A Randomized Trial of Trastuzumab Deruxtecan and Biology-Driven Selection of Neoadjuvant Treatment for HER2-positive Breast Cancer: ARIADNE

The primary objective of this study is to compare the locally assessed **pathologic complete remission (pCR)** rates between standard neoadjuvant therapy and **trastuzumab deruxtecan (T-DXd)** monotherapy in patients with molecularly **HER2-enriched** and clinically **HER2-positive**, non-metastatic breast cancer. This comparison is clinically relevant as it aims to determine the efficacy of T-DXd, potentially offering a more effective treatment option for this patient population.

Secondary objectives include: - Performing translational studies on clinicopathologic factors and tissues or peripheral blood to discover prognostic or predictive biomarkers relevant to the treatments in the trial. - Comparing locally assessed pCR rates between two patient groups of the initial randomization of molecularly unselected patients between standard and experimental therapy, regardless of administered therapy beyond cycle 3. - Investigating pCR rates for patients with HER2-positive, but non-HER2-enriched breast cancer, receiving sequential combinations of T-DXd and either ribociclib combined with endocrine therapy and dual HER2-blockade for Estrogen Receptor (ER) positive and molecularly luminal cancers or response-adjusted therapy for normal-like, basal-like, or ER-negative and luminal cancers. - Evaluating efficacy measures for the comparison of standard and experimental treatment, including time-to-event endpoints (relapse-free, distant disease-free, and overall survival) and short-term endpoints (pathologic response according to residual cancer burden [RCB], objective response rate). - Assessing the effect of standard and experimental treatment on the type of surgery performed in the breast and the axilla. - Evaluating patient-reported outcomes (PRO) measures for health-related quality of life in the two treatment arms. - Evaluating the safety and tolerability of the two treatment arms.

The clinical trial involves participants diagnosed with **non-metastatic HER2-positive breast cancer**. The study population includes both women and men aged 18 years or older. Participants are required to have a performance status of 0 or 1 at the time of randomization, ensuring they are in relatively good health. The trial population was selected based on specific inclusion criteria, such as histologically confirmed breast cancer with an invasive component measuring over 20 mm or with morphologically confirmed spread to regional lymph nodes. Both estrogen-receptor and progesterone receptor statuses are assessed locally, with a positivity cut-off of at least 10% of cell nuclei staining. Participants must have a Left Ventricular Ejection Fraction of 50% or higher within 28 days before randomization and demonstrate adequate bone marrow, hepatic, and renal function. The trial includes a vulnerable population, and both male and female subjects are eligible. However, the sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the efficacy of **trastuzumab deruxtecan** in comparison to standard neoadjuvant therapy for patients with **HER2-positive breast cancer**. This is a randomized, double-blind, controlled trial, which aims to assess the pathologic complete remission (pCR) rates in patients with molecularly HER2-enriched and clinically HER2-positive, non-metastatic breast cancer. The trial is expected to run from May 2023 to June 2032, with participant involvement lasting up to 18 months, depending on the treatment arm and response.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and specific cancer characteristics. Following randomization, participants will receive either the investigational drug or standard therapy. Study visits will include regular assessments to monitor treatment response and safety, with follow-up visits scheduled at specific intervals to evaluate the primary and secondary endpoints, including pCR rates and overall survival.

The end-of-study visit will occur after the completion of the treatment period or upon early termination. Conditions that may lead to early termination include significant adverse events, disease progression, or withdrawal of consent. Throughout the trial, data will be collected to explore secondary endpoints such as radiologic response rates, survival outcomes, and quality of life measures. The trial will adhere to rigorous ethical standards, ensuring that all participants provide informed consent and that their safety is prioritized throughout the study.

The clinical trial involves the administration of **Enhertu** (trastuzumab deruxtecan), a **powder for concentrate for solution for infusion**. This experimental medication is administered via **intravenous infusion**. The dosage is calculated based on body weight, with a maximum daily dose of 5.8 mg/kg and a total maximum dose of 32.4 mg/kg over a treatment period of up to 18 cycles. Participant compliance is monitored through regular assessments and infusion records.

**Docetaxel Accord** is used as a comparator treatment in the study. It is provided as an **80 mg/4 ml concentrate for solution for infusion** and administered via **intravenous infusion**. The maximum daily dose is 75 mg/m², with a total maximum dose of 600 mg/m² over 18 cycles. Compliance is ensured through infusion logs and patient monitoring.

**Dexamethasone Orifarm** is an auxiliary treatment in the form of **4 mg tablets**. It can be administered **orally or intravenously**, with a maximum daily dose of 16 mg and a total maximum dose of 336 mg over 18 cycles. Compliance is tracked through patient diaries and medication counts.

**Metoclopramide "Orifarm"** is another auxiliary treatment, provided as **tablets** for **oral administration**. The maximum daily dose is 30 mg, with a total maximum dose of 1470 mg over 18 cycles. Compliance is monitored through patient self-reports and pill counts.

**Olanzapine** is administered as **5 mg film-coated tablets** for **oral use**. The maximum daily dose is 5 mg, with a total maximum dose of 175 mg over 18 cycles. Compliance is tracked through patient logs and pill counts.

**Carboplatin Accord** is a comparator treatment provided as a **10 mg/ml concentrate for solution for infusion**. It is administered via **intravenous infusion**, with a maximum daily dose of 5 mg and a total maximum dose of 30 mg over 18 cycles. Compliance is ensured through infusion records and patient monitoring.

**Paclitaxel Actavis** is used as a comparator, available as a **6 mg/ml concentrate for solution for infusion**. It is administered via **intravenous infusion**, with a maximum daily dose of 80 mg/m² and a total maximum dose of 960 mg/m² over 18 cycles. Compliance is monitored through infusion logs.

**Neulasta** (pegfilgrastim) is an auxiliary treatment provided as a **6 mg solution for injection**. It is administered via **subcutaneous injection**, with a maximum daily dose of 6 mg and a total maximum dose of 42 mg over 18 cycles. Compliance is tracked through injection records.

**Kisqali** (ribociclib) is a comparator treatment in the form of **200 mg film-coated tablets** for **oral administration**. The maximum daily dose is 600 mg, with a total maximum dose of 25200 mg over 8 cycles. Compliance is monitored through patient diaries and pill counts.

**Ondansetron Bluefish** is an auxiliary treatment provided as **8 mg orodispersible tablets** for **oral use**. The maximum daily dose is 8 mg, with a total maximum dose of 168 mg over 18 cycles. Compliance is tracked through patient self-reports and pill counts.

**Epirubicin Accord** is a comparator treatment available as a **2 mg/ml solution for injection/infusion**. It is administered via **intravenous infusion**, with a maximum daily dose of 90 mg/m² and a total maximum dose of 360 mg/m² over 8 cycles. Compliance is ensured through infusion records.

**Perjeta** (pertuzumab) is used as a comparator, provided as a **420 mg concentrate for solution for infusion**. It is administered via **intravenous infusion**, with a maximum daily dose of 840 mg and a total maximum dose of 2940 mg over 18 cycles. Compliance is monitored through infusion logs.

**Palonosetron Fresenius Kabi** is an auxiliary treatment in the form of a **250 microgram solution for injection**. It is administered via **intravenous injection**, with a maximum daily dose of 250 micrograms and a total maximum dose of 1750 micrograms over 18 cycles. Compliance is tracked through injection records.

**Phesgo** is a combination of trastuzumab and pertuzumab, provided as a **600 mg/600 mg solution for injection**. It is administered via **subcutaneous injection**, with a maximum daily dose of 600 mg and a total maximum dose of 3600 mg over 18 cycles. Compliance is monitored through injection records.

**Herceptin** (trastuzumab) is a comparator treatment available as a **150 mg powder for concentrate for solution for infusion**. It is administered via **intravenous infusion**, with a maximum daily dose of 8 mg/kg and a total maximum dose of 38 mg/kg over 18 cycles. Compliance is ensured through infusion records.

**Zarzio** (filgrastim) is an auxiliary treatment provided as a **48 MU/0.5 ml solution for injection or infusion in a pre-filled syringe**. It is administered via **subcutaneous injection**, with a maximum daily dose of 48 MU and a total maximum dose of 2352 MU over 18 cycles. Compliance is tracked through injection records.

**EMEND** (aprepitant) is an auxiliary treatment in the form of **125 mg+80 mg hard capsules** for **oral administration**. The maximum daily dose is 125 mg, with a total maximum dose of 1995 mg over 18 cycles. Compliance is monitored through patient diaries and pill counts.

**Sendoxan** (cyclophosphamide) is a comparator treatment available as a **solution for injection**. It is administered via **intravenous infusion**, with a maximum daily dose of 600 mg/m² and a total maximum dose of 2400 mg/m² over 8 cycles. Compliance is ensured through infusion records.

**Betapred** (betamethasone) is an auxiliary treatment provided as **0.5 mg tablets**. It can be administered **orally or intravenously**, with a maximum daily dose of 16 mg and a total maximum dose of 336 mg over 18 cycles. Compliance is tracked through patient diaries and medication counts.

**Letrozole Bluefish** is a comparator treatment in the form of **2.5 mg film-coated tablets** for **oral administration**. The maximum daily dose is 2.5 mg, with a total maximum dose of 105 mg over 8 cycles. Compliance is monitored through patient diaries and pill counts.

**Goserelin** is a comparator treatment provided as a **3.6 mg implant in a pre-filled syringe**. It is administered via **subcutaneous injection**, with a maximum daily dose of 3.6 mg and a total maximum dose of 7.2 mg over 8 cycles. Compliance is tracked through injection records.

The efficacy of the clinical trial will be assessed primarily through the measurement of the pathologic complete remission (pCR) rates in patients with **HER2-positive breast cancer**. The primary endpoint is the locally assessed rate of pCR in the molecularly HER2-enriched population, defined as ypT0/Tis, ypN0, as determined at the surgical specimen by a pathologist blinded to treatment assignment. This assessment will be conducted using an intention-to-treat analysis.

Secondary endpoints include the locally assessed rate of pCR in various subgroups, such as ER-positive and luminal, ER-negative and luminal, basal-like, and normal-like subgroups. Additionally, the trial will evaluate rates of radiologic complete response after three courses of either standard therapy or trastuzumab deruxtecan (T-DXd), overall survival (OS), distant relapse-free survival (DRFS), and event-free survival (EFS). These endpoints will be measured for each molecular group, including comparisons between TCHP and T-DXd in HER2-enriched patients.

Other secondary endpoints involve the assessment of pathologic response according to Residual Cancer Burden Class, rates of breast conserving surgery, de-escalation of breast and axillary surgery, and rates of Sentinel Lymph Node Dissection (SLND). The trial will also monitor the frequency and grade of adverse events according to NCI CTCAE v. 5.0, and patient-reported outcomes (PRO) including health-related quality of life scores using the EORTC QLQ-C30 and EORTC QLQ-BR23 instruments.

Exploratory analyses will be conducted to identify clinicopathologic characteristics as predictors for response and to discover biomarkers of response or resistance to the administered neoadjuvant therapy at the protein, RNA, and DNA levels in both tumor tissue and blood/plasma.