Phase II Multicenter Study of Durvalumab and Olaparib in Platinum tReated Advanced Triple Negative Breast Cancer (DORA) (DORA)

• ClinicalTrials.gov Identifier: NCT03167619
• Recruitment Status: Completed
• First Posted: May 30, 2017
• Results First Posted: September 13, 2022
• Last Update Posted: September 13, 2022
• Sponsor: Duke University
• Collaborator: AstraZeneca
• Information provided by (Responsible Party): Sarah Sammons, MD, Duke University

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Triple Negative Breast Cancer
• Interventions: Drug: Olaparib Oral Product; Drug: Olaparib Oral Product in combination with Durvalumab
• Enrollment: 45

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	A - Olaparib Alone	B - Olaparib Plus Durvalumab
Arm/Group 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. Olaparib Oral Product: olaparib 300mg twice daily	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. Olaparib Oral Product in combination with Durvalumab: olaparib 300mg twice daily plus intravenous durvalumab every 28 days
Period Title: Overall Study
Started	23	22
Completed	11	11
Not Completed	12	11
Reason Not Completed
Death	11	8
Withdrawal by Subject	1	2
Physician Decision	0	1

Baseline Characteristics

Arm/Group Title		A - Olaparib Alone	B - Olaparib Plus Durvalumab	Total
Arm/Group 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. Olaparib Oral Product: olaparib 300mg twice daily	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. Olaparib Oral Product in combination with Durvalumab: olaparib 300mg twice daily plus intravenous durvalumab every 28 days	Total of all reporting groups
Overall Number of Baseline Participants		23	22	45
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	23 participants	22 participants	45 participants
		52.4 (11.9)	49.5 (11.7)	51 (11.8)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	23 participants	22 participants	45 participants
	Female	23 100.0%	22 100.0%	45 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	23 participants	22 participants	45 participants
	Hispanic or Latino	0 0.0%	0 0.0%	0 0.0%
	Not Hispanic or Latino	22 95.7%	22 100.0%	44 97.8%
	Unknown or Not Reported	1 4.3%	0 0.0%	1 2.2%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	23 participants	22 participants	45 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	16 69.6%	18 81.8%	34 75.6%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	0 0.0%	0 0.0%	0 0.0%
	White	5 21.7%	4 18.2%	9 20.0%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	2 8.7%	0 0.0%	2 4.4%

Outcome Measures

1. Primary Outcome

Title	Efficacy of Olaparib Alone as Assessed by PFS (Progression-free Survival) Reported as Events Per Month
Description	PFS, defined as the time from randomization to the first occurrence of disease progression or death from any cause on study for olaparib alone. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Death on study is defined as death from any cause within 30 days of the last dose of study treatment regimen. Reported as events (disease progression or death) per month.
Time Frame	From date of randomization until the date of documented progression or date of death, whichever came first, approximately 1 year.

Outcome Measure Data

Analysis Population Description

Intent To Treat population. Only applies to the "olaparib alone" arm.

Arm/Group Title	A - Olaparib Alone
Arm/Group 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. Olaparib Oral Product: olaparib 300mg twice daily
Overall Number of Participants Analyzed	23
Mean (95% Confidence Interval); Unit of Measure: events/month
	0.18; (0.11 to 0.27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	A - Olaparib Alone
	Comments	Assumed median PFS = 2.0 months as historical control, transformed to rate of 0.35/month
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0023
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	Comparison to mean of historical control
Method of Estimation	Estimation Parameter	MLE assuming exponential distribution
	Estimated Value	0.18
	Confidence Interval	(2-Sided) 95%; 0.11 to 0.27
	Estimation Comments	Presence of patients with long PFS may have violated exponential assumption.

2. Primary Outcome

Title	Efficacy of Olaparib in Combination With Durvalumab as Assessed by PFS (Progression-free Survival)
Description	PFS, as defined as the time from randomization to the first occurrence of disease progression (as determined using RECIST v1.1 criteria and assessed by the investigator) or death from any cause on study for olaparib in combination with durvalumab. Death on study is defined as death from any cause within 30 days of the last dose of study treatment regimen. Reported as (disease progression or death) events per month.
Time Frame	From date of randomization until the date of documented progression or date of death, whichever came first, approximately 1 year.

Outcome Measure Data

Analysis Population Description

Intent to Treat population. Only applies to the "olaparib plus durvalumab" arm.

Arm/Group Title	B - Olaparib Plus Durvalumab
Arm/Group 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. Olaparib Oral Product in combination with Durvalumab: olaparib 300mg twice daily plus intravenous durvalumab every 28 days
Overall Number of Participants Analyzed	22
Mean (95% Confidence Interval); Unit of Measure: events/month
	0.11; (0.07 to 0.19)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	B - Olaparib Plus Durvalumab
	Comments	Assumed median PFS = 2.0 months as historical control, transformed to rate of 0.35/month
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	Comparison to mean of historical control
Method of Estimation	Estimation Parameter	MLE assuming exponential distribution
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; 0.07 to 0.19
	Estimation Comments	Presence of patients with long PFS may have violated exponential assumption.

3. Secondary Outcome

Title	Overall Survival (Olaparib Alone)
Description	To determine the efficacy of maintenance olaparib following platinum based chemotherapy as assessed by overall survival (OS).
Time Frame	From date of randomization until death or last patient contact, approximately 2 years

Outcome Measure Data

Analysis Population Description

Only applies to the "olaparib alone" arm.

Arm/Group Title	A - Olaparib Alone
Arm/Group 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. Olaparib Oral Product: olaparib 300mg twice daily
Overall Number of Participants Analyzed	23
Median (95% Confidence Interval); Unit of Measure: months
	21.68 [1]; (7.69 to NA)

[1]

Did not observe enough death events among participants to estimate the upper limit of the 95% CI for median overall survival time.

4. Secondary Outcome

Title	Overall Survival (Olaparib in Combination With Durvalumab)
Description	To determine the efficacy of maintenance olaparib in combination with durvalumab following platinum based chemotherapy as assessed by overall survival (OS).
Time Frame	From date of randomization until death or last patient contact, approximately 2 years

Outcome Measure Data

Analysis Population Description

Only applies to the "olaparib plus durvalumab" arm.

Arm/Group Title	B - Olaparib Plus Durvalumab
Arm/Group 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. Olaparib Oral Product in combination with Durvalumab: olaparib 300mg twice daily plus intravenous durvalumab every 28 days
Overall Number of Participants Analyzed	22
Median (95% Confidence Interval); Unit of Measure: months
	18.27 [1]; (8.18 to NA)

[1]

Did not observe enough death events among participants to estimate the upper limit of the 95% CI for median overall survival time.

5. Secondary Outcome

Title	Overall Response Rate (ORR) as Measured by Number of Participants Achieving Complete Response (CR) or Partial Response (PR) as Defined by RECIST 1.1 (Olaparib Alone)
Description	To determine the efficacy of maintenance olaparib following platinum-based chemotherapy as assessed by overall response rate (ORR) based on RECIST 1.1 (Response Evaluation Criteria In Solid Tumors Criteria). Per RECIST v1.1 for target lesions and assessed by CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame	Assessed every 8 weeks from date of randomization until documented disease progression or last patient contact, approximately 1 year

Outcome Measure Data

Analysis Population Description

Only applies to the "olaparib alone" arm.

Arm/Group Title	A - Olaparib Alone
Arm/Group 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. Olaparib Oral Product: olaparib 300mg twice daily
Overall Number of Participants Analyzed	23
Measure Type: Count of Participants; Unit of Measure: Participants
	5 21.7%

6. Secondary Outcome

Title	Overall Response Rate (ORR) as Measured by Number of Participants Achieving Complete Response (CR) or Partial Response (PR) as Defined by RECIST 1.1 (Olaparib in Combination With Durvalumab)
Description	To determine the efficacy of maintenance olaparib in combination with durvalumab following platinum-based chemotherapy as assessed by overall response rate (ORR) based on RECIST 1.1 (Response Evaluation Criteria In Solid Tumors Criteria). Per RECIST v1.1 for target lesions and assessed by CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame	Assessed every 8 weeks from date of randomization until documented disease progression or last patient contact, approximately 1 year

Outcome Measure Data

Analysis Population Description

Only applies to the "olaparib plus durvalumab" arm.

Arm/Group Title	B - Olaparib Plus Durvalumab
Arm/Group 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. Olaparib Oral Product in combination with Durvalumab: olaparib 300mg twice daily plus intravenous durvalumab every 28 days
Overall Number of Participants Analyzed	22
Measure Type: Count of Participants; Unit of Measure: Participants
	3 13.6%

7. Secondary Outcome

Title	Clinical Benefit Rate (CBR) as Measured by the Number of Participants Achieving Complete Response (CR), Partial Response (PR) or Stable Disease for ≥ 24 Weeks (SD) as Defined by RECIST 1.1. (Olaparib Alone)
Description	To determine the efficacy of maintenance olaparib following platinum-based chemotherapy as assessed by clinical benefit rate (CBR) based on RECIST 1.1 (Response Evaluation Criteria In Solid Tumors Criteria). Per RECIST v1.1 for target lesions and assessed by CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease (PD); Clinical Benefit (CB) = CR + PR + SD for >= 24 weeks.
Time Frame	Assessed every 8 weeks from date of randomization until documented disease progression or last patient contact, approximately 1 year

Outcome Measure Data

Analysis Population Description

Only applies to the "olaparib alone" arm.

Arm/Group Title	A - Olaparib Alone
Arm/Group 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. Olaparib Oral Product: olaparib 300mg twice daily
Overall Number of Participants Analyzed	23
Measure Type: Count of Participants; Unit of Measure: Participants
	9 39.1%

8. Secondary Outcome

Title	Clinical Benefit Rate (CBR) as Measured by the Number of Participants Achieving Complete Response (CR), Partial Response (PR) or Stable Disease for ≥ 24 Weeks (SD) as Defined by RECIST 1.1. (Olaparib in Combination With Durvalumab)
Description	To determine the efficacy of maintenance olaparib in combination with durvalumab following platinum-based chemotherapy as assessed by clinical benefit rate (CBR) based on RECIST 1.1 (Response Evaluation Criteria In Solid Tumors Criteria). Per RECIST v1.1 for target lesions and assessed by CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease (PD); Clinical Benefit (CB) = CR + PR + SD for >= 24 weeks.
Time Frame	Assessed every 8 weeks from date of randomization until documented disease progression or last patient contact, approximately 1 year

Outcome Measure Data

Analysis Population Description

Only applies to the "olaparib plus durvalumab" arm.

Arm/Group Title	B - Olaparib Plus Durvalumab
Arm/Group 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. Olaparib Oral Product in combination with Durvalumab: olaparib 300mg twice daily plus intravenous durvalumab every 28 days
Overall Number of Participants Analyzed	22
Measure Type: Count of Participants; Unit of Measure: Participants
	8 36.4%

Adverse Events

Time Frame	From the first dose of either study drug through 30 days after the last dose of either study drug or until the initiation of an alternative anticancer therapy, up to 2 years
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	A - Olaparib Alone	B - Olaparib Plus Durvalumab
Arm/Group 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. Olaparib Oral Product: olaparib 300mg twice daily	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. Olaparib Oral Product in combination with Durvalumab: olaparib 300mg twice daily plus intravenous durvalumab every 28 days
All-Cause Mortality
	A - Olaparib Alone	B - Olaparib Plus Durvalumab
	Affected / at Risk (%)	Affected / at Risk (%)
Total	11/23 (47.83%)	8/22 (36.36%)
Serious Adverse Events
	A - Olaparib Alone	B - Olaparib Plus Durvalumab
	Affected / at Risk (%)	Affected / at Risk (%)
Total	2/23 (8.70%)	3/22 (13.64%)
Gastrointestinal disorders
Nausea † 1	0/23 (0.00%)	1/22 (4.55%)
Vomiting † 1	0/23 (0.00%)	1/22 (4.55%)
General disorders
Pyrexia † 1	0/23 (0.00%)	2/22 (9.09%)
Infections and infestations
Pneumonia † 1	0/23 (0.00%)	1/22 (4.55%)
Investigations
Neutrophil count decreased † 1	0/23 (0.00%)	1/22 (4.55%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour associated fever † 1	1/23 (4.35%)	0/22 (0.00%)
Respiratory, thoracic and mediastinal disorders
Pneumothorax † 1	1/23 (4.35%)	0/22 (0.00%)
1 Term from vocabulary, MedDRA Version 24.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	A - Olaparib Alone	B - Olaparib Plus Durvalumab
	Affected / at Risk (%)	Affected / at Risk (%)
Total	23/23 (100.00%)	21/22 (95.45%)
Blood and lymphatic system disorders
Anaemia † 1	9/23 (39.13%)	7/22 (31.82%)
Neutropenia † 1	2/23 (8.70%)	1/22 (4.55%)
Endocrine disorders
Hypothyroidism † 1	0/23 (0.00%)	2/22 (9.09%)
Gastrointestinal disorders
Nausea † 1	13/23 (56.52%)	9/22 (40.91%)
Vomiting † 1	5/23 (21.74%)	7/22 (31.82%)
Diarrhoea † 1	4/23 (17.39%)	5/22 (22.73%)
Constipation † 1	4/23 (17.39%)	2/22 (9.09%)
Dry mouth † 1	0/23 (0.00%)	3/22 (13.64%)
Dyspepsia † 1	2/23 (8.70%)	1/22 (4.55%)
Oral pain † 1	0/23 (0.00%)	2/22 (9.09%)
General disorders
Fatigue † 1	12/23 (52.17%)	6/22 (27.27%)
Mucosal inflammation † 1	4/23 (17.39%)	3/22 (13.64%)
Pain † 1	2/23 (8.70%)	2/22 (9.09%)
Pyrexia † 1	1/23 (4.35%)	3/22 (13.64%)
Influenza like illness † 1	1/23 (4.35%)	2/22 (9.09%)
Non-cardiac chest pain † 1	1/23 (4.35%)	2/22 (9.09%)
Chills † 1	0/23 (0.00%)	2/22 (9.09%)
Infections and infestations
Pneumonia † 1	2/23 (8.70%)	1/22 (4.55%)
Investigations
Neutrophil count decreased † 1	5/23 (21.74%)	4/22 (18.18%)
Platelet count decreased † 1	2/23 (8.70%)	3/22 (13.64%)
White blood cell count decreased † 1	2/23 (8.70%)	2/22 (9.09%)
Blood creatinine increased † 1	3/23 (13.04%)	0/22 (0.00%)
Alanine aminotransferase increased † 1	2/23 (8.70%)	0/22 (0.00%)
Metabolism and nutrition disorders
Decreased appetite † 1	6/23 (26.09%)	9/22 (40.91%)
Hypoalbuminaemia † 1	1/23 (4.35%)	3/22 (13.64%)
Hypokalaemia † 1	1/23 (4.35%)	2/22 (9.09%)
Hyponatraemia † 1	2/23 (8.70%)	0/22 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	2/23 (8.70%)	3/22 (13.64%)
Myalgia † 1	0/23 (0.00%)	2/22 (9.09%)
Pain in extremity † 1	2/23 (8.70%)	0/22 (0.00%)
Nervous system disorders
Dizziness † 1	6/23 (26.09%)	5/22 (22.73%)
Headache † 1	2/23 (8.70%)	6/22 (27.27%)
Peripheral sensory neuropathy † 1	2/23 (8.70%)	4/22 (18.18%)
Psychiatric disorders
Insomnia † 1	3/23 (13.04%)	2/22 (9.09%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	2/23 (8.70%)	7/22 (31.82%)
Dyspnoea † 1	3/23 (13.04%)	3/22 (13.64%)
Pneumonitis † 1	0/23 (0.00%)	2/22 (9.09%)
Rhinorrhoea † 1	0/23 (0.00%)	2/22 (9.09%)
Skin and subcutaneous tissue disorders
Rash † 1	3/23 (13.04%)	2/22 (9.09%)
Vascular disorders
Hypertension † 1	2/23 (8.70%)	0/22 (0.00%)
1 Term from vocabulary, MedDRA Version 24.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Senior Biostatistician
• Organization: Duke Clinical Research Institute
• Phone: 919-668-8052
• EMail: lilin.she@duke.edu

• Responsible Party: Sarah Sammons, MD, Duke University
• ClinicalTrials.gov Identifier: NCT03167619
• Other Study ID Numbers: Pro00080769
• First Submitted: May 23, 2017
• First Posted: May 30, 2017
• Results First Submitted: June 30, 2022
• Results First Posted: September 13, 2022
• Last Update Posted: September 13, 2022