Skip to main content

Precision medicine phase II study evaluating the efficacy of a double immunotherapy by durvalumab and tremelimumab combined with olaparib in patients with solid cancers and carriers of homologous recombination repair genes mutation in response or stable after olaparib treatment

Abstract

Background

Tumors with deficient homologous repair are sensitive to PARP inhibitors such as olaparib which is known to have immunogenic properties. Durvalumab (D) is a human monoclonal antibody (mAb) which inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor. Tremelimumab (T) is a mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). This study is designed to evaluate the efficacy of combination of olaparib, durvalumab and tremelimumab in patients with a solid tumors with a mutation in homologous gene repair.

Methods

This phase II study will assess the efficacy and safety of olaparib/D/T association in patients (n = 213) with several types of solid cancers (breast cancer, ovarian cancer, pancreatic cancer, endometrial cancer, prostate cancer and others) with at least one mutation in homologous repair genes (BRCA1, BRCA2, PALB2, ATM, FANCA, FANCB, FANCC, FANCE, FANCF, CHEK2, RAD51, BARD1, MRE11, RAD50, NBS1, HDAC2), LKB1/STK11, INPP4B, STAG2, ERG, CHEK1, BLM, LIG4, ATR, ATRX, CDK12). Good performance status patients and corresponding to specific inclusion criteria of each cohort will be eligible. STEP1: Patients will receive olaparib 300 mg BID. In absence of progression after 6 weeks of olaparib, they will follow STEP 2 with olaparib and immunotherapy by durvalumab (1500 mg Q4W) + tremelimumab (75 mg IV Q4W) during 4 months and will further pursue durvalumab alone until disease progression, death, intolerable toxicity, or patient/investigator decision to stop (for a maximum duration of 24 months, and 36 months for ovarian cohort). Primary endpoint is safety and efficacy according to progression-free survival (PFS) of olaparib + immunotherapy (durvalumab + tremelimumab) during 4 months followed by durvalumab alone as maintenance in patients with solid cancers and in response or stable, after prior molecular target therapy by olaparib; secondary endpoints include overall survival (OS), disease control rate (DCR), response rate after 6 weeks of olaparib, safety of olaparib/durvalumab/tremelimumab association. Blood, plasma and tumor tissue will be collected for potential prognostic and predictive biomarkers.

Discussion

This study is the first trial to test the combination of olaparib and double immunotherapy based on molecular screening.

Trial registration

NCT04169841, date of registration November 20, 2019

Peer Review reports

Background

With the development of cost effective and rapid technology of genome sequencing, precision medicine becomes a new way to think oncology. Current targets involve mainly tyrosine kinases but DNA repair machinery could also be targetable. Some of DNA repair aberrations have been associated with sensitivity to platinum and poly adenosine diphosphate [ADP]–ribose polymerase (PARP) inhibitors like olaparib, suggesting that treatment with a PARP inhibitor (PARPi) may exploit a synthetic lethal interaction, in the presence of alteration of the homologous repair pathway. PARP is involved in multiple aspects of DNA repair, and the PARP inhibitor olaparib has recently been approved for treating ovarian cancers with BRCA1/2 mutations [1, 2]. Similar results were also observed with clinical benefit of olaparib in BRCA2 mutated pancreatic cancer and in BRCA1/2 mutated breast cancer [3, 4]. In addition, a report in the New England Journal of Medicine using a high-throughput, next-generation sequencing assay in prostate cancer showed the detection of genomic alteration in genes involved in homologous repair pathway BRCA2, ATM, BRCA1, PALB2, CHEK2, FANCA, and HDAC2, is associated with response to olaparib [5]. Recently, TOPAR-B confirmed these results [6]. Thus demonstrating the clinical validation of the usage of precision medicine to position PARP inhibitors like olaparib based on molecular analysis rather than on tumor type.

Similarly, checkpoint inhibitors targeting PD-1 or PD-L1 have demonstrated an efficacy in multiple cancer types. Currently some biomarkers could be used to predict checkpoint inhibitor efficacy in a tumor type agnostic manner. High level of mutation results in high number of neoantigens and antitumor immune response, providing the rational to use immunotherapy to target such tumor types. Microsatellite instability gives rise to a high number of mutations and is associated with good response to immunotherapy whatever the cancer type. A large cohort of patients treated with pembrolizumab in multiple cancer types shows that high tumor mutation burden (TMB) is associated with response, no matter cancer type [7]. Additional DNA damage response (DDR) machinery dysfunction like deficit in homologous repair may lead to accumulation of mutations. After receiving anti-PD-1/PD-L1 treatment, patients with DDR deficiencies had a higher response rate compared to patients without these deficiencies.

Preclinical studies showed DNA damage promotes neoantigen expression [8]. PARPi-mediated catastrophic DNA damage induces accumulated chromosome rearrangements, generates neoantigens and thus increases mutation burden [9]. It is possible that increased DNA damage by PARPi would expand neoantigen expression, leading to greater immune recognition of the tumor. PARPi is also associated with immunomodulation. The PARPi talazoparib increases the number of peritoneal CD8+ T cells and natural killer cells and increases production of interferon (IFN)-γ and tumor necrosis factor–α (TNF)- α in a BRCA1-mutated ovarian cancer xenograft model [10]. Some preclinical reports also underline the capacity of PARP inhibitors to induce Type I IFN and enhance both MHC and PD-L1 expression. Hence, addition of PARPi to immune checkpoint blockade could complement the clinical benefit of immune checkpoint inhibition. Preclinical data underline a putative synergy and recent data of MEDIOLA study suggest a possible synergy between olaparib and durvalumab [11].

So, we propose to generate a clinical trial based on precision medicine to evaluate the use of immunotherapy in patients with different type of cancers with altered homologous recombination repair genes and without progression after prior targeted therapy.

The objective of this study is to determine whether the combination of olaparib plus durvalumab and tremelimumab could be effective in homologous repair deficient (HRD) tumors.

Methods

Study design

This is a multicenter, open label, non-randomized, prospective, phase II study. Patients with mutations in homologous recombination repair genes will be identified through NGS, performed at investigator sites. Analysis will be performed prior to study, as part of a clinical study or in accordance with the usual practice at the investigator site. Study design is depicted in Fig. 1.

Fig. 1
figure1

Study design

Study objectives

The primary objective of the study is to evaluate the efficacy of olaparib + immunotherapy (durvalumab + tremelimumab) during 4 months, followed by durvalumab alone as maintenance treatment in patients with solid cancers and in response or stable, after prior molecular target therapy by olaparib based on molecular sequencing (mutation in homologous gene repair).

Study secondary objectives are:

  1. 1

    To evaluate 6-month disease control rate (DCR) for all cohorts, except ovarian cohort which will be evaluated at 12-months.

  2. 2

    To evaluate 1 and 2-year PFS and overall survival (OS).

  3. 3

    To evaluate response rate after 6 weeks of olaparib therapy (STEP 1).

  4. 4

    To evaluate safety of molecular therapy by olaparib at the end of STEP1.

  5. 5

    To evaluate safety of molecular therapy (olaparib) + immunotherapy (durvalumab + tremelimumab) and immunotherapy in maintenance (durvalumab alone).

The study exploratory objective is to evaluate the immunogenic effect of olaparib (modification of immune infiltrate and immunogenic cell death markers on biopsy performed before and after olaparib treatment).

Study endpoints

The primary endpoint is progression free survival (PFS) 6 months after the initiation of immunotherapy for all cohorts, with the exception of ovarian cohort evaluated at 12 months. PFS is defined as the time from the date of first dose of immunotherapy to the date of progression or death from any cause. Progression will be defined using iRECIST criteria.

Secondary endpoints are:

  1. 1

    Disease control rate, including stable and responsive disease, evaluated 6 months after immunotherapy initiation for all cohorts except ovarian cohort, evaluated at 12 months.

  2. 2

    Overall survival (OS) evaluated at 12 and 24 months after immunotherapy initiation defined by the time of the first immunotherapy dose to the date of death from any cause.

  3. 3

    Response rate evaluated by CT scan, RECIST evaluation after 6 weeks of olaparib therapy.

  4. 4

    Olaparib toxicity evaluated at the end of STEP1 using CTCAE V5.

  5. 5

    Olaparib + immunotherapy (tremelimumab + durvalumab) toxicity evaluated at 3, 6 and 12 months after immunotherapy initiation using CTCAE V5.

Study population and eligibility criteria

Two hundred and seventy patients diagnosed with a solid malignancy, presenting the following histologically confirmed cancers: metastatic breast, lung, prostate, head and neck, endometrial, clear renal cell, pancreatic and urothelial cancer as well as locally advanced or metastatic ovarian cancer. Two hundred and thirteen are expected for STEP 2. Study inclusion and exclusion criteria are detailed in Tables 1 and 2.

Table 1 General and cohort specific study inclusion criteria
Table 2 Study exclusion criteria

Investigational products

Olaparib, durvalumab and tremelimumab will be supplied by AstraZeneca.

Study procedures

All patients respecting all eligibility criteria, namely presenting mutations in homologous repair genes will be included. Regimens sequence is presented in Fig. 1. Study will be divided into two successive steps:

  • Step 1

    After 6-weeks of olaparib, all patients from STEP 1 will have a CT scan.

  • Step 2

    Depending on CT scan results, two situations will occur:

    1. 1)

      Patients with stable disease or partial response will follow olaparib + immunotherapy by durvalumab + tremelimumab during 4 months and then continue with durvalumab alone until progression or until 24 dosing maximum of durvalumab for all cohorts except for ovarian cohort with a maximum of 36 dosing.

    2. 2)

      Patient with progression will be withdrawn from the study and treated according to standard care.

Ancillary studies

Ancillary studies will be conducted to evaluate the immunogenic effect of study treatments. Before any procedure, patients should consent to participate to the exploratory studies by signing a specific informed consent form.

Treatment doses and regimens

Olaparib

Patients will be administered olaparib study treatment tablets orally at a dose of 300 mg bid.

The maximum duration of treatment with olaparib is 8 weeks, corresponding to the duration of STEP 1, + 4 months, the duration of the initial part of STEP 2. The initial dose of 300 mg bid will be made up of 2 × 150 mg tablets bid. All doses of study treatment should be taken at the same time every day approximately 12 h apart.

Durvalumab + tremelimumab combination therapy

Patients in the durvalumab + tremelimumab combination therapy treatment will receive durvalumab (1500 mg Q4W) in combination with tremelimumab (75 mg IV Q4W) for up to 4 doses/cycles each, followed by durvalumab 1500 mg Q4W until confirmed PD (progressive disease), unacceptable toxicity, consent withdrawal, or occurrence of events leading to treatment discontinuation. With a maximum of 24 dosing of durvalumab (36 dosing for ovarian cohort).

Tremelimumab will be administered first. Durvalumab infusion will start approximately 1 h (maximum 2 h) after the end of the tremelimumab infusion. Standard infusion time for each is 1 h.

The first durvalumab monotherapy dose at 1500 mg Q4W will be 4 weeks after the final dose of durvalumab in combination with tremelimumab. (Cycle 5). After 20 cycles, durvalumab will be stopped for all cohorts, except for the ovarian cohort for a maximum of 32 months with durvalumab.

All patients will be followed for disease progression and survival until 24 months after the end of treatment.

Treatment duration and criteria for retreatment

Treatments will be administered on Day 1 for up to 4 months for olaparib + durvalumab + tremelimumab and then from day 1 of month 5 for up to day 1 of month 24 (all cohorts) or month 36 (only for ovarian cohort) for durvalumab alone or until confirmed PD, unacceptable toxicity, consent withdrawal or occurrence of events leading to treatment discontinuation (Fig. 2). Patient will have a maximum of 24 doses of durvalumab, except for ovarian cohort that will reach a maximum of 36.

Fig. 2
figure2

Olaparib + durvalumab + tremelimumab combination therapy dosing schedule

Patients with rapid tumor progression or with symptomatic progression requiring urgent medical intervention will not be eligible to continue durvalumab ± tremelimumab treatment.

For all patients who are treated through progression or patients who achieve disease control [i.e., CR, PR, or SD] at 12 months and restart treatment upon evidence of PD during follow-up, the investigator should evaluate whether patients have any significant, unacceptable or irreversible toxicities that might indicate that continuing or restarting treatment would not further benefit the patient. Patients who progressed during the first 4 months, during combination of durvalumab and tremelimumab are not allowed to be retreated.

Patients meeting the retreatment criteria below, will respect the same treatment guidelines followed during the initial 12-month treatment period, including the same dose and treatment frequency of durvalumab + tremelimumab without olaparib and the same schedule of assessments. The only exception will be the ancillary study, tumor biopsies won’t need to be collected a second time.

Patients who meet the criteria for retreatment may only receive retreatment once.

  • Patients may not undergo retreatment if:

    Patients have evidence of PD during the portion of the regimen concerning the combination period of durvalumab + tremelimumab. Olaparib will not be restarted.

  • Patients may undergo retreatment as described below:

    • Patients who complete the 4 dosing cycles of the combination olaparib + durvalumab and tremelimumab portion of the regimen (with clinical benefit per Investigator judgment), but subsequently have evidence of PD during the durvalumab monotherapy, with or without confirmation according to RECIST 1.1, may restart treatment with the combination, if there are 4 months between last cycle of first combination treatment and progression.

    • Patients who achieve and maintain disease control (i.e., CR, PR, or SD) through to the end of the 12-month treatment period may continue treatment with durvalumab alone until evidence of PD, with or without confirmation and according to RECIST 1.1, during follow-up.

For all patients who restart treatment with the combination as well as patients who continue Durvalumab alone, the investigator should ensure:

  • Patients do not have any significant, unacceptable, or irreversible toxicities that might indicate that continuing treatment would not further benefit the patient.

  • Absence of clinical symptoms or signs indicating clinically significant disease progression accompanied by a decline in WHO/ECOG performance status to > 1.

  • Absence of rapid disease progression or threat to vital organs or critical anatomical sites requiring urgent alternative medical intervention.

  • Patient still fulfills eligibility criteria for this study. Patients must also agree to fill an additional consent to restart durvalumab + tremelimumab combination therapy.

  • If applicable, retreatment will be possible:

During the retreatment period, patients in the durvalumab + tremelimumab combination therapy group will resume durvalumab dosing at 1500 mg Q4W with 75 mg of tremelimumab Q4W for 4 doses/cycles each. Patients will then continue with durvalumab monotherapy at 1500 mg Q4W, beginning at Week 16, 4 weeks after the last dose of combination therapy, until disease progression or up to a total of 9 additional doses/cycles with the final dose at Week 48 (Month 12). Olaparib will not be restarted.

Withdrawal and discontinuation criteria

At any time, subjects are free to withdraw from the study (investigational product and assessments), without prejudice of further treatment (withdrawal of consent). The reason(s) for withdrawal and the presence of any AEs will be investigated.

Patients who withdraw consent for further participation will not receive any further investigational product or further study observation, with the exception of follow-up for survival, which will continue until the end of the study unless the patient has expressly withdrawn his or her consent to survival follow-up.

Subject will be considered lost to follow-up only if no contact has been established by the time the study is completed such that there is insufficient information to determine the subject’s status at the time.

Reasons that will lead to permanent investigational product discontinuation are detailed in Table 3. Any patient who has not yet shown objective radiological disease progression at withdrawal from investigational product should continue to be followed as per RECIST 1.1.

Table 3 Criteria for permanent discontinuation of investigational product

Statistical analyses

Continuous variables will be summarized using descriptive statistics, i.e. number of subjects with available data (N), mean, median, standard deviation (S.D.), 25–75% quartiles (Q1-Q3) and range. Continuous variables could be transformed as categorical variable using median or using conventional cut-off from bibliography or clinical practice. If required comparison using Chi square (or exact Fisher test) or Student T test (or Wilcoxon Mann and Whitney) tests will be done. Categorical variables will be described by and percentages. The number of missing data will be described.

Each cohort will be described and analyzed separately.

Sample size calculation

Sample size was determined using an A’Hern’s single stage design. The primary endpoint is progression PFS. It will be evaluated at 6 months (except for ovarian cancer with an evaluation at 18 months given the results of olaparib in SOLO-2 trial). The hypotheses are the following:

  • one-sided alpha risk =10%, a power = 90%,

  • the expected rate of patients stable or in response after 6 weeks of olaparib is 80%,

  • the expected rate of patients non-evaluable the primary endpoint is 5%,

  • P0 and P1 are determined using hypotheses detailed above.

P0 is the highest level of inefficacy for which the new treatment will be rejected (maximal inefficacity). P1 defines the minimum required level of efficacy. The design of the trial focuses on demonstrating that this level is plausible given that the trial results and the efficacy is greater than the first proportion, P0. Taking into account these hypotheses: 270 patients will be included in the study, and at least 213 are required for statistical analyses. At the end the study, analysis of the primary endpoint will be performed on evaluable patients who were in response or stable after 8 weeks of olaparib.

Analysis of safety endpoint(s)

Safety analyses will be performed on the safety-evaluable population, defined as all subjects treated with at least one dose of investigational product.

In each cohort, toxicities and grades will be described according to the type of event at each cycle.

The global following data will also be given:

  • The number and percentage of patients with at least one adverse event over the study period,

  • The number and percentage of patients with at least one grade 3 or 4 adverse event over the study period,

  • The number and percentage of patients with at least one serious adverse event over the study period,

  • The number and percentage of patients with at least one adverse event leading to treatment premature stop over the study period.

In case a patient experience more than one toxicity, the toxicity with the highest grade will be considered.

Time until grade 3–4 toxicity will be determined using the Kaplan Meier method. Patients without toxicities will be censored.

Analysis of efficacy endpoint(s)

Efficacy analyses will be performed in modified intent-to-treat population (ITT) population ie, all patients with a 6-month evaluation (12-month for ovarian cohort) and at least one dose of durvalumab + tremelimumab. Analyses will be repeated in the per protocol population (patients who had received all the planned doses).

6-month PFS rate (12 month-rate in the ovarian cohort) will be determined using the Kaplan Meier method. 95% Confidence interval (CI) will be provided. Patients alive without progression will be censored.

Median follow-up will be estimated using the reverse Kaplan Meier method.

PFS and Overall survival will be estimated using the Kaplan Meier method. Six-month, 1-year, 2-year rates as well as median OS and PFS will be reported with their 95% CI.

Disease control rates at 6 months will be determined and described with its 95% binomial CI. The same method will be applied to describe the response rate after 6 months of olaparib in each cohort.

All statistical analysis will be performed with SAS 9.4. In case of comparison, tests will be two-sided.

Exploratory analyses

Analysis of immunogenicity will be performed based on IHC analysis. We will analyze the micro environment with T Cells and PD-L1 expression. Moreover, we will analyze immunogenic death with HMGB1 and LC3. These parameters will be compared before and after a target therapy to evaluate its impact on microenvironment.

Interim analyses

An Independent Data Monitoring Committee (IDMC) will be established for Guid2Repair trial. The IDMC will consist of designated sponsor, 2 or 3 experts in oncology and 1 statistician. The IDMC will be responsible for an independent evaluation of the safety for the patients participating in the clinical trial. Additional IDMC meetings could be required if more than 15% of ongoing patients have experienced an adverse event ≥ grade 3.

No interim analyses are planned for efficacy.

Ethical and regulatory requirements

The study will be performed in accordance with ethical principles that have their origin in the Declaration of Helsinki, including Decree no. 2016–1537 of 16/11/ 2016 on research involving human subjects, and are consistent with ICH/Good Clinical Practice, and applicable regulatory requirements Patient Data Protection; in France CNIL.

Before carrying out research on humans, the sponsor is required to submit the project to the opinion of one of the competent institutional ethical committee (Comité de protection des Personnes CPP) and to the regulatory authority (ANSM).

Prior to the implementation of the research on a person, eligible subject will be fully informed by the investigator during the consultation and after a period of reflection sufficient written informed consent form will be collected.

The information will also include information on data handling in accordance with the revised French Data Protection regulations including European General Data Protection Regulation N° 2016/679.

Discussion

Among all solid tumors, a subgroup of patients presents a deficiency in homologous recombination repair genes. This abnormal DNA repair system sensitizes these tumors to PARP inhibitors. There is a strong rational to combine PARP inhibitors and immune checkpoint inhibitors. Indeed, PARP inhibitors induce DNA damage causing neoantigen increase, leading to a reinforced recognition by the immune system. Moreover, PARP inhibitors increase PD-L1 expression. In 2017, Lee et al have shown that anti-PD-L1 and olaparib combination is safe [12]. Recently, phase 2 MEDIOLA has shown promising results in BRCA mutated breast cancer with a control rate of 80% at 12 weeks [13]. In the light of these results, immunogenic target therapy with olaparib in combination with immune checkpoint inhibitors could act synergistically and might be a promising treatment in tumors with deficiencies in homologous recombination. Furthermore, blood, plasma and tumor tissue will be collected and assessed for potential prognostic and predictive biomarkers. Study is ongoing and the first patient was included in February 11th 2020.

Availability of data and materials

Not applicable.

Abbreviations

Aes:

Adverse events

CI :

Confidence interval

CTLA-4 :

Cytotoxic T-Lymphocyte-Associated protein 4

DCR :

Disease control rate

DDR :

DNA damage response

HRD :

Homologous repair deficient

IDMC :

Independent Data Monitoring Committee

ITT :

Intent-to-treat population

NGS :

Next Generation Sequencing

OS :

Overall survival

PARP :

Poly-ADP-Ribose Polymerase

PD-1 :

Programmed Death – 1

PD-L1 :

Programmed Death Ligand 1

PFS :

Progression-Free Survival

Q4W :

Every 4 weeks

TMB :

Tumor mutation burden

References

  1. 1.

    Moore K, Colombo N, Scambia G, Kim B-G, Oaknin A, Friedlander M, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2495–505.

    CAS  Article  Google Scholar 

  2. 2.

    Pujade-Lauraine E, Ledermann JA, Selle F, Gebski V, Penson RT, Oza AM, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(9):1274–84.

    CAS  Article  Google Scholar 

  3. 3.

    Robson M, Im S-A, Senkus E, Xu B, Domchek SM, Masuda N, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523–33.

    CAS  Article  Google Scholar 

  4. 4.

    Golan T, Hammel P, Reni M, Cutsem EV, Macarulla T, Hall MJ, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019; Disponible sur: https://www.nejm.org/doi/10.1056/NEJMoa1903387. Cité 15 nov 2019.

  5. 5.

    Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373(18):1697–708.

    CAS  Article  Google Scholar 

  6. 6.

    Mateo J, Porta N, Bianchini D, McGovern U, Elliott T, Jones R, et al. Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2020;21(1):162–74.

    CAS  Article  Google Scholar 

  7. 7.

    Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20.

    CAS  Article  Google Scholar 

  8. 8.

    Galluzzi L, Senovilla L, Zitvogel L, Kroemer G. The secret ally: immunostimulation by anticancer drugs. Nat Rev Drug Discov. 2012;11(3):215–33.

    CAS  Article  Google Scholar 

  9. 9.

    Li A, Yi M, Qin S, Chu Q, Luo S, Wu K. Prospects for combining immune checkpoint blockade with PARP inhibition. J Hematol Oncol. 2019;12 Disponible sur: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744711/. Cité 15 nov 2019.

  10. 10.

    Huang J, Wang L, Cong Z, Amoozgar Z, Kiner E, Xing D, et al. The PARP1 inhibitor BMN 673 exhibits immunoregulatory effects in a Brca1(-/-) murine model of ovarian cancer. Biochem Biophys Res Commun. 2015;463(4):551–6.

    CAS  Article  Google Scholar 

  11. 11.

    A phase I/II study of MEDI4736 in combination with olaparib in patients with advanced solid tumors. - Full text view - ClinicalTrials.gov. Disponible sur: https://clinicaltrials.gov/ct2/show/NCT02734004. Cité 15 mars 2020.

  12. 12.

    Lee J-M, Cimino-Mathews A, Peer CJ, Zimmer A, Lipkowitz S, Annunziata CM, et al. Safety and clinical activity of the programmed death-ligand 1 inhibitor durvalumab in combination with poly (ADP-Ribose) polymerase inhibitor olaparib or vascular endothelial growth factor receptor 1–3 inhibitor cediranib in women’s cancers: a dose-escalation, phase I study. J Clin Oncol. 2017;35(19):2193–202.

    CAS  Article  Google Scholar 

  13. 13.

    Domchek SM, Postel-Vinay S, Im S-A, Park YH, Delord J-P, Italiano A, et al. Abstract PD5–04: an open-label, phase II basket study of olaparib and durvalumab (MEDIOLA): updated results in patients with germline BRCA-mutated (gBRCAm) metastatic breast cancer (MBC). Cancer Res. 2019;79(4 Supplement):PD5–PD5-04.

    Google Scholar 

Download references

Acknowledgements

We thank Isabel Grégoire, PhD Medical writer Centre Georges François Leclerc for carefully reading the manuscript.

Funding

The study is funded by AstraZeneca.

Author information

Affiliations

Authors

Contributions

JDF and FG designed the study and will include and follow patients. AB, CT and ER will perform statistical analyses and figures. EL, MT and JDF will perform ancillary analysis. FG supervised the study. JDF and FG wrote the manuscript. All coauthors read and approved the final manuscript.

Corresponding author

Correspondence to Jean-David Fumet.

Ethics declarations

Ethics approval and consent to participate

Obtained by Agence Nationale de Sécurité du Médicament (July 2th, 2019), and ethics committee “Comité de Protection des Personnes” (July 18th, 2019). Reference ethical committee 19 05 47, reference CNRIPH 19.05.07.54754. Number EUDRACT 2018–002971-17. Consent to participate was written.

Consent for publication

Not applicable.

Competing interests

The funding bodies played a role in the design of the study and in writing the manuscript but played no role in collection, analysis, and interpretation of data.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Fumet, J., Limagne, E., Thibaudin, M. et al. Precision medicine phase II study evaluating the efficacy of a double immunotherapy by durvalumab and tremelimumab combined with olaparib in patients with solid cancers and carriers of homologous recombination repair genes mutation in response or stable after olaparib treatment. BMC Cancer 20, 748 (2020). https://doi.org/10.1186/s12885-020-07253-x

Download citation

Keywords

  • PARP inhibitors
  • Immune checkpoint inhibitors
  • Olaparib
  • Durvalumab
  • Tremelilumab
  • Homologous repair