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.
The investigation of olaparib as monotherapy or olaparib in combination with durvalumab in patients with early stage BRCAm, oestrogen receptor (ER)-negative or ER-low, human epidermal growth factor receptor 2 (HER2)-negative breast cancer who are candidates for neoadjuvant therapy supports the ongoing effort to identify novel agents and new drug combinations that can improve pathological complete response (pCR) rates and event-free survival (EFS). In patients at a lower risk (T1b-c/N0) of disease recurrence and a higher chance for cure, monotherapy olaparib may provide adequate neoadjuvant treatment. In contrast, monotherapy olaparib may be inadequate neoadjuvant treatment for those patients at a higher risk (T2/N0 or T1/N1) of recurrence, and the addition of an immune checkpoint inhibitor (ICI) to the neoadjuvant regimen may improve long-term outcomes as was seen in KEYNOTE-522 and GeparNuevo. However, the risk of irreversible immune-mediated adverse events (AEs) of the endocrine system due to ICI use supports the use of ICIs only in the cohort of patients at higher risk for disease recurrence. For both the lower and higher risk groups, the study treatments have the potential for the development of de-escalation strategies in this disease setting where traditional chemotherapy regimens may be avoided altogether. While assessment of the efficacy of the combination of olaparib and durvalumab is ongoing, there are sufficient safety data available to develop a safety and tolerability profile for the combination.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
50
Neoadjuvant olaparib monotherapy (300 mg BID) for four to six 28-day cycles.
Neoadjuvant combination therapy with olaparib (300 mg BID) plus durvalumab (1500 mg IV Q4W) for four to six 28-day cycles.
Research Site
Loveland, Colorado, United States
Research Site
Boston, Massachusetts, United States
Research Site
Portland, Oregon, United States
Research Site
Philadelphia, Pennsylvania, United States
Research Site
East Melbourne, Australia
Research Site
Rankweil, Austria
Research Site
Salzburg, Austria
Research Site
Brussels, Belgium
Research Site
Liège, Belgium
Research Site
Augsburg, by, Germany
...and 26 more locations
pCR Rate of Olaparib Monotherapy and Olaparib Plus Durvalumab Combination Therapy, Assessed by Central Pathology Review
pCR = pathological complete response pCR was 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. Results of this outcome measure are from DCO1 (20 November 2024). The Clopper Pearson method is for the computation of the 95% confidence interval (CI).
Time frame: Approx. 4 to 6 months
pCR Rate of Olaparib Monotherapy and Olaparib Plus Durvalumab Combination Therapy, Assessed by Local Pathology Review
pCR was 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. Results of this outcome measure are from DCO1 (20 November 2024). The Clopper Pearson method is for the computation of the 95% CI.
Time frame: Approx. 4 to 6 months
RCB of Olaparib Monotherapy and Olaparib Plus Durvalumab Combination Therapy as Assessed by Central Pathology Review
RCB = residual cancer burden RCB index value using 6 variables to categorize response in 1 of 4 classes: RCB 0 (pCR), I (minimal RCB), II (moderate RCB), and III (extensive RCB). RCB III included patients who had clinical progression before surgery, and there was no central pCR performed. Results of this outcome measure are from DCO1 (20 November 2024).
Time frame: Approx. 4 to 6 months
RCB of Olaparib Monotherapy and Olaparib Plus Durvalumab Combination Therapy as Assessed by Local Pathology Review
RCB index value using 6 variables to categorize response in 1 of 4 classes: RCB 0 (pCR), I (minimal RCB), II (moderate RCB), and III (extensive RCB). RCB III included patients who had clinical progression before surgery, and there was no central pCR performed. Results of this outcome measure are from DCO1 (20 November 2024).
Time frame: Approx. 4 to 6 months
Percentage Change in Tumour Volume at Week 12 and Week 24 From Baseline
Percentage change in tumour volume at Week 12 and Week 24 from baseline was measured using magnetic resonance imaging (MRI). Baseline was defined as the most recent measurement prior to the first administration of study intervention. Percent change from baseline was defined as: (Difference in value between post-baseline volume and baseline volume) divided by baseline volume and multiplied by 100. Results of this outcome measure are from DCO1 (20 November 2024).
Time frame: Week 12 and Week 24
Number of Participants With EFS (Event-free Survival)
EFS was defined as time from the first dose of study intervention administration to any of the following events: progression of disease that precluded surgery, local or distant recurrence after surgery, second primary malignancy (breast or other invasive cancers), or death due to any cause. Results of this outcome measure are from final DCO (16 September 2025). One of 3 subjects in AZD2281 + MEDI4736 group had a disease progression recorded in error; 2 (8.0%) participants had an EFS event of progression of disease reported in the neoadjuvant period.
Time frame: Approx. 3 years
Number of Participants With AEs
AE = adverse event; ECG = electrocardiogram Data included clinical observations, ECG parameters, haematology/clinical chemistry, vital signs assessed as the number of participants with AEs. Results of participants with AEs are from final DCO (16 September 2025).
Time frame: Through study completion, approximately 34 months
Number of Participants With SAEs
SAE = serious adverse event Data included clinical observations, ECG parameters, haematology/clinical chemistry, vital signs assessed as the number of participants with AEs. Results of participants with SAEs are from final DCO (16 September 2025).
Time frame: Through study completion, approximately 34 months
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