Emerging Data from the DESTINY-Breast Trials Signal Shift in Standards of Care for HER2-Positive Breast Cancer

Data presented at the 2025 San Antonio Breast Cancer Symposium (SABCS) further clarify the role of trastuzumab deruxtecan (T-DXd, Enhertu; Daiichi Sankyo) across multiple stages of HER2-positive (HER2+) breast cancer. Three key updates from DESTINY-Breast05 (NCT04622319),¹ DESTINY-Breast11 (NCT05113251),² DESTINY-Breast09 (NCT04784715)³ highlight consistent clinical benefit, manageable safety, and meaningful patient-centered advantages with T-DXd–based regimens.

Interim Analysis of DESTINY-Breast05

The interim data presented at SABCS show T-DXd’s clinical benefits of trastuzumab emtansine (T-DM1, Kadcyla; Genentech) as a potential new standard-of-care in post-neoadjuvant (NAT) treatment of patients with HER2+ breast cancer and residual disease. T-DXd met the trial’s primary end point of invasive disease-free survival (IDFS) and demonstrated a manageable toxicity profile.⁴

The phase 3, multicenter, randomized, open-label, active-controlled study, included patients with residual invasive HER2+ breast cancer following NAT consisting of anti-HER2 therapy and taxane-based chemotherapy and at high risk for recurrence (cT4 N0–3 M0; cT1–3 N2–3 M0 before NAT; or cT1–3 N0–1 M0 with ypN1–3 axillary node–positive disease after NAT). Approximately 80% of patients had invasive residual disease in the axillary lymph nodes. Regarding prior treatments, 93% of patients received adjuvant radiotherapy (56% concurrent [n = 918]; 37% sequential [n = 605]), and 79% received dual HER2-targeted NAT.⁴

The patients (n = 1635) were randomized 1:1 to receive either T-DXd at a dosage of 5.4 mg/kg (n = 818) or T-DM1 3.6 mg/kg (n = 817) once every 3 weeks for 14 cycles. Over 70% of patients in both arms received 14 cycles of study therapy. Patients assigned to adjuvant radiotherapy (RT) underwent scheduled chest CT imaging throughout the treatment period. RT was allowed either before the start of study therapy or alongside it. Those who completed RT prior to initiating study treatment received one extra CT scan at the conclusion of their RT course.⁴

The data showed that he IDFS benefit favored T‑DXd and was consistent across all subgroups, including patients who had anthracycline‑containing vs anthracycline‑free neoadjuvant regimens or those with different HER2 immunohistochemistry status.⁴

Regarding safety, adjudicated drug-related interstitial lung disease (ILD) occurred in 9.6% of patients who received T‑DXd, of which were mostly grade 1 or 2 with 0.2% of patients having grade 5 events. Investigator-reported radiation pneumonitis (RP) incidence was similar in both arms: 31.4% with T-DXd and 30.5% with T-DM1. The investigators reported no grade 3 or greater events and the majority of RP cases was grade 1.⁴

“These additional analyses, I think, are very helpful to further characterize the clinical benefit and safety profile of T-DXd over T-DM1 in the post‑neoadjuvant [HER2+] early breast cancer residual invasive disease setting, supporting T-DXd as the potential new standard of care,” concluded Sibylle Loibl, MD, PhD, chair of the German Breast Group, chief executive officer of the GBG Forschungs GmbH, and associate professor of obstetrics and gynaecology at the Goethe University of Frankfurt.⁵

Updated Safety Data from DESTINY-Breast11

The current NAT standard of care for HER2+ early breast cancer relies on dual HER2-targeted therapy combined with cytotoxic chemotherapy, a regimen linked to both short- and long-term toxicities.

In the phase 3 open-label DestinyBreast-11 trial, T-DXd plus a taxane (ie, docetaxel or paclitaxel), trastuzumab (Herceptin; Genentech) and pertuzumab (Perjeta; Genentech; THP) led to clinically meaningful improvements in pathologic complete response (pCR) and safety. The regimen proved to be superior to the chemotherapy regimen consisting of doxorubicin, cyclophosphamide, paclitaxel, trastuzumab, pertuzumab (ddAC-THP).⁶

The trial investigators randomized 915 patients with high-risk (≥ T3, node positive [N1-3] or inflammatory) HER2+ early breast cancer to neoadjuvant T-DXd (8 cycles), T-DXd-THP (4 + 4 cycles), or ddAC-THP (4 + 4 cycles).⁶

Adverse events (AEs) of special interest were included interstitial lung disease (ILD)/pneumonitis and left ventricular dysfunction (LVD), as well as clinically relevant AEs (nausea/vomiting [N/V], neutropenia, and peripheral neuropathy).⁶

At the primary analysis, rates of all-grade adjudicated drug-related ILD/pneumonitis were low across all treatment arms. During the THP phase (cycles 5–8), rates remained stable with T-DXd-THP and were higher with ddAC-THP compared with cycles 1 to 4. Serious AEs were reported in 0.4% of patients receiving T-DXd, 0.6% with T-DXd-THP, and 2.9% with ddAC-THP. Grade 3 or greater adjudicated ILD/pneumonitis and both all-grade and grade 3 or higher LVD occurred most frequently in the ddAC-THP arm.⁶

Steroids were administered to 71.4%, 64.3%, and 56.3% of patients with adjudicated ILD/pneumonitis in the T-DXd, T-DXd-THP, and ddAC-THP groups, respectively; resolution occurred in 57.1%, 71.4%, and 81.3% of cases.⁶

N/V was more common with T-DXd and T-DXd-THP than ddAC-THP, although fewer patients in these arms received the recommended 3-drug antiemetic prophylaxis before cycle 1 (T-DXd 14.1%; T-DXd-THP 16.9%; ddAC-THP 39.7%). Two-drug prophylaxis was used in 55.5%, 57.2%, and 40.4% of patients, respectively. N/V events were generally low grade, nonserious, and decreased after cycles 1 to 4.⁶

Neutropenia occurred most frequently with ddAC-THP across cycles, consistent with higher granulocyte colony-stimulating factor use (87.2% vs 16.1% with T-DXd and 22.7% with T-DXd-THP). Peripheral neuropathy was least common with T-DXd and events were predominantly low grade and nonserious across all groups, most occurring during the THP phase.⁶

“In conclusion, in DestinyBreast-11, the safety profile of T‑DXd–THP was manageable and overall less toxic than dose‑dense AC followed by THP,” explained Giuseppe Curigliano, MD, PhD, director of the Early Drug Development Division and holds the co-chair for Experimental Therapeutics Program at the European Institute of Oncology in Milano, Italy. “…[the] results support, in my opinion, [indicate] T‑DXd–THP as a potential [NAT] option for patients with high‑risk [HER2+] early breast cancer.”⁵

Patient-Reported Outcomes (PROs) from DESTINY-Breast09

Emerging PRO data presented at SABCS support T-DXd and pertuzumab as a new first treatment in HER2+ advanced or metastatic breast cancer align with safety and efficacy outcomes reported in clinical trials.

DESTINY-Breast09 (NCT04784715) is a phase 3 trial evaluating T-DXd plus pertuzumab compared with standard-of-care THP as first line therapy for HER2+ advanced or metastatic breast. The trial enrolled patients who did not receive prior systemic therapy for advanced or metastatic breast or who received endocrine therapy. They were randomized 1:1:1 to receive either T-DXd (5.4 mg/kg once every 3 weeks), T-DXd plus pertuzumab (n = 383), or THP (n = 387).⁷

The end points measured included⁷:

• Time to deterioration (TTD) in pain via the EORTC QLQ-C30; the proportion of pts experiencing treatment-related symptoms via selected scales/items of the QLQ-C30, EORTC QLQ-BR45
• PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)
• Proportion of patients with ‘maintained or improved’ physical function via the QLQ-C30
• AE burden via the Patient Global Impression of Treatment Tolerability (PGI-TT)

Investigators assessed PROs on day 1 of each cycle until cycle 9, with the QLQ-C30/-BR45 assessed every second cycle thereafter until progression.⁷

According to the data, the median time to deterioration (TTD) in pain was not reached in either group, and the risk of pain worsening was comparable between arms (HR, 0.95; 95% CI, 0.74–1.21; maturity 35%). On the QLQ-C30/-BR45 scales, patients receiving T-DXd plus pertuzumab more often reported deterioration in N/V, constipation, and appetite loss; however, fewer reported worsening skin or mucosal symptoms than those treated with THP. In PRO-CTCAE assessments, nosebleeds and extremity swelling were less common with T-DXd plus pertuzumab than with THP. PGI-TT results were similar across arms.⁷

Most patients maintained or improved physical function: 82.9% vs 82.4% at cycle 2 and 75.4% vs 77.7% at cycle 27 (~18.7 months) in the T-DXd plus pertuzumab and THP groups, respectively.⁷

Together with the efficacy and safety findings, the PRO results support T-DXd plus pertuzumab as a new first-line option for HER2+ advanced or metastatic breast cancer, offering durable pain control and sustained physical function, with distinct quality-of-life advantages over THP.⁷

“This study… supports T-DXd plus pertuzumab as having a favorable profile versus THP for the management of metastatic breast cancer,” said Mothaffar F. Rimawi, MD, board certified internal medicine, hematology and medical oncologist.⁵

Across early-stage, neoadjuvant, and metastatic HER2+ disease, the DESTINY-Breast updates reinforce T-DXd’s emerging role as a versatile and clinically impactful therapy. Collectively, these findings point toward a future in which T-DXd-based regimens may redefine treatment paradigms across the HER2+ breast cancer continuum.

REFERENCES

1. A study of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in high-risk HER2-positive participants with residual invasive breast cancer following neoadjuvant therapy (DESTINY-Breast05). Clinicaltrials.gov. Updated May 9, 2025. Accessed December 11, 2025. https://clinicaltrials.gov/study/NCT04622319

2. Trastuzumab deruxtecan (T-DXd) alone or in sequence with THP, versus standard treatment (ddAC-THP), in HER2-positive early breast cancer. Clinicaltrials.gov. November 18, 2025. Accessed December 11, 2025. https://clinicaltrials.gov/study/NCT05113251

3. Trastuzumab deruxtecan (T-DXd) with or without pertuzumab versus taxane, trastuzumab and pertuzumab in HER2-positive metastatic breast cancer (DESTINY-Breast09). Clinicaltrials.com. November 12, 2025. Accessed December 11, 2025

4. Loibl S, Park Y, Shao Z, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients with high-risk human epidermal growth factor receptor 2-positive (HER2+) primary breast cancer (BC) with residual invasive disease after neoadjuvant therapy: Interim analysis of DESTINY-Breast05. Presented at SABCS 2025. December 9-12, 2025. San Antonio, TX. Abstract RF6-01.

5. Bardia A, Loibl S, Curigliano G, et al. Rapid Fire 6. Presented at SABCS 2025. December 9-12, 2025. San Antonio, TX.

6. Curigliano G, Harbeck N, Boileau J, et al. DESTINY-Breast11 (DB-11) safety: neoadjuvant trastuzumab deruxtecan (T-DXd) alone or followed by paclitaxel + trastuzumab + pertuzumab (THP) vs dose-dense doxorubicin + cyclophosphamide followed by THP (ddAC-THP) in high-risk, HER2+ early-stage breast cancer (eBC). Presented at SABCS 2025. December 9-12, 2025. San Antonio, TX. Abstract RF6-02. RF6-07

7. Rimawi M, Loibl S, Jiang Z, et al. Trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for first-line (1L) treatment of patients (pts) with HER2-positive (HER2+) advanced/metastatic breast cancer (a/mBC): patient-reported outcomes (PROs) from the DESTINY-Breast09 study. Presented at SABCS 2025. December 9-12, 2025. San Antonio, TX. Abstract RF6-07.