Study of Neoadjuvant Olaparib Monotherapy and Olaparib and Durvalumab Combination in HER2 Negative BRCAm Breast Cancer

NCT05498155 | Active Not Recruiting Phase 2 FDA Drug

• 3 other identifiers: D931CC000012023-503529-20-002021-005231-22
• Study Type: interventional
• Target: 50
• Locations: 8 countries
• Sites: 36

Brief Summary

This study to learn more about olaparib and olaparib plus durvalumab combination therapy and also to better understand the studied disease, breast cancer, and associated health problems. Olaparib is a type of drug called a PARP (poly \[adenosine diphosphate-ribose\] polymerase) inhibitor. PARP inhibitors can destroy cancer cells that are not good at repairing DNA damage. Olaparib is also approved by US Food and Drug Administration (FDA), European Medicines Agency (EMA) and in other countries for treating women with BRCA-mutated, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. Durvalumab is a type of anticancer drug called immunotherapy that targets cancer cells by blocking the signal that prevents the immune system from seeing the cancer cell. Your immune system can then attack and kill the cancer cells. Durvalumab is approved by the FDA and the EMA for the treatment of patients with locally advanced non-small cell lung cancer after receiving chemoradiation therapy and extensive-stage small cell lung cancer in combination with chemotherapy. Some parts of this study are experimental, which means that durvalumab and the combination of olaparib and durvalumab are still in the development stage for the treatment of breast cancer, and they are not approved for treatment of breast cancer, except for use in research studies like this.

Conditions

Breast Cancer

Keywords

BRCA Mutations; Early Stage; HER2-Negative Breast Cancer

Outcome Measures

Primary Outcomes (1)

• To evaluate the efficacy, measured by pCR (pathological complete response) rate, of olaparib monotherapy and olaparib plus durvalumab combination therapy, as assessed by central pathology review.

  pCR is defined as ypT0/Tis ypN0 (ie, no invasive residual in breast and the axillary lymph nodes on evaluation of the complete resected breast specimen and all sampled regional lymph nodes) following completion of neoadjuvant systemic therapy.

  Approx. 4 to 6 months

Secondary Outcomes (14)

• To evaluate the efficacy, measured by pCR rate, of olaparib monotherapy and olaparib plus durvalumab combination therapy as assessed by local pathology review

  Approx. 4 to 6 months

• To evaluate the efficacy, measured by RCB (residual cancer burden), of olaparib monotherapy and olaparib plus durvalumab combination therapy as assessed by central pathology review

  Approx. 4 to 6 months

• To evaluate the efficacy, measured by RCB, of olaparib monotherapy and olaparib plus durvalumab combination therapy as assessed by local pathology review

  Approx. 4 to 6 months

• To evaluate the efficacy of olaparib monotherapy and olaparib plus durvalumab combination therapy in terms of change from baseline tumour volume. Tumour volume will be assessed by local radiology review.

  Approx. 4 to 6 months

• To evaluate the efficacy of olaparib monotherapy and olaparib plus durvalumab combination therapy in terms of change from baseline tumour volume. Tumour volume will be assessed by local radiology review.

  Approx. 4 to 6 months

Study Arms (2)

Cohort A

EXPERIMENTAL

Cohort A will consist of a lower-risk population of participants with HER2-negative ER-negative or ER-low defined as having a tumour size \>5 mm and ≤20 mm and N0 (T1b-c/N0).

Drug: Neoadjuvant Olaparib monotherapy group

Cohort B

EXPERIMENTAL

Cohort B will consist of a higher-risk population of participants with HER2-negative ER-negative or ER-low defined as having a tumour size of \>20 mm but ≤50 mm and N0 (T2/N0), or having a tumour size of \>1 mm but ≤20 mm and N1 (T1/N1).

Combination Product: Neoadjuvant combination therapy with olaparib plus durvalumab

Interventions

Neoadjuvant Olaparib monotherapy group DRUG

Neoadjuvant olaparib monotherapy (300 mg BID) for four to six 28-day cycles.

Also known as: Cohort A

Cohort A

Neoadjuvant combination therapy with olaparib plus durvalumab COMBINATION_PRODUCT

Neoadjuvant combination therapy with olaparib (300 mg BID) plus durvalumab (1500 mg IV Q4W) for four to six 28-day cycles.

Also known as: Cohort B

Cohort B

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Males or Females ≥18 years
• Minimum body weight of 30 kg
• Capable of giving signed informed consent.
• Male and Female participants of childbearing potential must use effective methods of contraception
• Histologically confirmed, newly diagnosed, primary, operable, nonmetastatic invasive breast cancer with the following characteristics:
• ER-negative or ER-low defined as IHC nuclear staining ≤10%
• HER2-negative (not eligible for anti-HER2 therapy) defined as:
• IHC 0, 1+ without in situ hybridization OR
• In situ hybridization non-amplified with ratio less than 2.0 OR
• In situ hybridization average HER2 copy number \< 6 signals/cells
• Clinical TNM staging (per AJCC 8th Edition) as follows:
• T1b (\>5 mm but ≤10 mm), N0, no known metastases (M0 or MX); OR
• T1c (\>10 mm but ≤20 mm), N0, no known metastases (M0 or MX); OR
• T1 (\>1 mm but ≤20 mm), N1, no known metastases (M0 or MX); OR
• T2 (\>20 mm but ≤50 mm), N0, no known metastases (M0 or MX).).

You may not qualify if:

• Any evidence of other diseases (such as severe or uncontrolled systemic diseases or active, uncontrolled infections, including but not limited to, uncontrolled ventricular arrhythmia, uncontrolled hypertension, recent \[within 3 months\] myocardial infarction, uncontrolled major seizure disorder, renal transplant, active bleeding diseases, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography scan
• Refractory nausea and vomiting, chronic gastrointestinal disease likely to interfere with absorption of the study medication, inability to swallow the formulated product
• History of another primary malignancy except for malignancy treated with curative intent with no known active disease for ≥5 years before the first dose of study intervention and of low potential risk for recurrence
• Participants with MDS or AML
• For higher risk (Cohort B) participants only: Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[eg, colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, sarcoidosis, granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc), autoimmune pneumonitis, and autoimmune myocarditis
• Known active hepatitis infection, positive hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus core antibody
• Known to have tested positive for human immunodeficiency virus unless currently on effective anti-retroviral therapy with an undetectable viral load within 6 months
• History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (Common Terminology Criteria for Adverse Events \[CTCAE\] Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia
• Participant must not have had any prior treatment for the current breast cancer, including surgery, chemotherapy, hormonal therapy, radiation, or experimental therapy
• For higher risk (Cohort B) participants only: Prior exposure to anti-PD1, anti-PD-L1, or anti-CTLA4 agents (ICIs); OR an agent directed to other co-inhibitory or co-stimulatory T-cell receptors
• Any concurrent anticancer treatment
• Major surgical procedure (excluding placement of vascular access, local surgery of isolated lesions, or diagnostic staging) within 2 weeks of the first dose of study intervention
• For higher risk (Cohort B) participants only: Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab.
• Concomitant use of:
• Known strong cytochrome P450 (CYP3A) inhibitors or moderate CYP3A inhibitors within 2 weeks prior to first dose of study intervention

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (37)

Research Site

Greeley, Colorado, 80631, United States

Location

Research Site

Loveland, Colorado, 80537, United States

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Boston, Massachusetts, 02215, United States

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Portland, Oregon, 97239, United States

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Philadelphia, Pennsylvania, 19104, United States

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Melbourne, 3000, Australia

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Rankweil, 6830, Austria

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Salzburg, 5020, Austria

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Brussels, 1200, Belgium

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Liège, 4000, Belgium

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Augsburg, by, 86156, Germany

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Cologne, 50931, Germany

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Essen, 45130, Germany

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Hamburg, 20246, Germany

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Hanover, 30625, Germany

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Heidelberg, 69120, Germany

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München, 81377, Germany

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Jerusalem, 91120, Israel

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Kfar Saba, 44218, Israel

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Ramat Gan, 5262000, Israel

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Rehovot, 76100, Israel

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Bologna, 40138, Italy

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Meldola, 47014, Italy

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Modena, 41124, Italy

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Roma, 00168, Italy

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A Coruña, 15006, Spain

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Barcelona, 08036, Spain

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Barcelona, 8035, Spain

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Cáceres, 10003, Spain

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Hospitalet deLlobregat, 08907, Spain

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Lleida, 25198, Spain

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Madrid, 28041, Spain

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Málaga, 29010, Spain

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Seville, 41009, Spain

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Seville, 41013, Spain

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Valencia, 46010, Spain

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Nottingham, NG5 1PB, United Kingdom

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

olaparib; durvalumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Anitra Fielding, MBChB

  AstraZeneca

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: There will be 2 cohorts: Cohort A will consist of a lower-risk population Cohort B will consist of a higher-risk population Participants will be allocated to receive 300 mg oral olaparib twice daily as monotherapy or in combination with durvalumab 1500 mg via intravenous infusion every 4 weeks for a minimum of 4 and a maximum of six 28-day cycles before undergoing definitive surgery. Each participant will undergo definitive surgery, preferably within 6 weeks after receiving the final dose of neoadjuvant olaparib therapy, followed by standard treatment (radiation therapy, systemic therapy per institutional standards). Participants who achieve pCR at surgery, will be allowed to continue on treatment with olaparib in the adjuvant setting in lieu of standard adjuvant systemic therapy, per physician's choice. If the physician chooses adjuvant olaparib, then the total duration of olaparib therapy in the neoadjuvant and adjuvant setting should be 12 cycles.

Study Record Dates

• First Submitted: July 5, 2022
• First Posted: August 11, 2022
• Study Start: November 7, 2022
• Primary Completion: November 20, 2024
• Study Completion (Estimated): December 31, 2026
• Last Updated: June 10, 2025

Record last verified: 2025-06

Locations

AU (2); DE (7); GB (1); IL (4); IT (4); US (5); BE (2); ES (11)