Trastuzumab Deruxtecan Plus Pertuzumab Does Not Worsen QOL in HER2+ Metastatic Breast Cancer

Frontline treatment with the combination of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) and pertuzumab (Perjeta) was associated with better quality of life (QOL) and less gastrointestinal and skin and mucosal symptoms compared with a taxane, trastuzumab (Herceptin), and pertuzumab (THP) in patients with HER2-positive advanced or metastatic breast cancer, according to data from the phase 3 DESTINY-Breast09 trial (NCT04784715) that were presented during the 2025 San Antonio Breast Cancer Symposium.1,2

Previous results showed that T-DXd plus pertuzumab demonstrated an improvement in progression-free survival.

In September 2025, the FDA granted priority review to the supplemental biologics license application of T-DXd for the first-line treatment of patients with unresectable or metastatic HER2-positive breast cancer.

In total, 383 patients received 5.4 mg/kg of T-DXd once every 3 weeks plus an 840 mg loading dose of pertuzumab followed by 420 mg once every 3 weeks. In the THP arm, 387 patients received a standard-of-care combination of the 3 drugs.

What were the patient-reported outcomes?

Compared with THP, T-DXd plus pertuzumab presents a distinct QOL profile. Patients receiving T-DXd plus pertuzumab more gastrointestinal symptoms, including nausea, vomiting, constipation, and appetite loss. This patient group also experienced fewer issues with skin and mucosal symptoms, nosebleeds, and extremity swelling.

Patients in both arms reported similar levels of pain control, fatigue, and overall treatment tolerability. Furthermore, the majority of patients on both treatments successfully maintained or improved their physical function throughout the study.

The PRO end points were time to deterioration in pain, proportion of patients experiencing deterioration in treatment-related symptoms, proportion of patients with maintained or improved physical function, and the overall adverse effect (AE) burden as reported by patients.

The impact on pain and physical function was largely similar between the investigational T-DXd plus pertuzumab arm and the THP arm.

The median time to deterioration in pain was not reached in either treatment arm. The statistical analysis showed a similar risk of pain deterioration for both groups (HR, 0.95; 95% CI, 0.74–1.21).

A high percentage of patients in both arms maintained or improved their physical function. At cycle 2, 82.9% of patients in the T-DXd plus pertuzumab arm (n = 328) maintained or improved physical function vs 82.4% of patients in the THP arm (n = 341). At cycle 27 (18.7 months), 75.4% of patients in the T-DXd plus pertuzumab arm (n = 187) maintained or improved their physical function vs 77.7% of patients in the THP arm (n = 166).

The primary differences in patient experience emerged in the specific types of AEs reported. Patients in the T-DXd plus pertuzumab arm experienced a worsening of gastrointestinal issues, specifically nausea/vomiting (49.1% vs 30.2%). Conversely, patients in this arm reported less deterioration in skin and mucosal symptoms, including nosebleeds and extremity swelling (22.9% vs 33.5% at cycle 2; 37.4% vs 41.8% at cycle 27). Deterioration in fatigue was comparable between both arms at cycles 2 (41.2% vs 41.9%) and 27 (38.0% vs 35.5%), recognized as 2 key time points in the study. A similar overall of treatment between the regimens was reported.

The patient-reported outcomes from the DESTINY-Breast09 trial provide crucial context to the primary efficacy and safety results. The data concludes that T-DXd plus pertuzumab offers durable pain control and allows for the maintenance of physical function, outcomes that are comparable to the standard-of-care THP regimen.

“Patients reported T-DXd and [THP] as similarly tolerable over time,” Mothaffar F. Rimawi, MD, of the Dan L. Duncan Comprehensive Cancer Center and Baylor College of Medicine in Houston, Texas, concluded during the presentation. “The risk of clinically meaningful deterioration was similar, although data are still immature at this interim analysis.”

References

1. Rimawi M, Loibl S, Jiang Z, et al. Trastuzumab deruxtecan (T-DXd) + pertuzumab vs taxane + trastuzumab + pertuzumab (THP) for first-line treatment of patients with HER2+ advanced/metastatic breast cancer: patient-reported outcomes from the DESTINY-Breast09 study. Presentation RF6-07. San Antonio Breast Cancer Symposium. December 10, 2025.
2. 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 the San Antonio Breast Cancer Symposium. December 10, 2025. https://tinyurl.com/28xrar89