A clinically meaningful progression-free survival (PFS) benefit was observed with Enhertu (fam-trastuzumab deruxtecan-nxki) plus Perjeta (pertuzumab), despite prior treatment, hormone receptor status, or PIK3CA mutations, when compared versus Taxol, trastuzumab and Perjeta (THP), for patients with HER2-positive advanced or metastatic breast cancer. The results were presented as a subgroup analysis for the phase 3 trial at the 2025 ESMO Congress.
What was the DESTINY-Breast09 Study Prior Treatment Status?
The PFS assessment for prior treatment status looked at those with de novo disease or recurrent disease. The median PFS for patients with de novo disease and treated with Enhertu plus Perjeta was not calculable (NC) compared versus 31.2 months for patients treated with THP. The PFS for those with recurrent disease in the Enhertu plus Perjeta arm was 38 months and 22.5 months for those in the THP arm.
The confirmed objective response rate (cORR) for patients with de novo disease receiving Enhertu plus Perjeta (200 patients) was 90.5% with 16.5% of patients having a complete response (CR) and 74% having a partial response (PR) versus 82% in the THP arm (200 patients) and 6.5% having a CR and 75.5% having a PR. For those with recurrent disease, the cORR for those with de novo disease (183 versus 187) was 79.2% with 13.7% having a CR and 65.6% having a PR versus a cORR of 74.9% with 10.7% having a CR and 64.2% having a PR.
The median duration of response (DOR) for de novo disease in the Enhertu plus Perjeta arm was 39.2 months versus 31.3 months for those in the THP arm. For those with recurrent disease, the median DOR was 35.3 months versus 21.9 months in the THP arm.
Baseline characteristics for those with de novo disease in the Enhertu plus Perjeta arm compared versus the THP arm was an ECOG performance status of zero (68% versus 60.5%), brain metastases (5% versus 3.5%), visceral metastases (73% versus 68.5%), hormone receptor positive status (56% versus 53%), and PIK3CA mutations not detected (73% versus 72.5%). For those with recurrent disease, the characteristics included an ECOG performance status of zero (65.6% versus 66.8%), brain metastases (8.2% versus 8%), visceral metastases (73.8% versus 70.1%), hormone receptor positive status (51.9% versus 55.1%), and PIK3CA mutations not detected (65.6% versus 64.7%).
For those with de novo or recurrent disease, any treatment-emergent side effects occurred in 100% versus 99.4% of patients in the Enhertu arm versus 99% versus 98.9% in the THP arm. Side effects of grade 3 or higher were noted in 57% versus 52.5% in the Enhertu arm and 51% versus 53.8% in the THP arm. Any side effects leading to discontinuation occurred in 23% versus 18.2% of patients in the Enhertu arm versus 33.3% versus 22.8% in the THP arm. Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis occurred in 14.5% versus 9.4% in the Enhertu arm and 1% versus 1.1% in the THP arm.
Hormone Receptor Status
The median PFS for patients who were hormone receptor-positive was 38 months in the Enhertu plus Perjeta arm and 27.7 months for patients in the THP arm. For patients who were hormone receptor-negative, the median PFS in the Enhertu plus Perjeta arm was 40.7 months versus 22.6 months in the THP arm.
“Patients with [hormone receptor-positive disease] could receive concurrent [endocrine therapy] benefit after six cycles of Enhertu or discontinuation of Taxol [therapy], which occurred in 13.5% [of patients in the Enhertu plus Perjeta arm] versus 38.3% [in the THP arm],” Dr. Sibylle Loibl, chair of the German Breast Group and the Chief Executive Officer, and associate professor of obstetrics and gynecology at the Goethe University of Frankfurt, said in the presentation.
Regarding cORR for patients with hormone receptor-positive disease in the Enhertu plus Perjeta arm (207 patients) was 81.2%, with 14.5% of patients having a CR and 66.7% having a PR. In the THP arm (209 patients), the cORR was 77% with 7.2% of patients having a CR and 69.9% having a PR. For patients with hormone receptor-negative disease, the cORR in the Enhertu plus Perjeta arm (176 patients) was 89.8%, with 15.9% of patients having a CR and 73.9% having a PR. In the THP arm (178 patients), the cORR was 80.3% with 10.1% of patients having a CR and 70.2% having a PR.
The median DOR for patients with hormone receptor-positive disease receiving Enhertu plus Perjeta was 35.3 months versus 26.4 months for patients in the THP arm. For those with hormone receptor-negative disease, the median DOR in the Enhertu plus Perjeta arm was 39.2 months versus 26.3 months in the THP arm.
Baseline characteristics for patients who are hormone receptor-positive in the Enhertu plus Perjeta versus THP arms included an ECOG performance status of zero (68.1% versus 61.7%), brain metastases (4.8% versus 3.3%), visceral metastases 71% versus 67.5%), de novo disease (54.1% versus 50.7%), and PIK3CA mutations not detected (70.5% versus 69.4%). For patients who are hormone receptor-negative, the baseline characteristics included an ECOG performance score of zero (65.3% versus 65.7%), brain metastases (8.5% versus 8.4%), visceral metastases (76.1% versus 71.3%), de novo status (50% versus 52.8%), recurrent status (50% versus 47.2%), and PIK3CA mutations not detected (68.2% versus 68%).
Regarding safety for hormone receptor-positive and hormone receptor-negative status, any treatment-emergent side effects occurred in 100% versus 99.4% in the Enhertu arm and 98.1% versus 100% in the THP arm; and side effects of grade 3 or higher occurred in 52.4% versus 57.7% in the Enhertu arm and 52.7% versus 52% in the THP arm; serious treatment-emergent side effects were noted in 28.2% versus 25.7% compared versus 29% versus 20.6%; treatment-emergent side effects leading to discontinuation occurred in 17% versus 25.1% and 27.1% versus 29.7%; and adjudicated drug-related ILD/pneumonitis occurred in 9.7% versus 14.9% and 0.5% versus 1.7%, respectively.
PIK3CA Mutation Status of the DESTINY-Breast09 Study
The median PFS for patients with PIK3CA mutations was 36.0 months versus 18.1 months in both arms, respectively. For those with PIK3CA not detected, the median PFS was 40.7 months for patients in the Enhertu plus Perjeta arm and 32.7 months in the THP arm.
The cORR for patients with PIK3CA mutations in the Enhertu plus Perjeta arm (116 patients) was 81% with 14.7% of patients having a CR and 66.4% having a PR versus a cORR of 73.6% in the THP arm (121 patients) with 4.1% having a CR and 69.4% having a PR. For those who did not have PIK3CA mutations detected, the cORR was 87.2% with 15.4% having a CR and 71.8% having a PR in the Enhertu plus Perjeta arm (266 patients) versus 80.8% with 10.5% having a CR and 70.3% having a PR in the THP arm (266 patients).
The median DOR for patients with PIK3CA mutations was 34.8 months in the Enhertu plus Perjeta arm versus 18.4 months in the THP arm. For those with PIK3CA mutations not detected, the median DOR was 39.2 months versus NC.
Baseline characteristics for patients with PIK3CA mutations between either arm included an ECOG performance status of zero (61.2% versus 62.8%), brain metastases (6.9% versus 5%), visceral metastases (64.7% versus 63.6%), recurrent disease status (53.4% versus 54.5%), and hormone receptor positive status (52.6% versus 52.9%). For those with PIK3CA mutations not detected, characteristics included an ECOG performance status of zero (69.5% versus 63.9%), brain metastases (6.4% versus 6%), visceral metastases (77.1% versus 71.8%), de novo disease (54.9% versus 54.5%), and hormone receptor positive status (54.9% versus 54.5%).
For those with PIK3CA status detected or not detected, any treatment-emergent side effects occurred in 100% versus 99.6% in the Enhertu arm and 99.2% versus 98.9% in the THP arm; grade 3 or higher treatment-emergent side effects occurred in 53% versus 55.8% and 45% versus 55.7%; treatment-emergent side effects leading to discontinuation in 17.4% versus 22.3% and 24.2% versus 30.2%; and adjudicated drug-related ILD/pneumonitis in 9.6% versus 13.2% and 2.5% versus 0.4%, respectively.
What was the DESTINY-Breast09 Study Design
Patients were randomly assigned one to one to one to either Enhertu plus placebo (blinded until the PFS analysis; 387 patients), Enhertu plus Perjeta (383 patients), or THP (387 patients). This analysis focused on the Enhertu plus Perjeta and THP arms.
The primary end point was PFS by blinded independent central review, with secondary end points including overall survival, PFS by investigator, objective response rate (ORR) by blinded independent central review/investigator, DOR, PFS-2 by investigator, and safety and tolerability.
The investigators noted that if patients discontinued Enhertu due to side effects except for higher than grade 2 interstitial lung disease, patients could switch to trastuzumab. For patients with hormone receptor-positive disease, concurrent use of endocrine therapy was allowed after six cycles of Enhertu or who discontinued Taxol.
Patients were enrolled if they had first-line HER2-positive advanced/metastatic breast cancer; a disease-free interval of six months or more from last neoadjuvant or adjuvant therapy; one prior line of endocrine therapy for advanced/metastatic breast cancer; and asymptomatic brain metastases were allowed.
Reference
“Enhertu (T-DXd) + Perjeta versus Taxol + trastuzumab + Perjeta (THP) for patients with HER2+ advanced/metastatic breast cancer: additional analyses of DESTINY-Breast9 in key subgroups of interest,” by Loibl S, Jiang Z, Barroso-Sousa R, et al Presented at the European Society for Medical Oncology Congress 2025, October 17–21, 2025; Berlin, Germany. LBA18.
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