Study of Patritumab Deruxtecan Plus Pembrolizumab With Other Anticancer Agents in Participants With High-Risk Early-Stage Triple-Negative or Hormone Receptor-Low Positive/HER-2 Negative Breast Cancer (MK-1022-010, HERTHENA-Breast-03)

Phase 2

Recruiting

Conditions: Breast Neoplasms
Breast Cancer

Interventions: Biological: Patritumab deruxtecan
Biological: Pembrolizumab
Drug: Paclitaxel
Drug: Carboplatin
Drug: Doxorubicin hydrochloride
Drug: Epirubicin hydrochloride
Drug: Cyclophosphamide
Drug: Capecitabine
Drug: Olaparib

Registration Number: NCT06797635

Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary: Researchers are looking for new ways to treat triple-negative breast cancer (TNBC) and hormone receptor (HR) low positive/human epidermal growth factor receptor-2 (HER2) negative breast cancer. The main goals of this study are to learn:

* About the safety of the study treatments and if people tolerate them

* If people who receive patritumab deruxtecan, pembrolizumab, and chemotherapy before surgery have fewer cancer cells removed during surgery compared to those who receive only pembrolizumab (pembro) and chemotherapy.

Detailed Description: Not available

Recruitment & Eligibility

Status: RECRUITING

Sex: All

Target Recruitment: 372

Inclusion Criteria

The main inclusion criteria include but are not limited to the following:

Has locally advanced, non-metastatic (M0), breast cancer, defined as any of the following combined primary tumor (T) and regional lymph node (N) staging per current American Joint Committee on Cancer (AJCC) criteria: cT1c, N1-N2; cT2, N0-N2; cT3, N0-N2; or cT4a-d, N0-N2
Has centrally confirmed diagnosis of breast cancer that is triple-negative or HR-low+/HER2- breast cancer that will be treated according to the triple-negative breast cancer (TNBC) paradigm
Participants who are Hepatitis B surface antigen (HBsAg) positive are eligible if they have received Hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load
Participants with a history of Hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable
Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 28 days prior to allocation/randomization
Has left ventricular ejection fraction (LVEF) of ≥50% or ≥ lower limit of normal (LLN) as assessed by echocardiogram (ECHO) or multigate acquisition scan (MUGA) scan

Exclusion Criteria

The main exclusion criteria include but are not limited to the following:

Has uncontrolled or significant cardiovascular disease before randomization
Has clinically significant corneal disease
Has human immunodeficiency virus (HIV) infection with a history of Kaposi sarcoma and/or multicentric Castleman disease
Has received prior therapy with an anti-programmed death (PD)-1, anti-PD-L1, or anti-PD-L2 agent, or with an agent directed to another stimulatory or coinhibitory T-cell receptor
Has received any prior treatment, including radiation, systemic therapy, and/or definitive surgery for currently diagnosed breast cancer
Has received prior treatment with an anti-human epidermal growth factor receptor 3 (HER3) antibody and/or antibody-drug conjugate (ADC) that consists of an exatecan derivative that is a topoisomerase I inhibitor (e.g., trastuzumab deruxtecan)
Has metastatic (Stage IV) breast cancer or cN3 nodal involvement
Has known additional malignancy that is progressing or has required active treatment within the past 5 years
Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease, or where suspected ILD/pneumonitis cannot be ruled out by standard diagnostic assessments
Has an active infection requiring systemic therapy
Has concurrent active HBV and HCV infection
Has clinically severe respiratory compromise resulting from intercurrent pulmonary illness

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part 1, A: Pembrolizimab + patritumab deruxtecan → Pembrolizumab + paclitaxel + carboplatin	Patritumab deruxtecan	In Part 1, participants receive neoadjuvant pembrolizumab 200 mg via intravenous (IV) infusion every 3 weeks (Q3W) plus patritumab deruxtecan via IV infusion Q3W for 12 weeks, followed by pembrolizumab 200 mg via IV infusion Q3W plus paclitaxel 80 mg/m\^2 via IV infusion every week (QW) and carboplatin AUC1.5 mg/ml/min via IV infusion QW for 12 weeks. At 3 to 6 weeks after last dose of neoadjuvant treatment, participants will undergo surgery for their breast cancer.
Part 1, A: Pembrolizimab + patritumab deruxtecan → Pembrolizumab + paclitaxel + carboplatin	Pembrolizumab	In Part 1, participants receive neoadjuvant pembrolizumab 200 mg via intravenous (IV) infusion every 3 weeks (Q3W) plus patritumab deruxtecan via IV infusion Q3W for 12 weeks, followed by pembrolizumab 200 mg via IV infusion Q3W plus paclitaxel 80 mg/m\^2 via IV infusion every week (QW) and carboplatin AUC1.5 mg/ml/min via IV infusion QW for 12 weeks. At 3 to 6 weeks after last dose of neoadjuvant treatment, participants will undergo surgery for their breast cancer.
Part 1, A: Pembrolizimab + patritumab deruxtecan → Pembrolizumab + paclitaxel + carboplatin	Paclitaxel	In Part 1, participants receive neoadjuvant pembrolizumab 200 mg via intravenous (IV) infusion every 3 weeks (Q3W) plus patritumab deruxtecan via IV infusion Q3W for 12 weeks, followed by pembrolizumab 200 mg via IV infusion Q3W plus paclitaxel 80 mg/m\^2 via IV infusion every week (QW) and carboplatin AUC1.5 mg/ml/min via IV infusion QW for 12 weeks. At 3 to 6 weeks after last dose of neoadjuvant treatment, participants will undergo surgery for their breast cancer.
Part 1, A: Pembrolizimab + patritumab deruxtecan → Pembrolizumab + paclitaxel + carboplatin	Carboplatin	In Part 1, participants receive neoadjuvant pembrolizumab 200 mg via intravenous (IV) infusion every 3 weeks (Q3W) plus patritumab deruxtecan via IV infusion Q3W for 12 weeks, followed by pembrolizumab 200 mg via IV infusion Q3W plus paclitaxel 80 mg/m\^2 via IV infusion every week (QW) and carboplatin AUC1.5 mg/ml/min via IV infusion QW for 12 weeks. At 3 to 6 weeks after last dose of neoadjuvant treatment, participants will undergo surgery for their breast cancer.
Part 2, A: Pembrolizimab + patritumab deruxtecan → Pembrolizumab + paclitaxel + carboplatin	Patritumab deruxtecan	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion every Q3W plus patritumab deruxtecan (dose to be determined in part 1) IV infusion Q3W for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min IV infusion QW for 12 weeks. At 3-6 weeks after last dose of neoadjuvant treatment, participants undergo surgery for breast cancer. After surgery, participants receive adjuvant pembrolizumab 400 mg IV every 6 weeks (Q6W) for \~30 weeks. Additional adjuvant treatment of physician's choice (TPC) may be given to participants with residual disease. TPC options are olaparib 300 mg oral twice daily (BID) for 1 year (participants with germline BRCA mutation \[gBRCAm\] only), capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles or doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV Q3W or every 2 weeks (Q2W) and cyclophosphamide 600 mg/m\^2 IV Q3W or Q2W for 4 doses.
Part 2, A: Pembrolizimab + patritumab deruxtecan → Pembrolizumab + paclitaxel + carboplatin	Pembrolizumab	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion every Q3W plus patritumab deruxtecan (dose to be determined in part 1) IV infusion Q3W for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min IV infusion QW for 12 weeks. At 3-6 weeks after last dose of neoadjuvant treatment, participants undergo surgery for breast cancer. After surgery, participants receive adjuvant pembrolizumab 400 mg IV every 6 weeks (Q6W) for \~30 weeks. Additional adjuvant treatment of physician's choice (TPC) may be given to participants with residual disease. TPC options are olaparib 300 mg oral twice daily (BID) for 1 year (participants with germline BRCA mutation \[gBRCAm\] only), capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles or doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV Q3W or every 2 weeks (Q2W) and cyclophosphamide 600 mg/m\^2 IV Q3W or Q2W for 4 doses.
Part 2, A: Pembrolizimab + patritumab deruxtecan → Pembrolizumab + paclitaxel + carboplatin	Paclitaxel	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion every Q3W plus patritumab deruxtecan (dose to be determined in part 1) IV infusion Q3W for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min IV infusion QW for 12 weeks. At 3-6 weeks after last dose of neoadjuvant treatment, participants undergo surgery for breast cancer. After surgery, participants receive adjuvant pembrolizumab 400 mg IV every 6 weeks (Q6W) for \~30 weeks. Additional adjuvant treatment of physician's choice (TPC) may be given to participants with residual disease. TPC options are olaparib 300 mg oral twice daily (BID) for 1 year (participants with germline BRCA mutation \[gBRCAm\] only), capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles or doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV Q3W or every 2 weeks (Q2W) and cyclophosphamide 600 mg/m\^2 IV Q3W or Q2W for 4 doses.
Part 2, A: Pembrolizimab + patritumab deruxtecan → Pembrolizumab + paclitaxel + carboplatin	Carboplatin	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion every Q3W plus patritumab deruxtecan (dose to be determined in part 1) IV infusion Q3W for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min IV infusion QW for 12 weeks. At 3-6 weeks after last dose of neoadjuvant treatment, participants undergo surgery for breast cancer. After surgery, participants receive adjuvant pembrolizumab 400 mg IV every 6 weeks (Q6W) for \~30 weeks. Additional adjuvant treatment of physician's choice (TPC) may be given to participants with residual disease. TPC options are olaparib 300 mg oral twice daily (BID) for 1 year (participants with germline BRCA mutation \[gBRCAm\] only), capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles or doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV Q3W or every 2 weeks (Q2W) and cyclophosphamide 600 mg/m\^2 IV Q3W or Q2W for 4 doses.
Part 2, A: Pembrolizimab + patritumab deruxtecan → Pembrolizumab + paclitaxel + carboplatin	Doxorubicin hydrochloride	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion every Q3W plus patritumab deruxtecan (dose to be determined in part 1) IV infusion Q3W for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min IV infusion QW for 12 weeks. At 3-6 weeks after last dose of neoadjuvant treatment, participants undergo surgery for breast cancer. After surgery, participants receive adjuvant pembrolizumab 400 mg IV every 6 weeks (Q6W) for \~30 weeks. Additional adjuvant treatment of physician's choice (TPC) may be given to participants with residual disease. TPC options are olaparib 300 mg oral twice daily (BID) for 1 year (participants with germline BRCA mutation \[gBRCAm\] only), capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles or doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV Q3W or every 2 weeks (Q2W) and cyclophosphamide 600 mg/m\^2 IV Q3W or Q2W for 4 doses.
Part 2, A: Pembrolizimab + patritumab deruxtecan → Pembrolizumab + paclitaxel + carboplatin	Epirubicin hydrochloride	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion every Q3W plus patritumab deruxtecan (dose to be determined in part 1) IV infusion Q3W for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min IV infusion QW for 12 weeks. At 3-6 weeks after last dose of neoadjuvant treatment, participants undergo surgery for breast cancer. After surgery, participants receive adjuvant pembrolizumab 400 mg IV every 6 weeks (Q6W) for \~30 weeks. Additional adjuvant treatment of physician's choice (TPC) may be given to participants with residual disease. TPC options are olaparib 300 mg oral twice daily (BID) for 1 year (participants with germline BRCA mutation \[gBRCAm\] only), capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles or doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV Q3W or every 2 weeks (Q2W) and cyclophosphamide 600 mg/m\^2 IV Q3W or Q2W for 4 doses.
Part 2, A: Pembrolizimab + patritumab deruxtecan → Pembrolizumab + paclitaxel + carboplatin	Cyclophosphamide	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion every Q3W plus patritumab deruxtecan (dose to be determined in part 1) IV infusion Q3W for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min IV infusion QW for 12 weeks. At 3-6 weeks after last dose of neoadjuvant treatment, participants undergo surgery for breast cancer. After surgery, participants receive adjuvant pembrolizumab 400 mg IV every 6 weeks (Q6W) for \~30 weeks. Additional adjuvant treatment of physician's choice (TPC) may be given to participants with residual disease. TPC options are olaparib 300 mg oral twice daily (BID) for 1 year (participants with germline BRCA mutation \[gBRCAm\] only), capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles or doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV Q3W or every 2 weeks (Q2W) and cyclophosphamide 600 mg/m\^2 IV Q3W or Q2W for 4 doses.
Part 2, A: Pembrolizimab + patritumab deruxtecan → Pembrolizumab + paclitaxel + carboplatin	Capecitabine	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion every Q3W plus patritumab deruxtecan (dose to be determined in part 1) IV infusion Q3W for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min IV infusion QW for 12 weeks. At 3-6 weeks after last dose of neoadjuvant treatment, participants undergo surgery for breast cancer. After surgery, participants receive adjuvant pembrolizumab 400 mg IV every 6 weeks (Q6W) for \~30 weeks. Additional adjuvant treatment of physician's choice (TPC) may be given to participants with residual disease. TPC options are olaparib 300 mg oral twice daily (BID) for 1 year (participants with germline BRCA mutation \[gBRCAm\] only), capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles or doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV Q3W or every 2 weeks (Q2W) and cyclophosphamide 600 mg/m\^2 IV Q3W or Q2W for 4 doses.
Part 2, A: Pembrolizimab + patritumab deruxtecan → Pembrolizumab + paclitaxel + carboplatin	Olaparib	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion every Q3W plus patritumab deruxtecan (dose to be determined in part 1) IV infusion Q3W for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min IV infusion QW for 12 weeks. At 3-6 weeks after last dose of neoadjuvant treatment, participants undergo surgery for breast cancer. After surgery, participants receive adjuvant pembrolizumab 400 mg IV every 6 weeks (Q6W) for \~30 weeks. Additional adjuvant treatment of physician's choice (TPC) may be given to participants with residual disease. TPC options are olaparib 300 mg oral twice daily (BID) for 1 year (participants with germline BRCA mutation \[gBRCAm\] only), capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles or doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV Q3W or every 2 weeks (Q2W) and cyclophosphamide 600 mg/m\^2 IV Q3W or Q2W for 4 doses.
Part 2, B: Pembrolizumab + paclitaxel + carboplatin → Pembrolizumab + patritumab deruxtecan	Patritumab deruxtecan	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min IV infusion QW for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus patritumab deruxtecan (dose to be determined in part 1) via IV infusion Q3W for 12 weeks. At 3 to 6 weeks after last dose of neoadjuvant treatment, participants will undergo surgery for their breast cancer. After surgery, participants will receive adjuvant pembrolizumab 400 mg IV infusion Q6W for \~30 weeks. Additional adjuvant TPC may be administered to participants with residual disease. TPC options include olaparib 300 mg oral BID for 1 year (participants with gBRCAm only), capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles or doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV infusion Q3W or Q2W and cyclophosphamide 600 mg/m\^2 IV infusion Q3W or Q2W for 4 doses.
Part 2, B: Pembrolizumab + paclitaxel + carboplatin → Pembrolizumab + patritumab deruxtecan	Pembrolizumab	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min IV infusion QW for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus patritumab deruxtecan (dose to be determined in part 1) via IV infusion Q3W for 12 weeks. At 3 to 6 weeks after last dose of neoadjuvant treatment, participants will undergo surgery for their breast cancer. After surgery, participants will receive adjuvant pembrolizumab 400 mg IV infusion Q6W for \~30 weeks. Additional adjuvant TPC may be administered to participants with residual disease. TPC options include olaparib 300 mg oral BID for 1 year (participants with gBRCAm only), capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles or doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV infusion Q3W or Q2W and cyclophosphamide 600 mg/m\^2 IV infusion Q3W or Q2W for 4 doses.
Part 2, B: Pembrolizumab + paclitaxel + carboplatin → Pembrolizumab + patritumab deruxtecan	Paclitaxel	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min IV infusion QW for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus patritumab deruxtecan (dose to be determined in part 1) via IV infusion Q3W for 12 weeks. At 3 to 6 weeks after last dose of neoadjuvant treatment, participants will undergo surgery for their breast cancer. After surgery, participants will receive adjuvant pembrolizumab 400 mg IV infusion Q6W for \~30 weeks. Additional adjuvant TPC may be administered to participants with residual disease. TPC options include olaparib 300 mg oral BID for 1 year (participants with gBRCAm only), capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles or doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV infusion Q3W or Q2W and cyclophosphamide 600 mg/m\^2 IV infusion Q3W or Q2W for 4 doses.
Part 2, B: Pembrolizumab + paclitaxel + carboplatin → Pembrolizumab + patritumab deruxtecan	Carboplatin	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min IV infusion QW for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus patritumab deruxtecan (dose to be determined in part 1) via IV infusion Q3W for 12 weeks. At 3 to 6 weeks after last dose of neoadjuvant treatment, participants will undergo surgery for their breast cancer. After surgery, participants will receive adjuvant pembrolizumab 400 mg IV infusion Q6W for \~30 weeks. Additional adjuvant TPC may be administered to participants with residual disease. TPC options include olaparib 300 mg oral BID for 1 year (participants with gBRCAm only), capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles or doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV infusion Q3W or Q2W and cyclophosphamide 600 mg/m\^2 IV infusion Q3W or Q2W for 4 doses.
Part 2, B: Pembrolizumab + paclitaxel + carboplatin → Pembrolizumab + patritumab deruxtecan	Doxorubicin hydrochloride	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min IV infusion QW for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus patritumab deruxtecan (dose to be determined in part 1) via IV infusion Q3W for 12 weeks. At 3 to 6 weeks after last dose of neoadjuvant treatment, participants will undergo surgery for their breast cancer. After surgery, participants will receive adjuvant pembrolizumab 400 mg IV infusion Q6W for \~30 weeks. Additional adjuvant TPC may be administered to participants with residual disease. TPC options include olaparib 300 mg oral BID for 1 year (participants with gBRCAm only), capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles or doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV infusion Q3W or Q2W and cyclophosphamide 600 mg/m\^2 IV infusion Q3W or Q2W for 4 doses.
Part 2, B: Pembrolizumab + paclitaxel + carboplatin → Pembrolizumab + patritumab deruxtecan	Epirubicin hydrochloride	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min IV infusion QW for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus patritumab deruxtecan (dose to be determined in part 1) via IV infusion Q3W for 12 weeks. At 3 to 6 weeks after last dose of neoadjuvant treatment, participants will undergo surgery for their breast cancer. After surgery, participants will receive adjuvant pembrolizumab 400 mg IV infusion Q6W for \~30 weeks. Additional adjuvant TPC may be administered to participants with residual disease. TPC options include olaparib 300 mg oral BID for 1 year (participants with gBRCAm only), capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles or doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV infusion Q3W or Q2W and cyclophosphamide 600 mg/m\^2 IV infusion Q3W or Q2W for 4 doses.
Part 2, B: Pembrolizumab + paclitaxel + carboplatin → Pembrolizumab + patritumab deruxtecan	Cyclophosphamide	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min IV infusion QW for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus patritumab deruxtecan (dose to be determined in part 1) via IV infusion Q3W for 12 weeks. At 3 to 6 weeks after last dose of neoadjuvant treatment, participants will undergo surgery for their breast cancer. After surgery, participants will receive adjuvant pembrolizumab 400 mg IV infusion Q6W for \~30 weeks. Additional adjuvant TPC may be administered to participants with residual disease. TPC options include olaparib 300 mg oral BID for 1 year (participants with gBRCAm only), capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles or doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV infusion Q3W or Q2W and cyclophosphamide 600 mg/m\^2 IV infusion Q3W or Q2W for 4 doses.
Part 2, B: Pembrolizumab + paclitaxel + carboplatin → Pembrolizumab + patritumab deruxtecan	Capecitabine	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min IV infusion QW for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus patritumab deruxtecan (dose to be determined in part 1) via IV infusion Q3W for 12 weeks. At 3 to 6 weeks after last dose of neoadjuvant treatment, participants will undergo surgery for their breast cancer. After surgery, participants will receive adjuvant pembrolizumab 400 mg IV infusion Q6W for \~30 weeks. Additional adjuvant TPC may be administered to participants with residual disease. TPC options include olaparib 300 mg oral BID for 1 year (participants with gBRCAm only), capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles or doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV infusion Q3W or Q2W and cyclophosphamide 600 mg/m\^2 IV infusion Q3W or Q2W for 4 doses.
Part 2, B: Pembrolizumab + paclitaxel + carboplatin → Pembrolizumab + patritumab deruxtecan	Olaparib	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min IV infusion QW for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus patritumab deruxtecan (dose to be determined in part 1) via IV infusion Q3W for 12 weeks. At 3 to 6 weeks after last dose of neoadjuvant treatment, participants will undergo surgery for their breast cancer. After surgery, participants will receive adjuvant pembrolizumab 400 mg IV infusion Q6W for \~30 weeks. Additional adjuvant TPC may be administered to participants with residual disease. TPC options include olaparib 300 mg oral BID for 1 year (participants with gBRCAm only), capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles or doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV infusion Q3W or Q2W and cyclophosphamide 600 mg/m\^2 IV infusion Q3W or Q2W for 4 doses.
Part 2, C: Pembro + paclitaxel + carboplatin→ Pembro + doxorubicin (or epirubicin) +cyclophosphamide	Pembrolizumab	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min via IV infusion QW for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV infusion Q3W and cyclophosphamide 600 mg/m\^2 IV infusion Q3W for 12 weeks. At 3 to 6 weeks after last dose of neoadjuvant treatment, participants will undergo surgery for their breast cancer. After surgery, participants will receive adjuvant pembrolizumab 400 mg IV infusion Q6W for approximately 30 weeks. Additional adjuvant TPC may be administered to participants with residual disease. TPC options include olaparib 300 mg oral BID for 1 year (participants with gBRCAm only) or capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles.
Part 2, C: Pembro + paclitaxel + carboplatin→ Pembro + doxorubicin (or epirubicin) +cyclophosphamide	Paclitaxel	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min via IV infusion QW for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV infusion Q3W and cyclophosphamide 600 mg/m\^2 IV infusion Q3W for 12 weeks. At 3 to 6 weeks after last dose of neoadjuvant treatment, participants will undergo surgery for their breast cancer. After surgery, participants will receive adjuvant pembrolizumab 400 mg IV infusion Q6W for approximately 30 weeks. Additional adjuvant TPC may be administered to participants with residual disease. TPC options include olaparib 300 mg oral BID for 1 year (participants with gBRCAm only) or capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles.
Part 2, C: Pembro + paclitaxel + carboplatin→ Pembro + doxorubicin (or epirubicin) +cyclophosphamide	Carboplatin	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min via IV infusion QW for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV infusion Q3W and cyclophosphamide 600 mg/m\^2 IV infusion Q3W for 12 weeks. At 3 to 6 weeks after last dose of neoadjuvant treatment, participants will undergo surgery for their breast cancer. After surgery, participants will receive adjuvant pembrolizumab 400 mg IV infusion Q6W for approximately 30 weeks. Additional adjuvant TPC may be administered to participants with residual disease. TPC options include olaparib 300 mg oral BID for 1 year (participants with gBRCAm only) or capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles.
Part 2, C: Pembro + paclitaxel + carboplatin→ Pembro + doxorubicin (or epirubicin) +cyclophosphamide	Doxorubicin hydrochloride	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min via IV infusion QW for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV infusion Q3W and cyclophosphamide 600 mg/m\^2 IV infusion Q3W for 12 weeks. At 3 to 6 weeks after last dose of neoadjuvant treatment, participants will undergo surgery for their breast cancer. After surgery, participants will receive adjuvant pembrolizumab 400 mg IV infusion Q6W for approximately 30 weeks. Additional adjuvant TPC may be administered to participants with residual disease. TPC options include olaparib 300 mg oral BID for 1 year (participants with gBRCAm only) or capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles.
Part 2, C: Pembro + paclitaxel + carboplatin→ Pembro + doxorubicin (or epirubicin) +cyclophosphamide	Epirubicin hydrochloride	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min via IV infusion QW for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV infusion Q3W and cyclophosphamide 600 mg/m\^2 IV infusion Q3W for 12 weeks. At 3 to 6 weeks after last dose of neoadjuvant treatment, participants will undergo surgery for their breast cancer. After surgery, participants will receive adjuvant pembrolizumab 400 mg IV infusion Q6W for approximately 30 weeks. Additional adjuvant TPC may be administered to participants with residual disease. TPC options include olaparib 300 mg oral BID for 1 year (participants with gBRCAm only) or capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles.
Part 2, C: Pembro + paclitaxel + carboplatin→ Pembro + doxorubicin (or epirubicin) +cyclophosphamide	Cyclophosphamide	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min via IV infusion QW for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV infusion Q3W and cyclophosphamide 600 mg/m\^2 IV infusion Q3W for 12 weeks. At 3 to 6 weeks after last dose of neoadjuvant treatment, participants will undergo surgery for their breast cancer. After surgery, participants will receive adjuvant pembrolizumab 400 mg IV infusion Q6W for approximately 30 weeks. Additional adjuvant TPC may be administered to participants with residual disease. TPC options include olaparib 300 mg oral BID for 1 year (participants with gBRCAm only) or capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles.
Part 2, C: Pembro + paclitaxel + carboplatin→ Pembro + doxorubicin (or epirubicin) +cyclophosphamide	Capecitabine	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min via IV infusion QW for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV infusion Q3W and cyclophosphamide 600 mg/m\^2 IV infusion Q3W for 12 weeks. At 3 to 6 weeks after last dose of neoadjuvant treatment, participants will undergo surgery for their breast cancer. After surgery, participants will receive adjuvant pembrolizumab 400 mg IV infusion Q6W for approximately 30 weeks. Additional adjuvant TPC may be administered to participants with residual disease. TPC options include olaparib 300 mg oral BID for 1 year (participants with gBRCAm only) or capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles.
Part 2, C: Pembro + paclitaxel + carboplatin→ Pembro + doxorubicin (or epirubicin) +cyclophosphamide	Olaparib	In Part 2, participants receive neoadjuvant pembrolizumab 200 mg IV infusion Q3W plus paclitaxel 80 mg/m\^2 IV infusion QW and carboplatin AUC1.5 mg/ml/min via IV infusion QW for 12 weeks, followed by pembrolizumab 200 mg IV infusion Q3W plus doxorubicin 60mg/m\^2 (or epirubicin 90 mg/m\^2) IV infusion Q3W and cyclophosphamide 600 mg/m\^2 IV infusion Q3W for 12 weeks. At 3 to 6 weeks after last dose of neoadjuvant treatment, participants will undergo surgery for their breast cancer. After surgery, participants will receive adjuvant pembrolizumab 400 mg IV infusion Q6W for approximately 30 weeks. Additional adjuvant TPC may be administered to participants with residual disease. TPC options include olaparib 300 mg oral BID for 1 year (participants with gBRCAm only) or capecitabine 1000-1250 mg/m\^2 oral BID days 1-14 and 22-35 Q6W for 4 six-week cycles.

Primary Outcome Measures

Name	Time	Method
Part 1: Number of Participants Experiencing an Adverse Event (AE)	Up to ~43 weeks	An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. The number of participants who experience an AE will be presented for Part 1.
Part 1: Number of Participants Who Experience One or More Dose-Limiting Toxicities (DLTs)	Up to 21 days	A DLT is defined by the National Cancer Institute Common Terminology for Adverse Events (NCI CTCAE) Version 5.0, assessed by investigator as drug-related: Grade (gr) 3 or 4 nonhematologic toxicity (with exceptions); gr 3 or gr 4 laboratory values (with exceptions); gr 3 or 4 febrile neutropenia; prolonged delay (\>2 weeks) in initiating Cycle 2 (cycle length = 3 weeks) due to intervention-related toxicity; any intervention-related toxicity that causes the participant to discontinue intervention during Cycle 1; interstitial lung disease as per investigator; any other gr ≥3 pulmonary toxicity; or gr 5 toxicity.
Part 1: Number of Participants who Discontinued Study Treatment Due to an AE	Up to ~30 weeks	An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. The number of participants who discontinued study treatment due to an AE will be presented for Part 1.
Part 2: Pathological Complete Response (pCR) Rate Using the Definition of ypT0/Tis ypN0	Up to ~30 weeks	pCR (ypT0/Tis ypN0) is defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes after completion of neoadjuvant systemic therapy at the time of definitive surgery.
Part 2: Number of Participants Experiencing an AE	Up to ~103 weeks	An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. The number of participants who experience an AE will be presented for Part 2.
Part 2: Number of Participants who Discontinued Study Treatment Due to an AE	Up to ~90 weeks	An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. The number of participants who discontinued study treatment due to an AE will be presented for Part 2.

Secondary Outcome Measures

Name	Time	Method
Part 2: pCR-No Ductal Carcinoma in Situ (DCIS) Rate Using the Definition of ypT0 ypN0	Up to ~30 weeks	pCR-no DCIS (ypT0 ypN0) is defined as the absence of residual invasive and in situ cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes after completion of neoadjuvant systemic therapy at the time of definitive surgery.
Part 2: Event-Free Survival (EFS)	Up to ~100 months	EFS is defined as the time from randomization to disease progression that precludes surgery, local or distant recurrence, or death due to any cause, whichever occurs first.
Part 2: Overall Survival (OS)	Up to ~100 months	OS is defined as the time from randomization to date of death due to any cause.
Part 2: Distant Progression or Distant Recurrence-Free Survival (DPDRFS)	Up to ~100 months	DPDRFS is defined as the time from randomization to first distant progression or distant recurrence event as assessed or death due to any cause, whichever occurs first.
Part 2: Residual Cancer Burden (RCB)	Up to ~30 weeks	RCB is defined as residual disease in either the breast or lymph node at the time of surgery. RCB score provides a continuous measurement of the extent of residual cancer. There are four RCB classes: RCB-0 (RCB score 0), RCB-1 (0\< RCB score \<1.36), RCB-2 (1.36 \<RCB score \<3.28), and RCB-3 (RCB score \>3.28).

Trial Locations

Locations (6): Northwest Cancer Specialists (Compass Oncology) ( Site 8003)
🇺🇸
Tigard, Oregon, United States
Intermountain Health St. Vincent Regional Hospital - Cancer Centers of Montana ( Site 0003)
🇺🇸
Billings, Montana, United States
SCRI Oncology Partners ( Site 7000)
🇺🇸
Nashville, Tennessee, United States
Texas Oncology - DFW ( Site 8000)
🇺🇸
Dallas, Texas, United States
Virginia Oncology Associates (VOA) ( Site 8001)
🇺🇸
Norfolk, Virginia, United States
Orchard Healthcare Research Inc. ( Site 0006)
🇺🇸
Skokie, Illinois, United States

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