Trastuzumab Deruxtecan Plus Pertuzumab Improves Progression-Free Survival in Patients With HER2+ Metastatic Breast Cancer

Trastuzumab deruxtecan (T-DXd, Enhertu; AstraZeneca) in combination with pertuzumab (Perjeta; Genentech) demonstrated clinically meaningful improvement in progression-free survival (PFS) compared with a taxane, trastuzumab, and pertuzumab (THP) as a first-line treatment for patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC). The promising outcomes were observed in the phase 3 DESTINY-Breast09 trial (NCT04784715).¹

3D rendering of antibody drug conjugates | Image Credit: © Alpha Tauri 3D - stock.adobe.com

HER2 mutations are the most common alterations, of which HER2+ BC accounts for about 20% of all diagnoses. HER2+ mBC is challenging to treat due to its aggressiveness and accelerated growth with higher mortality rates compared with other BC subtypes. Historically, these patients had significantly poor prognoses, but the development of novel agents has greatly improved these outcomes, increasing survival rates to approximately 90%; however, this is typically for patients with an early diagnosis who receive prompt treatment. Additionally, of the patients diagnosed in early stages, 30% will progress to mBC.^2-4

Antibody-drug conjugates (ADCs) have become a cornerstone for treatment of patients with HER2+ mBC due to their substantial efficacy and improved tolerability compared with other available therapies. T-DXd is an ADC comprised of a HER2 monoclonal antibody attached to multiple topoisomerase I inhibitor payloads. This allowed the agent to selectively bind and target HER2+ mutations on mBC tumors. Its efficacy has been repeatedly reported across various clinical trials, which has led to the drug’s FDA approval across multiple BC indications and in more than 75 countries.^4,5

Other DESTINY-Breast trials continue to assess T-DXd across a variety of combinations and patient populations, reporting continued success in improving outcomes for patients. In the DESTINY-Breast09 trial, T-DXd’s use with pertuzumab demonstrated superior efficacy in the first line compared with the standard of care for patients with HER2+ mBC.⁴

“The results from DESTINY-Breast09 reinforce the importance of effectively targeting HER2 to achieve durable disease control early in the treatment of HER2+ [mBC],” Ken Takeshita, global head, R&D, Daiichi Sankyo, said in a press release. “Building on the positive results seen with [T-DXd] in the second-line setting, these new findings suggest that starting treatment with [T-DXd] in combination with pertuzumab at the time of metastatic diagnosis delays disease progression, postponing the time until additional treatment may be needed."⁴

DESTINY-Breast09 is a global, multicenter, randomized, open-label, phase 3 trial assessing the efficacy and safety of T-DXd as a monotherapy or in combination with pertuzumab compared with standard of care THP as a first-line treatment in patients with HER2+ mBC. A total of 1157 patients were randomly assigned to receive either T-DXd—at a dosage of 5.4mg/kg—as a monotherapy with a matching placebo; T-DXd in combination with pertuzumab; or THP. The primary end point was PFS by blinded independent review, and secondary end points were investigator-assessed PFS, overall survival (OS), objective response rate, duration of response, investigator-assessed time to second progression or death, patient-reported tolerability, pharmacokinetics, and safety.⁴

All patient subgroups—hormone receptor-positive and PIK3CA status—achieved an improvement in PFS when treated with T-DXd and pertuzumab. At the time of this intermediate analysis, OS was not yet mature; nonetheless, interim OS data indicated an early trend favoring the T-DXd combination over THP. Patients and researchers are blinded to the second arm, which compares T-DXd monotherapy to THP, and it will continue until the final PFS analysis.⁴

“This is the first trial in more than a decade to demonstrate superior efficacy across a broad [HER2+ mBC] patient population compared to the current 1st-line standard of care,” Susan Galbraith, executive vice president, Oncology Haematology R&D, AstraZeneca, said in a press release. “This is a significant milestone for patients and sets the foundation for [T-DXd] in combination with pertuzumab as an important treatment option in the first-line HER2-positive setting.”⁴

REFERENCES

1. Trastuzumab deruxtecan (T-DXd) with or without pertuzumab versus taxane, trastuzumab and pertuzumab in HER2-positive metastatic breast cancer (DESTINY-Breast09). Updated December 16, 2024. Accessed April 21, 2025. https://clinicaltrials.gov/study/NCT04784715

2. Vepdegestrant demonstrates progression-free survival in patients with ER+/HER2- metastatic breast cancer. Pharmacy Times. March 11, 2025. Accessed April 21, 2025. https://www.pharmacytimes.com/view/vepdegestrant-demonstrates-progression-free-survival-in-patients-with-er-her2--metastatic-breast-cancer

3. HER2-positive breast cancer: testing, treatment, research. Breast Cancer Research Foundation. Accessed April 21, 2025. https://www.bcrf.org/about-breast-cancer/her2-positive-breast-cancer-treatment-research/

4. Enhertu plus pertuzumab demonstrated highly statistically significant and clinically meaningful improvement in progression-free survival vs. THP as 1st-line therapy for patients with HER2-positive metastatic breast cancer. AstraZeneca. April 21, 2025. Accessed April 21, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/enhertu-combination-improved-pfs-in-1l-her-positive-mbc.html#

5. Real-world data show improved survival with sacituzumab govitecan as first-line ADC in HER2-low breast cancer. Pharmacy Times. April 18, 2025. Accessed April 21, 2025. https://www.pharmacytimes.com/view/real-world-data-show-improved-survival-with-sacituzumab-govitecan-as-first-line-adc-in-her2-low-breast-cancer