Which Tx Combo Is Best for HER2+ Breast Cancer?

The combination of trastuzumab deruxtecan (Enhertu) with pertuzumab (Perjeta) as a first-line treatment for HER2-positive advanced metastatic breast cancer has been shown to reduce the risk for disease progression or death by more than the current standard-of-care treatment.

Sara Tolaney, MD, MPH, of the Dana-Farber Cancer Institute in Boston, presented this finding and other interim results of the phase 3 DESTINY-Breast09 study, at the American Society of Clinical Oncology (ASCO) 2025 annual meeting in Chicago.

“Trastuzumab deruxtecan, or T-DXd, in combination with pertuzumab demonstrated a statistically significant and clinically meaningful improvement in progression-free survival, with a 44% reduction in the risk of disease progression or death when compared to a taxane, trastuzumab, and pertuzumab (THP),” said Tolaney, during her presentation.

New First-line Standard?

Similar results were observed across all patient subgroups, with no new safety signals, Tolaney said.

“These data suggest that T-DXd and pertuzumab may represent a new first-line standard of care for patients with metastatic HER2-positive breast cancer,” she said.

The study randomized 1157 patients to three treatment groups: T-DXd 5.4 mg/kg every three weeks plus placebo, T-DXd-pertuzumab, or a taxane plus trastuzumab with pertuzumab (THP). The interim study readout includes only data from the T-DXd-pertuzumab and the taxane plus trastuzumab with pertuzumab groups.

Pertuzumab + T-Dxd or Standard of Care?

Median progression-free survival (PFS) was 40.7 months in the T-DXd-pertuzumab patients and 26.9 months in the taxane plus trastuzumab with pertuzumab patients (P < .00001).

Tolaney explained that the study was designed to have an interim analysis for PFS after approximately 399 events across the three arms with at least 277 events for comparison. At the time of the interim analysis, she said, only the TDX-pertuzumab and THP groups met the criteria for superiority, a P-value < .00043, which was not met for the comparison of T-DXd plus placebo to THP. The T-DXd-placebo arm remains blinded until the final progression-free survival analysis, Tolaney said.

Twenty-one percent of the patients in the T-DXd-pertuzumab arm had discontinued T-DXd due to adverse events, Tolaney said; 9% of patients elected to continue with trastuzumab and pertuzumab after they discontinued T-DXd.

Among hormone receptor-positive patients, 13.5% in the T-DXd-pertuzumab group and 38% in the THP group elected to add endocrine treatment. At the data cutoff, 46% of the T-DXd-pertuzumab patients and 33% of those in the THP group remained on study treatment. Median follow-up duration was 29 months.

The treatment effect of T-DXd-pertuzumab became evident early in the study, Tolaney said. Six months after starting treatment, 7% of the T-DXd-pertuzumab group vs 12% of the THP group had progressed. The gap continued to widen over time, she said. 

“With 26% of patients still on steady treatment with T-DXd and pertuzumab, it suggests that this median is likely to evolve with further follow-up,” she said. 

Objective response rates were also higher with T-DXd–pertuzumab, 86% vs 79% with THP, Tolaney said. 

“The complete response rate for T-DXd and pertuzumab was 15%, which was almost double what was seen with THP (8.5%),” she said. Response duration was also longer with T-DXd-pertuzumab, with 73% remaining in response at 24 months vs 55% in the THP arm. 

“Overall survival data are very immature at this timepoint with just 16% of survival events seen, but you can see that there is an early trend favoring T-DXd plus pertuzumab with a hazard ratio of 0.84,” she said. 

A similar number of patients in both groups had serious treatment-emergent adverse events: 27% for T-DXd-pertuzumab and 25.1% for THP, which Tolaney said, was consistent with the known toxicity profiles of both agents, with no new toxicities identified.

The median duration of treatment in the DESTINY-Breast09 study was 21 months. 

‘A Pivotal Advancement?’

Rebecca Dent, MD, deputy CEO at the National Cancer Center Singapore, called the DESTINY-Breast09 results “a pivotal advancement in the treatment of HER2-positive metastatic breast cancer that is both clinically and statistically significant.”

HER2-positive metastatic breast cancer was once considered a “death sentence,” Dent said at a press conference, but now patients can survive on therapy for years, which presents its own challenges.

Regarding the T-DXd-plus-pertuzumab regimen, Dent said, “Is this for all patients at the beginning of their treatment for metastatic disease?” The truth of the matter is we don’t know.”

Having better biomarkers would provide answers, she said, but for patients with extensive disease with central nervous system metastasis, pertuzumab in combination with other agents “is clearly your first-line choice.”

How to best sequence therapies is another challenge emerging with these evolving treatment regimens, Dent added. “And then I think finally we do have to appreciate that there are toxicities: One in terms of quality of life but also cost toxicity,” she said. 

Which Therapeutic Regimen Costs More?

Tolaney acknowledged the cost implications of adding pertuzumab to T-DXd, in an interview with Medscape Medical News.

“But I would also note,” Tolaney said, “that the standard-of-care arm does involve getting continued trastuzumab and pertuzumab therapy.”

In the PATINA study, which added palbociclib (Ibrance) to standard maintenance therapy in patients with HER2-positive metastatic breast cancer, the cost profile was similar to those of the treatments used in the newer trial, Tolaney said.

“You are looking at substantial continued cost because we’re continuing to suppress the HER2 pathway for years in these patients,” she said.

AstraZeneca and Daiichi Sankyo funded the study. Tolaney reported financial relationships with ADi, Ambrx, Artios Biopharmaceuticals, Arvinas, AstraZeneca, Bayer, BeiGene, Bicycle Therapeutics, BioNTech, Blueprint Medicines, Bristol Myers Squibb, Circle Pharma, Cullinan Oncology, Daiichi Sankyo, eFFECTOR Therapeutics, Eisai, Exelixis, Genentech, Gilead Sciences, Hengrui Pharmaceutical (USA), Immunomedics/Gilead, Incyte, Jazz Pharmaceuticals, Johnson & Johnson, Launch Therapeutics, Lilly, Menarini Group, Merck, Mersana, NanoString Technologies, Natera, Novartis, OncoPep, Pfizer, Reveal Genomics, Sanofi, Seagen, Sumitovant Biopharma, Summit Therapeutics, Systimmune, Tango Therapeutics, Zentalis, Zuellig Pharma, and Zymeworks. 

Dent reported having financial relationships with AstraZeneca, Daiichi Sankyo/Astra Zeneca, DKSH, Eisai, Gilead Sciences, Merck Sharpe and Dohme, Novartis, Pfizer, and Roche.

Richard Mark Kirkner is a medical journalist based in Philadelphia.