used were poly(ADP-ribose) polymerase inhibitors/nicotinamide

adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor, antineoplastic

agents, immunological/antineoplastic monocloncal antibody, and breast

neoplasms/breast tumor. No language preferences were specified. At the time of the

initial protocol approval (September 2015), there were no published reports of a clinical

trial combining a PARP inhibitor with an immune checkpoint inhibitor in patients with

breast cancer. Previous studies had shown that in germline BRCA-mutated (gBRCAm)

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 demonstrated.

Furthermore, preclinical data indicated that PARP inhibition upregulates PD-L1

expression and elicits an anti-tumour immune response through a STING pathway in

BRCA1-deficient mice. These data provided the rationale for combining olaparib with

durvalumab, an inhibitor of PD-L1, in patients with gBRCAm metastatic breast cancer.

Added value of this study

To our knowledge, this report on the MEDIOLA study of a PARP inhibitor combined with

immunotherapy in the treatment of BRCAm breast cancer is unique in reporting results

for HR+ disease to date. Combining olaparib with durvalumab demonstrated no new

safety signals for either agent administered at full doses. While sample sizes are small,

survival results suggest greater benefit in patients with TNBC and those with fewer prior

lines of chemotherapy. The role of PD-L1 expression in predicting benefit for the

combination remains inconclusive. The chemo-free combination was well tolerated, with

few dose delays or interruptions for AEs. Further research is needed to determine

whether there are subsets of patients who benefit from the addition of durvalumab to

olaparib, to elucidate resistance mechanisms, and understand how olaparib impacts the

immune system.

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 gBRCA mutation. Further research in a randomised setting is justified to

determine whether there are subsets of patients with metastatic breast cancer who may

benefit from the addition of durvalumab to olaparib. Understanding mechanisms of

PARPi innate and acquired resistance will lead to new insights into targeting the DNA

damage response in cancers, and since PARP failures represent an emerging

population with unmet medical need, new therapeutic options for these patients are

required.

Declaration of interests

SMD has received honoraria from AstraZeneca, Clovis and BMS, and the University of

Pennsylvania research funding from AstraZeneca and Clovis. SP-V, as part of the Drug

Development Department (DITEP), is Principal/sub-Investigator of Clinical Trials for

Abbvie, Adaptimmune, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba,

Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, AstraZeneca Ab, Aveo, Bayer

AG, Bbb Technologies Bv, Beigene, Bioalliance Pharma, Biontech Ag, Blueprint

Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb,

Bristol-Myers Squibb International Corporation, Ca, Celgene Corporation, Cephalon,

Chugai Pharmaceutical Co., Clovis Oncology, Cullinan-Apollo, Daiichi Sankyo,

Debiopharm S.A., Eisai, Eli Lilly, Exelixis, Forma Tharapeutics, 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 Pharm. Dev., 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, Y's Therapeutics. S-AI reports receiving research

grants from AstraZeneca, Pfizer and Roche, and personal fees and non-financial support

for presenting results of clinical trial from Novartis, personal fees from AstraZeneca,

Hanmi, Pfizer, Eisai, Amgen, MediPacto, Roche , Lilly, outside the submitted work;.

YHP reports receiving grants and non-financial support from Pfizer, grants and non-

financial support from AstraZeneca, grants and non-financial support from Novartis,

grants and non-financial support from Merck, grants from Eisai, grants and non-financial

support from Roche, grants from Hanmi, outside the submitted work. AI reports grants

from AstraZeneca, BMS, MSD and Pharmamar, and grants and personal fees from

Merck, Roche, and personal fees from Springworks, and Daiichy Sanko; JA reports

receiving personal fees from AstraZeneca, GSK/TESARO, Pharmamar and Roche, and

personal fees and non-financial support from Novartis, and grants and non-financial

support from Janssen. MGK has participated in advisory boards or acted a consultant for

Achilles Therapeutics Ltd, Janssen, Octimet Oncology, and Roche, and received travel

grants from AstraZeneca and BerGenBio, and research funding from MSD, BerGenBio,

and Roche. SNW reports grants from 1 UM1 CA186704-01, 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 and/or have stock ownership with

AstraZeneca. SB, J-PD, BY, DW and declare no conflict of interest.

Author contributions

SMD: was involved in study conception and design, acquisition of data, interpretation of

data, writing, review and/or revision of the manuscript. SP-V: was involved in acquisition

of data, interpretation of data, review and/or revision of the manuscript. S-AI: was

involved in study conception and design, acquisition of data; interpretation of data,

review and/or revision of the manuscript. YHP: was involved in data collection and

analyzed or interpreted data. Additionally, Yeon Hee Park revised the manuscript and

approved the final manuscript. J-PD: was involved in acquisition of data, interpretation of

data, review and/or revision of the manuscript. AI: was involved in data collection,

analysis and interpretation of data, manuscript review and approval. JA: was involved in

acquisition of data, interpretation of data, review and revision of the manuscript. BY: was

involved in data collection, data analyses, data interpretation, article preparation and

reviewing. SB: was involved in acquisition of data, interpretation of data, review and/or

revision of the manuscript. MK: was involved in acquisition of data, interpretation of data,

review and/or revision of the manuscript. DW: was involved in patient enrolment, data

acquisition, data queries resolution, interpretation and discussion/revision of the

manuscript. SNW: was involved in acquisition of data, interpretation of data, review

and/or revision of the manuscript. ML: was involved in data analysis and data

interpretation, review and/or revision of the manuscript. JR: was involved in study

conception and design, acquisition of data, interpretation of data, review and/or revision

of the manuscript. HG: was responsible for the statistical analysis, and was involved in

writing, review and/or revision of the manuscript. VR-R: was involved in acquisition of

data, interpretation of data, review and/or revision of the manuscript. EVJ: was involved

in acquisition of data, interpretation of data, review and/or revision of the manuscript.

SG: was involved in acquisition of data, interpretation of data, review and/or revision of

the manuscript. AC-S: was involved in acquisition of data, interpretation of data, review

and/or revision of the manuscript. IK: was involved in acquisition of data, interpretation of

data, review and/or revision of the manuscript. ZL: was involved in acquisition of data,

interpretation of data, review and/or revision of the manuscript. HKA: was involved in

study conception and design, acquisition of data; interpretation of data, and writing,

review and/or revision of the manuscript. LO: was involved in study conception and

design, literature search, acquisition of data, interpretation of data, and writing, review

and/or revision of the manuscript. PH: was involved in study conception and design,

acquisition of data, interpretation of data, and writing, review and/or revision of the

manuscript. BK: was involved in study conception and design, acquisition of data,

interpretation of data, and writing, review and/or revision of the manuscript.

Acknowledgements

This study was funded by AstraZeneca. The authors would like to acknowledge Alienor

Berges, PharmD and Yuhong Chen, MD, PhD for their support of the pharmacokinetic

work, and Dongmei Lan, MSc, for supporting the statistical analysis. MK would like to

acknowledge support by NIHR Manchester Biomedical Research Centre, NIHR

Manchester Clinical Research Facility at The Christie, and Manchester Experimental

Cancer Medicine Centre, Manchester, UK. Medical writing assistance was provided by

Martin Goulding, DPhil of Mudskipper Business Ltd, funded by AstraZeneca.

Data sharing statement

Data underlying the findings described in this manuscript may be obtained in accordance

with AstraZeneca’s data sharing policy described at:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

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Figure legends

Figure 1: Trial profile

Patients were permitted to discontinue either one of the two study drugs and remain on the other if an

adverse event (AE) was attributed only to one study drug. Three patients discontinued one or both

study treatments due to AEs; one patient experienced grade 2 anaemia thought to be related to

olaparib resulting in a dose interruption for olaparib and a treatment discontinuation of durvalumab, a

second patient discontinued durvalumab due to grade 2 arthralgia attributed to durvalumab, and a

third patient discontinued both drugs due to grade 4 dyspnoea not thought to be related to study

therapy.

Figure 2: Kaplan–Meier estimates of (A) duration of response, (B) progression-free

survival, and (C) overall survival for full analysis set.

DoR, duration of response; PFS, progression-free survival; OS, overall survival

Figure 3: Swimmer plot by hormone receptor status and length of overall survival.

Length of solid coloured bar = time to disease progression or end of therapy, whichever is shorter; LumA, Luminal A; LumB, Luminal B; N/A, not applicable;

RECIST, Response Evaluation Criteria in Solid Tumours

Table 1: Baseline characteristics (FAS*)

Characteristic Patients (N=30)

Age (years), median (IQR) 45 (37–53)

Gender, n (%)

Female 29 (97)

Male 1 (3)

Race, n (%)

White 17 (57)

Asian 7 (23)

Not available† 6 (20)

BRCA mutation status, n (%)

BRCA1 14 (47)

BRCA2 16 (53)

Hormone receptor status, n (%)

HR+ (ER+ and/or PgR+) 13 (43)

TNBC 17 (57)

Prior lines of chemotherapy, n (%)

0 9 (30)

1 11 (37)

2 10 (33)

Prior platinum therapy, n (%) 13 (43)

PD-L1 expression in tumour cell (TC), n (%)

Positive (≥1%) 10 (33)

Negative (<1%) 17 (57)

Not available 3 (10)

PD-L1 expression in immune cell (IC), n (%)‡

Positive (≥1%) 17 (57)

Negative (<1%) 10 (33)

Not available 3 (10)

*Full analysis set included all patients who received at least one dose of study treatment and who

had not been excluded from the study for administrative reasons. †Collection of these data not

permitted in France. ‡All patients except one who were positive in tumour cell at the ≥1% cut-off

were also positive in immune cells. ER+, oestrogen receptor positive; FAS, full analysis set; HR+,

hormone receptor positive; PD-L1, programmed cell death ligand 1; PgR+, progesterone receptor

positive; TNBC, triple-negative breast cancer

Table 2: Adverse Events

Patients (N=34) All grades

n (%)

Grades 1–2 Grade 3 Grade 4

Patients with any AE 34 (100) 23 (68) 9 (27) 2 (6)

Fatigue 22 (65) 21 (62) 1 (3) 0

Nausea 20 (59) 20 (59) 0 0

Anaemia 14 (41) 10 (29) 4 (12) 0

Diarrhoea 12 (35) 11 (32) 1 (3) 0

Vomiting 10 (29) 9 (26) 1 (3) 0

Constipation 10 (29) 10 (29) 0 0

Cough 10 (29) 10 (29) 0 0

Asthenia 8 (24) 8 (24) 0 0

Dysgeusia 8 (24) 8 (24) 0 0

Headache 7 (21) 7 (21) 0 0

Abdominal pain 6 (18) 6 (18) 0 0

White blood cell count decreased 6 (18) 5 (15) 1 (3) 0

Arthralgia 6 (18) 6 (18) 0 0

Anxiety 6 (18) 6 (18) 0 0

Decreased appetite 5 (15) 5 (15) 0 0

Dry skin 5 (15) 5 (15) 0 0

Hypothyroidism 5 (15) 5 (15) 0 0

Influenza-like illness 5 (15) 5 (15) 0 0

Myalgia 5 (15) 5 (15) 0 0

Neutropenia 5 (15) 2 (6) 3 (9) 0

Insomnia 5 (15) 5 (15) 0 0

Dyspnoea 4 (12) 3 (9) 0 1 (3)

Abdominal pain upper 4 (12) 3 (9) 1 (3) 0

Musculoskeletal pain 4 (12) 4 (12) 0 0

Neutrophil count decreased 4 (12) 4 (12) 0 0

Pancreatitis 2 (6) 0 1 (3) 1 (3)

Hepatitis 1 (3) 0 1 (3) 0

Lymphoedema 1 (3) 0 1 (3) 0

Haemolysis 1 (3) 0 1 (3) 0

Immune-mediated AEs*

Any immune-mediated event 12 (35) 10 (29) 1 (3) 1 (3)

Hypothyroidism 5 (15) 5 (15) 0 0

Arthralgia 2 (6) 2 (6) 0 0

Hyperthyroidism 2 (6) 2 (6) 0 0

Pancreatitis 2 (6) 0 1 (3) 1 (3)

Pruritis 2 (6) 2 (6) 0 0

Rash 2 (6) 2 (6) 0 0

Haemolysis 1 (3) 0 1 (3) 0

Thyroiditis 1 (3) 1 (3) 0 0

Peripheral sensory neuropathy 1 (3) 1 (3) 0 0

Colitis 1 (3) 1 (3) 0 0

Diarrhoea 1 (3) 1 (3) 0 0

Hepatitis 1 (3) 0 1 (3) 0

Dry skin 1 (3) 1(3) 0 0

Maculopapular rash 1 (3) 1 (3) 0 0

Myalgia 1 (3) 1 (3) 0 0

Fatigue 1 (3) 1 (3) 0 0

Flu-like illness 1 (3) 1 (3) 0 0

Shown are adverse events of grade 1 or 2 occurring in ≥10% of patients and all grade 3, 4, and 5 (no grade 5 adverse events were reported in this study).

*Immune-mediated adverse events are a subset of overall adverse events. The designation of these events as immune-mediated was at the discretion of the

investigator.

Table 3: a) Disease control rates at weeks 12 and 28 and b) disease response status

at week 12, in the FAS

a)

Disease controlWeek 12 (N=30) Week 28 (N=30)

N % 90% CI N % 90% CI

Yes 24 80·0 64·3–90.9 15 50·0 33·9–66·1

No 6 20·0 13 43·3

Not evaluable/missing 0 0 2 6·7

b)

Response status

(modified RECIST 1.1)

Week 12 (N=30)

N % 95% CI

ORR 19 63·3 48·9–80·1

CR 1 3·3

PR 18 60·0

SD 5 16·7

PD 6 20·0

CR, complete response; ORR, objective response rate; PD, disease progression; PR, partial response;

SD, stable disease (≥ 11 weeks)39

APPENDIX

Definition of measurable disease

A lesion, not previously irradiated or biopsied per the protocol prior to enrolment, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have short axis ≥15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for accurate repeated measurements.

Definitions of study endpoints

Endpoint Definition

Disease control rate (DCR) Percentage of patients who have at least one complete or partial response in the first 12 weeks or have demonstrated stable disease that is maintained until the Response Evaluation Criteria in Solid Tumours (RECIST 1.1) assessment at 12 weeks

Objective response rate (ORR)

Percentage of patients with a best objective response (assessed by RECIST 1.1) of complete or partial response prior to progression or subsequent cancer therapy, as assessed by the investigator

Duration of response (DoR) Time from first documented RECIST response until documented progression (or death in the absence of disease progression)

Progression free survival (PFS)

Time from start of study treatment until the date of objective disease progression according to RECIST 1.1 or death (by any cause in the absence of disease progression), regardless of whether the patient withdraws from therapy or receives another anticancer therapy prior to disease progression

The percentage change in target lesion (TL)

Tumour size at each time point was obtained by taking the difference between the sum of the TLs at each time point and the sum of TLs at baseline divided by the sum of the TLs at baseline times 100

40

Time to study treatment discontinuation or death (TDT)

Time from the start of study treatment (Day 1) until the earlier of the date of study treatment discontinuation or death

Overall survival (OS) Time from the start of study treatment (Day 1) until death due to any cause

41

Summary of efficacy in the FAS, by breast cancer subtype and by previous lines of cytotoxic chemotherapy for

metastatic disease

Endpoint FAS (n=30

)

TNBC (n=17)

HR+ (n=13

)

0–1 prior lines (n=20

)

Two prior lines

(n=10)

CD3≥458

cells/mm2

(n=13)

CD3<458

cells/mm2

(n=13)

CD8≥140 cells/mm2

(n=13)

CD8<140 cells/mm2

(n=12)

PD-L1 TC

≥1% cut-off(n=10)

PD-L1 TC

<1% cut-off(n=17)

PD-L1 IC≥1% cut-off

(n=17)

PD-L1 IC

<1% cut-off(n=10)

ORR, % (95% CI) 63·3 (43·9

–80·1)

58·8 (32·9–81·6)

69·2 (38·6

–90·9)

70·0 (45·7–88·1)

50·0 (18·7–81·3)

53·8(25·1– 80·8)

61·5(31·6– 86·1)

61·5(31·6

– 86·1)

58·3(27·7

– 84·8)

80·0 (44·4– 97·5)

52·9 (27·8– 77·0)

64·7 (38·3

– 85·8)

60·0 (26·2– 87·8)

Median DoR– months (IQR)

9·2 (5·5–20·3)

12·9 (5.5–20.3)*

7·2 (5.5–10.9)*

12·9 (9.1–NC)*

5·5 (5·4–5·5)*

9·2 (5.8– 13·1)*

7.2 (5.4–20.3)*

9·2 (7.2– 13·1)*

5·5 (4.0– 20·3)*

9·1 (4.0– 12·9)*

7·2 (5.5– 13.1

9·2 (5.8– 12·9)

5·5 (5.4– NC)*

Median PFS– months (95% CI)

8·2 (4·6–11·8)

4·9 (2·6–13·8)

9·9 (6·2–21·5)

11·7 (4·6–13·8)

6·5 (1·0–8·3)

6·7 (4·5– 13·8)

8·3 (2·6– 21·5)

9·9 (4·5– 13·8)

7·2 (1.0– 21·5)

6·7 (2·6– 13·8)

8·2 (2·2– 11·7)

6·7 (2·8– 11·7)

8·2 (0·9–NC)

Median OS– months (95% CI)

21·5 (16·2

–25·7)

20·5(12·3–NC)

22·4 (14·4

–25·5)

23·4 (16·3–

NC)

16·9 (4·6–25·5)

19·2 (16·2– 25·5)

19·2(10·1–23·4)

23·6 (16·2– NC)

18·6 (10·1

– 25·7)

23·9 (4·6– NC)

18·8 (15·6– 25·7)

21·5 (16·2

– 25·5)

16·9 (9.0–NC)

*In evaluable patients: TNBC, n=10; HR+, n=9; 0–1 prior lines, n=14; two prior lines, n=5; CD3 ≥457·72, n=7; CD3 <457·72, n=8; CD8 ≥140, n=8; CD8 <140, n=7; PD-L1 TC ≥1%, n=8; PD-L1 TC <1%, n=9; PD-L1 IC ≥1%, n=11; PD-L1 IC <1%, n=6;

42

CI, confidence interval; DoR, duration of response; FAS, full analysis set; HR+, hormone receptor positive; IQR, interquartile range; NC, not calculable; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; TNBC, triple-negative breast cancer

Post-hoc subgroup analysis endpoints

Subgroup Endpoint

Triple negative breast cancer versus hormone receptor positive

Duration of responseProgression-free survival

Overall survivalPD-L1 tumour cell (≥1%) versus PD-L1 tumour

cell (<1%)Median overall survival

PD-L1 immune cell (≥1%) versus PD-L1 immune cell (<1%)

Median overall survival

CD3 tumour-infiltrating lymphocytes (≥458 cells/mm2) versus CD3 tumour-infiltrating

lymphocytes (<458 cells/mm2)

Median overall survival

CD8 tumour-infiltrating lymphocytes Median overall survival43

(≥140 cells/mm2) versus CD8 tumour-infiltrating lymphocytes (<140 cells/mm2)

44

Kaplan–Meier estimates of (A) duration of response, (B) progression-free

survival, and (C) overall survival by hormone receptor status

DoR, duration of response; HR+, hormone receptor positive; PFS, progression-free survival; OS, overall survival; TNBC, triple-negative breast cancer

45

Kaplan–Meier estimates of (A) duration of response, (B) progression-free

survival, and (C) overall survival by line of chemotherapy

DoR, duration of response; HR+, hormone receptor positive; PFS, progression-free survival; OS, overall survival; TNBC, triple-negative breast cancer

46

Summary of additional secondary endpoints in the FAS

Endpoint Median (IQR) / (95% CI)*

Median percentage change from baseline in target lesion size at 12 weeks (IQR), n=29*

−40·0 (−57·3 to 1·3)

Median percentage change from baseline in target lesions size at 28 weeks (IQR), n=19*

−50·0 (−64·4 to −18·8)

Median best percentage change from baseline in target lesions size (IQR), n=30†

−51·4 (−74·7 to −20·0)

Median time to study treatment discontinuation or death, (95% CI) months‡

7·8 (6·2 to 12·1)

*n is the number of patients with either a tumour size recorded at the time point or enough information to impute a value†n is the number of patients with at least one post baseline RECIST target lesion assessment scan‡Calculated using the Kaplan–Meier technique; IQR, interquartile range

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Overall survival in PD-L1 subgroups

PD-L1; programmed cell death ligand 1, IC; immune cells; TC, tumour cells

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Overall survival in TIL subgroups

TIL, tumour-infiltrating lymphocyte

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Summary of adverse events of ≥ Grade 3 causally-related to study treatment of patients receiving olaparib and durvalumab

Patients (N=34) ≥ Grade 3Causally-related to study treatment* n (%)

Patients with any AE 8 (24)

Fatigue 1 (3)†

Anaemia 3 (9)†

Vomiting 1 (3)†

White blood cell count decreased 1 (3)†

Neutropenia 2 (6)†

Pancreatitis 2 (6)‡

Hepatitis 1 (3)‡

Haemolysis 1 (3)‡

*Any grade, investigator-determined, †Olaparib-related (no adverse events in ≥10% of patients receiving durvalumab and causally-related to study treatment by the investigator were recorded) ‡Durvalumab-related

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MEDIOLA – List of study centres, investigators and number of patients recruited

Site PI Patients recruited, n

Chaim Sheba Medical Center, Tel Hashomer, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Bella Kaufman 8

Basser Center for BRCA University of Pennsylvania, Philadelphia Susan Domchek 5

Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Yeon Hee Park 4

Drug Development Department (DITEP) and U981 INSERM ATIP-Avenir, Gustave Roussy, Villejuif, France Sophie Postel-Vinay 3

Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea Seock-Ah Im 3

Institut Universitaire du Cancer de Toulouse, Toulouse, France Jean-Pierre Delord 2

Institut Bergonié, Bordeaux, France Antoine Italiano 2

Medical Oncology; Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL); CITOHL; Centre Hospitalier Lyon-Sud; GINECO; Université Claude Bernard Lyon 1; Lyon; France Benoit You 1

Hôpital Cochin, Paris, France Jerome Alexandre 1

Department of Oncology (Surrey), Royal Marsden Hospital-Sutton, London, UK Susana Banerjee 1

Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester and The Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK Matthew Krebs 1

Kantonsspital Graubuenden, Chur, Switzerland Sara Bastian 1

Henry Ford Medical Center, Detroit, USA Ding Wang 1

Washington University School of Medicine, Saint Louis, USA Saiama Waqar 1

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