This is a randomized, international, multicenter, Phase II study designed to explore the efficacy of Olaparib or Olaparib in combination with Durvalumab in platinum-treated mTNBC(metastatic triple negative breast cancer). The primary objectives are to explore Olaparib or Olaparib in combination with Durvalumab as maintenance therapy following clinical benefit with platinum-based therapy in subjects with mTNBC(metastatic triple negative breast cancer).
Subjects suitable for enrollment into this trial are adult subjects with histologically documented triple negative adenocarcinoma of the breast that is inoperable, locally advanced, or metastatic, and is not amenable to resection with curative intent, and who have received at least 4 cycles of platinum-based chemotherapy in the 1st or 2nd line setting AND derived clinical benefit (CR;complete response / PR;partial response / SD;stable disease) per RECIST(Response Evaluation Criteria in Solid Tumors) 1.1 with platinum-based therapy as determined by the treating physician.

Eligible subjects will be randomized to either Olaparib or Olaparib in combination with Durvalumab. Study treatment will continue until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination. Upon treatment discontinuation, subjects will be followed every 2 months for survival.

Although randomization will be used to allocate subjects to either the Olaparib or Olaparib in combination with Durvalumab arm, no comparisons between treatment regimens are planned. The purpose of randomization was to reduce bias due to subject selection into either treatment arm.

Treatment

Twice daily oral Olaparib 300mg alone for Olaparib alone arm or Twice daily oral Olaparib plus intravenous Durvalumab every 4 weeks for Olaparib plus Durvalumab as maintenance therapy until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.

Arm Label

Target Number of Participant

Arm Type

Arm Description

Twice daily oral Olaparib 300mg alone as maintenance therapy until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.

Arm Label

Target Number of Participant

Arm Type

Arm Description

Twice daily oral Olaparib plus intravenous Durvalumab every 4 weeks as maintenance therapy until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.

Gender

Age

Description

1.Age≥ 21years of age
2.ECOG(Eastern Cooperative Oncology Group) performance status 0-2
3.Inoperable locally advanced or metastatic breast cancer not amenable to resection with curative intent and histologically confirmed to be estrogen receptor(ER) negative, progesterone receptor(PR) negative, and HER2 negative :
 - ER(estrogen receptor) negative status is defined as <1% tumour cells positive for ER by immunohistochemistry(IHC), irrespective of staining intensity.
 - Progesterone receptor(PR) negative status is defined as <1% tumour cells positive for PR by IHC, irrespective of staining intensity
    NOTE : Enrollment is permitted for ER/PR low-expression subjects(defined as ≤10%) who are expected to benefit from this trial at the investigator's discretion.
 - HER2(human epidermal growth factor receptor 2) negative status is determined by:
   - IHC 1+, asdefined by incomplete membrane staining that is faint/barely perceptible and within >10% of invasive tumour cells, or
   - IHC 0, as defined by no staining observed or membrane staining that is incomplete and is faint/barely perceptible and within ≤10% of the invasive tumour cells, or
   - FISH(Fluorescent In Situ hybridization) negative based on:
        - single-probe average HER2 copy number <4.0 signals/cell, or
        - Dual-probe HER2/CEP17 ratio <2.0 with an average HER2 copy number <4.0 signals/cell

4. Prior treatment of platinum chemotherapy (minimum 6weekly doses or 3 every 21 day doses)with documented stable disease (SD), partial response (PR) or complete response (CR) per RECIST(Response Evaluation Criteria in Solid Tumors) 1.1 to the platinum therapy.
5.Has received no more than 2 prior chemotherapy regimens for metastatic breast cancer including current platinum based chemotherapy.
6.Able to provide a representative formalin-fixed, paraffin embedded tumour specimen archival or fresh tissue for correlative studies and biomarker analysis
7.Hemoglobin ≥ 10.0 g/dL and no blood transfusions in the 28 days prior to study entry. White blood cells (WBC) >3 x 10^9/L.
8.Platelet count >100 x 10^9/L.
9.Total bilirubin <1.5 x the upper limit of normal (ULN) with the following exception: subjects with known Gilbert's disease who have serum bilirubin <3 x ULN may be enrolled.
10.Aspartate transaminase (AST) and alanine transaminase (ALT) <2.5 x ULN with the following exceptions: subjects with documented liver or bone metastases may have AST and ALT <5 x ULN.
11.Alkaline phosphatase (ALP) <2 x ULN (<5 x ULN in subjects with known liver involvement and <7 ULN in subjects with known bone involvement).
12.Serum creatinine <1.5 x ULN or creatinine clearance >51 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.
13.For subjects of childbearing potential, agreement (by both subject and partner) to use an effective form of contraception, including surgical sterilization, reliable barrier method, birth control pills, contraceptive hormone implants, or true abstinence and to continue its use for the duration of the study and for 6 months after last dose of study treatment.
14.Subjects of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
15.Subjects willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examination.
16.For inclusion in genetic research, subjects must provide informed consent for genetic research collection of specimens to be stored at repository for future research.

1.Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of first dose of treatment. Subjects who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks since last dose of the previous investigational agent of device.
2.Concurrent enrolment in another clinical study, unless it is an observational (non interventional) clinical study or the follow-up period of an interventional study.
3.Active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, or similar treatment) is not considered a form of systemic treatment.
4.Current or prior use of immunosuppressive medication within 28 days before the first dose of investigational drug(s), with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone or an equivalent corticosteroid.
5.Previous treatment with PARP inhibitors including olaparib.
6.Patients that have required discontinuation of treatment due to treatment-related toxicities from prior therapy with PD-1, PDL-1 or CTLA-4 inhibitors or previous history of immune-related grade 3 or 4 adverse event.
7.Known active central nervous system metastasis and / or carcinomatous meningitis. Subjects with previously treated brain metastases may participate, provided they have:
A.Stable brain metastases [without evidence of progression by imaging (confirmed by computerized tomography {CT} scan if CT used at prior imaging) for at least four weeks prior to the first dose of trial treatment**,
B.No evidence of new or enlarging brain metastases; any neurologic symptoms should have returned to baseline,
C.Not used steroids for brain metastases in the 28 days prior to trial initiation.
**This exception does not include carcinomatous meningitis, as subjects with carcinomatous meningitis are excluded regardless of clinical stability.
8.History and/or confirmed pneumonitis, or extensive bilateral lung disease on high resolution/spiral CT scan. Patients with suspected or confirmed myelodysplastic syndrome/acute myeloid leukemia.
9.History of another primary malignancy except for:
A.Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of study drug and of low potential risk for recurrence.
B.Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
C.Adequately treated carcinoma in situ without evidence of disease eg, cervical cancer in situ.
10.Major surgery within 2 weeks of starting the study, and subjects must have recovered from any effects of any major surgery.
11.Receipt of radiation therapy within 4 weeks prior to starting study drug(s). Limited field of radiation for palliation within 2 weeks of the first dose of study treatment is allowed provided:
A.The lung is not in the radiation field
B.Irradiated lesion(s) cannot be used as target lesions
12.Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease, active bleeding diatheses including any subjects known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness / social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent.
13.Subjects unable to swallow orally administered medication, and subjects with gastrointestinal disorders likely to interfere with absorption of the study medication.
14.Subjects requiring treatment with potent inhibitors or inducers of CYP3A4.
15.Pregnant or breast-feeding women. If breastfeeding can be stopped prior to study enrollment until 1 month after the last study dose, then the patient could be allowed to enter the study.
16.Immunodeficient subjects, eg, receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment, and subjects who are known to be serologically positive for human immunodeficiency virus (HIV).
17.Received a live vaccine within 30 days of planned start of study therapy.
18.Subjects with a known hypersensitivity to olaparib or durvalumab, or any of the excipients of the product.
19.Active or prior documented inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis)
20.History of allogeneic organ transplant
21.Active bleeding diatheses
22.Patients with known active hepatic disease (ie, Hepatitis B or C)
23.Known history of previous clinical diagnosis of tuberculosis.

To determine the efficacy as assessed by PFS(progression free survival) of maintenance olaparib or olaparib in combination with durvalumab following clinical benefit (complete response [CR], partial response [PR] or stable disease [SD]) with platinum based chemotherapy in the 1st or 2nd line setting for treatment of metastatic triple negative breast cancer (mTNBC).

From date of randomization until the date of documented progression or date of death, whichever came first, approximately 1 year

Determine safety and tolerability as determined by adverse events of maintenance olaparib plus durvalumab

through study completion, approximately 1 year

To determine the efficacy of maintenance olaparib following platinum-based chemotherapy as assessed by overall response rate (ORR).

through study completion, approximately 1 year

Determine safety and tolerability as determined by adverse events of maintenance olaparib alone

through study completion, approximately 1 year

To determine the efficacy of maintenance olaparib in combination with durvalumab following platinum-based chemotherapy as assessed by overall response rate (ORR).

through study completion, approximately 1 year

To determine the efficacy of maintenance olaparib following platinum based chemotherapy as assessed by overall survival (OS).

study duration, approximately 2 years

To determine the efficacy of maintenance olaparib in combination with durvalumab following platinum based chemotherapy as assessed by overall survival (OS).

study duration, approximately 2 years

Between February 4, 2019 and December 24, 2020, 45 patients were randomized (23 to olaparib alone, 22 to the combination). At 9.8 months’ median follow-up,
median PFS from randomization was 4.0 (95% CI, 2.6–6.1) months with olaparib and 6.1 (95% CI, 3.7–10.1) months with the combination, both significantly longer than the historical  control (P = 0.0023 and P < 0.0001, respectively). Clinical benefit rates (SD ≥24 weeks or CR/PR) were 44% (95% CI, 23–66%) and 36% (95% CI, 17%–59%) in the monotherapy and combination arms, respectively. Sustained clinical benefit was seen irrespective of germline BRCA mutation or PD-L1 status but tended to be associated with CR/PR to prior platinum, particularly in the olaparib-alone arm. No new safety signals were reported.