A Phase III Randomised Study to Evaluate Dato-DXd and Durvalumab for Neoadjuvant/Adjuvant Treatment of Triple-Negative or Hormone Receptor-low/HER2-negative Breast Cancer

Phase 3

Recruiting

• Conditions: Breast Cancer
• Interventions: Drug: Pembrolizumab; Drug: Dato-DXd; Drug: Durvalumab; Drug: Doxorubicin; Drug: Epirubicin; Drug: Cyclophosphamide; Drug: Paclitaxel; Drug: Carboplatin; Drug: Capecitabine; Drug: Olaparib

• Registration Number: NCT06112379
• Lead Sponsor: AstraZeneca

Brief Summary

This is a Phase III, 2-arm, randomised, open-label, multicentre, global study assessing the efficacy and safety of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy compared with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab with or without chemotherapy in participants with previously untreated TNBC or hormone receptor-low/HER2-negative breast cancer.

Detailed Description

The primary objectives of the study are to demonstrate superiority of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy relative to neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab with or without chemotherapy in participants with previously untreated TNBC or hormone receptor low/HER2-negative breast cancer, by central assessment of pCR and/or to demonstrate superiority of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy relative to neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab with or without chemotherapy in participants with previously untreated TNBC or hormone receptor-low/HER2-negative breast cancer, by investigator assessment of EFS

Study Timeline

• Study First Submitted: 2023-10-12
• Study First Submitted QC: 2023-10-31
• Study First Posted: 2023-11-01
• Study Start: 2023-11-14
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-07
• Last Update Posted: 2025-03-10
• Primary Completion: 2028-03-29
• Study Completion: 2030-08-28

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 1728

Inclusion Criteria

• Participant must be ≥ 18 years, at the time of signing the ICF.
• Histologically confirmed Stage II or III unilateral or bilateral primary invasive TNBC or hormone receptor-low/HER2-negative breast cancer
• ECOG PS of 0 or 1
• Provision of acceptable tumor sample
• Adequate bone marrow reserve and organ function
• Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies and aligned with protocol requirements.

Exclusion criteria:

• History of any prior invasive breast malignancy
• History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 5 years before randomization.
• active or prior documented autoimmune or inflammatory disorders.
• Evidence of distant disease.
• Clinically significant corneal disease.
• Has active or uncontrolled hepatitis B or C virus infection.
• Known HIV infection that is not well controlled.
• Uncontrolled infection requiring i.v. antibiotics, antivirals or antifungals; suspected infections; or inability to rule out infections.
• Known to have active tuberculosis infection
• Mean resting corrected QTcF interval > 470 ms obtained from ECG
• Uncontrolled or significant cardiac disease.
• History of non-infectious ILD/pneumonitis
• Has severe pulmonary function compromise
• Any prior or concurrent surgery, radiotherapy or systemic anticancer therapy for TNBC or hormone receptor-low/HER2-negative breast cancer
• For females only: is pregnant (confirmed with positive serum pregnancy test) or breastfeeding, or planning to become pregnant.
• Female participants should refrain from breastfeeding from enrolment throughout the study and for at least 7 months after last dose of study intervention, or as dictated by local PI for SoC if longer.
• Concurrent use of systemic hormone replacement therapy or oral hormonal contraception

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Pembrolizumab plus chemotherapy	Pembrolizumab	Participants receive pembrolizumab every 3 weeks (Q3W) + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by pembrolizumab Q3W + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of pembrolizumab Q3W as adjuvant therapy post-surgery. Adjuvant capecitabine (Q3W) for 8 cycles may be given in combination with pembrolizumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease.
Dato-DXd plus durvalumab	Dato-DXd	Participants receive durvalumab every 3 weeks (Q3W) + Dato-DXd Q3W as neoadjuvant therapy prior to surgery; followed by 9 cycles of durvaluamb Q3W as adjuvant therapy post-surgery. Adjuvant chemotherapy may be given in combination with durvalumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease Adjuvant chemotherapy may be one of these: 1. Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) and carboplatin (weekly or Q3W) for 4 cycles (12 weeks); 2. Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) for 4 cycles (12 weeks); 3. Carboplatin (weekly or Q3W) + paclitaxel (weekly) for 4 cycles (12 weeks); 4. Capecitabine (Q3W) for 8 cycles.
Dato-DXd plus durvalumab	Epirubicin	Participants receive durvalumab every 3 weeks (Q3W) + Dato-DXd Q3W as neoadjuvant therapy prior to surgery; followed by 9 cycles of durvaluamb Q3W as adjuvant therapy post-surgery. Adjuvant chemotherapy may be given in combination with durvalumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease Adjuvant chemotherapy may be one of these: 1. Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) and carboplatin (weekly or Q3W) for 4 cycles (12 weeks); 2. Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) for 4 cycles (12 weeks); 3. Carboplatin (weekly or Q3W) + paclitaxel (weekly) for 4 cycles (12 weeks); 4. Capecitabine (Q3W) for 8 cycles.
Dato-DXd plus durvalumab	Cyclophosphamide	Participants receive durvalumab every 3 weeks (Q3W) + Dato-DXd Q3W as neoadjuvant therapy prior to surgery; followed by 9 cycles of durvaluamb Q3W as adjuvant therapy post-surgery. Adjuvant chemotherapy may be given in combination with durvalumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease Adjuvant chemotherapy may be one of these: 1. Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) and carboplatin (weekly or Q3W) for 4 cycles (12 weeks); 2. Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) for 4 cycles (12 weeks); 3. Carboplatin (weekly or Q3W) + paclitaxel (weekly) for 4 cycles (12 weeks); 4. Capecitabine (Q3W) for 8 cycles.
Dato-DXd plus durvalumab	Durvalumab	Participants receive durvalumab every 3 weeks (Q3W) + Dato-DXd Q3W as neoadjuvant therapy prior to surgery; followed by 9 cycles of durvaluamb Q3W as adjuvant therapy post-surgery. Adjuvant chemotherapy may be given in combination with durvalumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease Adjuvant chemotherapy may be one of these: 1. Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) and carboplatin (weekly or Q3W) for 4 cycles (12 weeks); 2. Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) for 4 cycles (12 weeks); 3. Carboplatin (weekly or Q3W) + paclitaxel (weekly) for 4 cycles (12 weeks); 4. Capecitabine (Q3W) for 8 cycles.
Dato-DXd plus durvalumab	Doxorubicin	Participants receive durvalumab every 3 weeks (Q3W) + Dato-DXd Q3W as neoadjuvant therapy prior to surgery; followed by 9 cycles of durvaluamb Q3W as adjuvant therapy post-surgery. Adjuvant chemotherapy may be given in combination with durvalumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease Adjuvant chemotherapy may be one of these: 1. Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) and carboplatin (weekly or Q3W) for 4 cycles (12 weeks); 2. Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) for 4 cycles (12 weeks); 3. Carboplatin (weekly or Q3W) + paclitaxel (weekly) for 4 cycles (12 weeks); 4. Capecitabine (Q3W) for 8 cycles.
Dato-DXd plus durvalumab	Paclitaxel	Participants receive durvalumab every 3 weeks (Q3W) + Dato-DXd Q3W as neoadjuvant therapy prior to surgery; followed by 9 cycles of durvaluamb Q3W as adjuvant therapy post-surgery. Adjuvant chemotherapy may be given in combination with durvalumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease Adjuvant chemotherapy may be one of these: 1. Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) and carboplatin (weekly or Q3W) for 4 cycles (12 weeks); 2. Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) for 4 cycles (12 weeks); 3. Carboplatin (weekly or Q3W) + paclitaxel (weekly) for 4 cycles (12 weeks); 4. Capecitabine (Q3W) for 8 cycles.
Dato-DXd plus durvalumab	Carboplatin	Participants receive durvalumab every 3 weeks (Q3W) + Dato-DXd Q3W as neoadjuvant therapy prior to surgery; followed by 9 cycles of durvaluamb Q3W as adjuvant therapy post-surgery. Adjuvant chemotherapy may be given in combination with durvalumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease Adjuvant chemotherapy may be one of these: 1. Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) and carboplatin (weekly or Q3W) for 4 cycles (12 weeks); 2. Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) for 4 cycles (12 weeks); 3. Carboplatin (weekly or Q3W) + paclitaxel (weekly) for 4 cycles (12 weeks); 4. Capecitabine (Q3W) for 8 cycles.
Dato-DXd plus durvalumab	Capecitabine	Participants receive durvalumab every 3 weeks (Q3W) + Dato-DXd Q3W as neoadjuvant therapy prior to surgery; followed by 9 cycles of durvaluamb Q3W as adjuvant therapy post-surgery. Adjuvant chemotherapy may be given in combination with durvalumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease Adjuvant chemotherapy may be one of these: 1. Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) and carboplatin (weekly or Q3W) for 4 cycles (12 weeks); 2. Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) for 4 cycles (12 weeks); 3. Carboplatin (weekly or Q3W) + paclitaxel (weekly) for 4 cycles (12 weeks); 4. Capecitabine (Q3W) for 8 cycles.
Dato-DXd plus durvalumab	Olaparib	Participants receive durvalumab every 3 weeks (Q3W) + Dato-DXd Q3W as neoadjuvant therapy prior to surgery; followed by 9 cycles of durvaluamb Q3W as adjuvant therapy post-surgery. Adjuvant chemotherapy may be given in combination with durvalumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease Adjuvant chemotherapy may be one of these: 1. Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) and carboplatin (weekly or Q3W) for 4 cycles (12 weeks); 2. Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) for 4 cycles (12 weeks); 3. Carboplatin (weekly or Q3W) + paclitaxel (weekly) for 4 cycles (12 weeks); 4. Capecitabine (Q3W) for 8 cycles.
Pembrolizumab plus chemotherapy	Cyclophosphamide	Participants receive pembrolizumab every 3 weeks (Q3W) + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by pembrolizumab Q3W + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of pembrolizumab Q3W as adjuvant therapy post-surgery. Adjuvant capecitabine (Q3W) for 8 cycles may be given in combination with pembrolizumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease.
Pembrolizumab plus chemotherapy	Doxorubicin	Participants receive pembrolizumab every 3 weeks (Q3W) + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by pembrolizumab Q3W + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of pembrolizumab Q3W as adjuvant therapy post-surgery. Adjuvant capecitabine (Q3W) for 8 cycles may be given in combination with pembrolizumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease.
Pembrolizumab plus chemotherapy	Epirubicin	Participants receive pembrolizumab every 3 weeks (Q3W) + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by pembrolizumab Q3W + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of pembrolizumab Q3W as adjuvant therapy post-surgery. Adjuvant capecitabine (Q3W) for 8 cycles may be given in combination with pembrolizumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease.
Pembrolizumab plus chemotherapy	Paclitaxel	Participants receive pembrolizumab every 3 weeks (Q3W) + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by pembrolizumab Q3W + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of pembrolizumab Q3W as adjuvant therapy post-surgery. Adjuvant capecitabine (Q3W) for 8 cycles may be given in combination with pembrolizumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease.
Pembrolizumab plus chemotherapy	Carboplatin	Participants receive pembrolizumab every 3 weeks (Q3W) + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by pembrolizumab Q3W + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of pembrolizumab Q3W as adjuvant therapy post-surgery. Adjuvant capecitabine (Q3W) for 8 cycles may be given in combination with pembrolizumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease.
Pembrolizumab plus chemotherapy	Olaparib	Participants receive pembrolizumab every 3 weeks (Q3W) + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by pembrolizumab Q3W + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of pembrolizumab Q3W as adjuvant therapy post-surgery. Adjuvant capecitabine (Q3W) for 8 cycles may be given in combination with pembrolizumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease.
Pembrolizumab plus chemotherapy	Capecitabine	Participants receive pembrolizumab every 3 weeks (Q3W) + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by pembrolizumab Q3W + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of pembrolizumab Q3W as adjuvant therapy post-surgery. Adjuvant capecitabine (Q3W) for 8 cycles may be given in combination with pembrolizumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease.

Primary Outcome Measures

Name	Time	Method
Pathologic Complete Response (pCR) in the experimental vs control arms	At the time of definitive surgery	pCR rate is defined as the proportion of participants who have no evidence by haematoxylin and eosin staining of residual invasive disease or lymphovascular invasion at the time of definitive surgery in the complete resected breast specimen and all sampled regional lymph nodes (ypT0/Tis ypN0) by blinded central evaluation.; The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy or receives another anticancer therapy.; The measure of interest will be the difference between the pCR rates.
Event-free survival (EFS) in the experimental vs control arms	Date of randomization to date of the EFS event, up to 68 months after the first subject randomized	EFS is defined as the time from the date of randomisation until the date of the first occurrence of any of the following events: disease progression precluding surgery, disease recurrence (local, regional, distant, or contralateral), second primary invasive cancer (other than squamous or basal cell skin cancer), or relapse from prior malignancy, or death by any cause (in the absence of recurrence).; The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy or receives another anticancer therapy.; The measure of interest will be the Hazard Ratio of EFS.

Secondary Outcome Measures

Name	Time	Method
Immunogenicity of Dato-DXd (in combination with durvalumab)	Day 1 of cycles 1,2,4,8 (Each cycle is 21 days) and at pre-surgery safety follow up visit	Presence of antidrug antibodies (ADAs) for Dato-DXd (confirmatory results: positive or negative, titres).
Safety of Dato-DXd (in combination with durvalumab)	Randomization to final safety follow-up visit, either 90 days after last dose of study intervention for those who complete planned study intervention or 90 days after date of discontinuation for those who discontinue study intervention prematurely	Safety and tolerability will be evaluated in terms of AEs graded by CTCAE version 5.0
Overall Survival (OS) in the experimental vs control arms	Date of randomization to date of death due to any cause, up to 82 months after the first subject randomized	Key Secondary - OS is defined as the time from the date of randomisation until the date of death due to any cause.; The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy or receives another anticancer therapy.; The measure of interest will be the Hazard Ratio of OS.
Distant disease-free survival (DDFS) in the experimental vs control arms	Date of randomization to date of the DDFS event, up to 68 months after the first subject randomized	DDFS is defined as the time from the date of randomisation until the date of the first occurrence of any of the following events: distant metastasis, occurrence of second primary invasive cancer (other than squamous or basal cell skin cancer), relapse from prior malignancy or death by any cause (in the absence of recurrence).; The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy or receives another anticancer therapy.; The measure of interest will be the Hazard Ratio of DDFS.
Participant-reported breast and arm symptoms in the experimental vs. control arms	From Cycle 1 Day 1 of neoadjuvant treatment until pre-surgery safety FU visit (for approximately 24 weeks) or EOT - whichever occurs first.	Breast and arm symptoms measured by the EORTC IL116. The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy or receives another anticancer therapy.; The measure of interest is the mean between-arm difference in breast and arm symptom scores.
Participant-reported physical function in the experimental vs. control arms	From Cycle 1 Day 1 of neoadjuvant treatment until pre-surgery safety FU visit (for approximately 24 weeks) or EOT - whichever occurs first, and then from Cycle 1 Day 1 of adjuvant treatment until EOT (for approximately 27 weeks).	Physical function measured by the PROMIS Physical Function Short Form 8c. The analysis will include all dosed participants. The measure of interest is the mean between-arm difference in physical function scores.
Participant-reported fatigue in the experimental vs. control arms	From Cycle 1 Day 1 of neoadjuvant treatment until pre-surgery safety FU visit (for approximately 24 weeks) or EOT - whichever occurs first, and then from Cycle 1 Day 1 of adjuvant treatment until EOT (for approximately 27 weeks).	Fatigue measured by the PROMIS Fatigue Short Form 7a. The analysis will include all dosed participants. The measure of interest will be the difference on the proportions of participants reporting different levels of fatigue and mean between-arm difference in the fatigue scores.
Participant-reported Global health status/Quality of life (GHS/QoL)in the experimental vs. control arms	From Cycle 1 Day 1 of neoadjuvant treatment until pre-surgery safety FU visit (for approximately 24 weeks) or EOT - whichever occurs first, and then from Cycle 1 Day 1 of adjuvant treatment until EOT (for approximately 27 weeks).	Global health status/Quality of life measured by EORTC IL172. The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy or receives another anticancer therapy.; The measure of interest is the mean between-arm difference in GHS/QoL scores.
Pharmacokinetics of Dato-DXd (in combination with durvalumab)	Day 1 of cycles 1,2,4,8 (Each cycle is 21 days) and at pre-surgery safety follow up visit	Plasma concentrations of DXd (MAAA-1181a) (ng/ml)

Trial Locations

Locations (1)

Research Site; 🇻🇳 Vinh, Vietnam