Transforming HER2+ Metastatic Breast Cancer Treatment With Targeted ADC Therapy

At the European Society for Medical Oncology (ESMO) 2025 Congress, investigators presented pivotal findings that strengthen the role of antibody-drug conjugates (ADCs) in the treatment of HER2-positive (HER2+) metastatic breast cancer. The results underscore the growing impact of ADCs in extending survival and improving quality of life for patients with HER2-positive disease.

Antibody Drug Conjugates

Next-generation therapies continue to redefine standards of care by combining targeted precision with potent cytotoxic delivery, such as ADCs. ADCs are made of a monoclonal antibody (mAb), chemotherapy, and a linker protein to connect the mAb to the chemotherapeutic agent. Across clinical trials, these agents continue to establish their place in the HER2+ breast cancer treatment paradigm.¹

“ADCs can enter tumor cells, and after killing the targeted cell, they can have a bystander effect because the payload is released and can kill neighboring tumor cells,” said Erwei Song, professor of Breast Surgery at Sun Yat-sen University and member of the Chinese Academy of Sciences.²

Among the highlights were data on ADCs trastuzumab deruxtecan (T-DXd; Enhertu, Daiichi Sankyo/AstraZeneca) and trastuzumab rezetecan (SHR-A1811; Jiangsu Hengrui Pharmaceuticals), both of which demonstrated statistically significant improvements in survival outcomes compared with standard treatment regimens.

DESTINY-Breast09

DESTINY-Breast09 (NCT04784715) is a phase 3 trial assessing the efficacy and safety of T-DXd, either alone or in combination with pertuzumab (Perjeta; Genentech Inc), in treating patients with metastatic HER2+ breast cancer as a first line of treatment.^3,4

Sibylle Loibl, MD, chair of the German Breast Group and the Chief Executive Officer of the GBG Forschungs GmbH and associate professor of obstetrics and gynaecology at the Goethe University of Frankfurt, shared statistically significant interim analysis data from DESTINY-Breast09, showing meaningful improvements in progression-free survival (PFS) across patient subgroups.³

The trial aims to evaluate the efficacy and safety of trastuzumab deruxtecan, alone or with pertuzumab, compared with the standard of care treatment (taxane [docetaxel or paclitaxel], trastuzumab and pertuzumab [THP]).^3,4

Researchers assessed 770 patients with HER2+ (IHC 3+ or ISH+) advanced, metastatic breast (a/mBC) cancer who had no prior systemic therapy and 1 or fewer lines of endocrine therapy. Of the population, about 52% had de-novo a/mBC, approximately 54% had hormone receptor-positive (HR+) status, and almost 31% had detected PIK3CAm.^3,4

Eligibility criteria required patients to have a disease-free interval of 6 or more months between (neo)adjuvant therapy and a/mBC. The primary end point was PFS by blinded independent central review (BICR), with secondary end points including confirmed objective response rate (ORR) by BICR, duration of response (DOR) by BICR, and safety.^3,4

Patients were randomized 1:1:1 to receive T-DXd plus placebo, T-DXd plus pertuzumab, or the standard regimen of THP. Randomization was stratified by disease type (de novo or recurrent), HR status, and presence of a PIK3CA mutation.^3,4

Results

Patients With Prior Treatment Status

Among patients with de novo metastatic breast cancer, treatment with trastuzumab deruxtecan (T-DXd) plus pertuzumab achieved a median progression-free survival (PFS) that was not yet reached at the time of data cutoff, compared with 31.2 months for those receiving trastuzumab, pertuzumab, and a taxane (THP). The hazard ratio of 0.49 indicates a 51% reduction in the risk of progression or death, highlighting the strong efficacy of the combination in patients newly diagnosed with metastatic disease. ^3,4

In patients with recurrent metastatic breast cancer, median PFS was 38.9 months with T-DXd plus pertuzumab compared with 22.5 months for THP. These results demonstrate that the benefit of T-DXd extends beyond treatment-naïve patients, offering durable disease control even in those who previously received therapy for early-stage disease. ^3,4

HR Status

When analyzed by HR status, the combination showed consistent benefit. Among HR+ patients, median PFS was 38 months with T-DXd plus pertuzumab versus 27.7 months with THP. In HR-negative patients, outcomes were even stronger, with a median PFS of 47 months versus 22.6 months, suggesting enhanced benefit in more aggressive disease subtypes. ^3,4

PIK3CA Status

The advantage of T-DXd plus pertuzumab was seen across PIK3CA mutation subgroups. In PIK3CA-mutant tumors, median PFS was 36 months with T-DXd plus pertuzumab compared with 18 months for THP. Among PIK3CA wild-type tumors, median PFS reached 40 months versus 32.7 months, confirming consistent efficacy regardless of mutational status. Overall, these findings reinforce T-DXd plus pertuzumab as a highly effective first-line option for patients with HER2-positive advanced or metastatic breast cancer. ^3,4

Overall, T-DXd plus pertuzumab provided a clinically meaningful efficacy benefit over standard THP therapy, regardless of disease history, HR status, or PIK3CA mutation status. These findings support the use of T-DXd plus pertuzumab as a potential new first-line treatment option for patients with HER2-positive advanced or metastatic breast cancer. ^3,4

"It demonstrated for T-DXd plus pertuzumab statistically significant as well as clinically meaningful improvement in [PFS] versus THP,” explained Loibl, “with the hazard ratio being 0.56 and the median PFS increasing from 26.9 months with THP to 40.7 with T-DXd plus pertuzumab."³

HORIZON-Breast01

The randomized, open-label, multicenter phase 3 HORIZON-Breast01 trial (NCT05424835) evaluated T-DXd-receptacle versus pyrotinib (Irene; Jiangsu Hengrui Medicine) plus capecitabine as second-line or later therapy for patients with HER2+ advanced breast cancer.^5,6

The study showed a marked improvement in efficacy outcomes with T-DXd-receptacle. The median PFS reached 30.6 months compared with 8.3 months in the control arm, corresponding to a hazard ratio of 0.32, indicating a substantial reduction in disease progression risk. ^5,6

Among enrolled patients, 100% in the treatment arm previously received trastuzumab (Herceptin; Genentech) and 71.8% received prior pertuzumab. The median follow-up period was 15.9 months. ^5,6

The overall response rate (ORR) was significantly higher with T-DXd (81.7%) compared with the control group (55.9%). The median DOR was also notably prolonged—27.8 months versus 10.9 months, respectively. ^5,6

The rate of interstitial lung disease was 2.8%, and the most common adverse events were hematopoietic toxicities.^5,6

Overall, the findings demonstrated a significant improvement in PFS, response rate, and durability of benefit compared with the control arm, reinforcing trastuzumab deruxtecan-receptacle as a highly effective treatment option in this setting.

“T-DXd offers high clinical activity... and represents a promising practice-changing therapeutic alternative in this patient population,” concluded Song.²

Clinical trial data, including DESTINY-Breast09 and HORIZON-Breast01, demonstrate robust and consistent improvements in PFS, ORRs, and DOR across diverse patient subgroups. These findings reinforce ADCs as a potent, precision-based approach that offers durable disease control and a potential new first-line option for patients with HER2+ advanced or metastatic breast cancer.

REFERENCES

1. Antibody-drug conjugates (ADCs). Cleveland Clinic. March 28, 2024. Accessed October 19, 2025. https://my.clevelandclinic.org/health/treatments/antibody-drug-conjugates

2. Bartsch R, Im S, Loibl S, et al. Proffered paper session 2: Breast cancer, metastatic. Presented at: European Society for Clinical Oncology. October 17, 2025 to October 21, 2025. Berlin Germany.

3. Trastuzumab deruxtecan (T-DXd) with or without pertuzumab versus taxane, trastuzumab and pertuzumab in HER2-positive metastatic breast cancer (DESTINY-Breast09). Clinicaltrials.gov. Updated August 1, 2025. Accessed October 19, 2025. https://clinicaltrials.gov/study/NCT04784715

4. Loibl S, Jiang Z, Barroso-Sousa R, et al. Trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for patients (pts) with HER2+ advanced/metastatic breast cancer (a/mBC): Additional analyses of DESTINY-Breast09 in key subgroups of interest. Presented at: European Society for Clinical Oncology. October 17, 2025 to October 21, 2025. Abstract LBA18

5. A trial of SHR-A1811versus pyrotinib in combination with capecitabine in HER2-positive, unresectable and/​or metastatic breast cancer subjects previously treated with trastuzumab and taxane. Clinicaltrials.gov. Updated August 22, 2025. Accessed October 19, 2025. https://clinicaltrials.gov/study/NCT05424835

6. Song E, Yao H, Li H, et al. LBA19 - SHR-A1811 versus pyrotinib plus capecitabine in human epidermal growth factor receptor 2-positive (HER2+) advanced/metastatic breast cancer (BC): A multicenter, open-label, randomized, phase III study (HORIZON-Breast01). . Presented at: European Society for Clinical Oncology. October 17, 2025 to October 21, 2025. Abstract LBA19