Findings from the DESTINY-Breast09 trial showed that first-line trastuzumab deruxtecan combined with pertuzumab significantly improved progression-free survival in patients with HER2-positive locally advanced or metastatic breast cancer compared with the standard regimen of trastuzumab, pertuzumab, and a taxane. The benefit was observed regardless of hormone receptor status, and the results have led to trastuzumab deruxtecan becoming a frontline treatment option alongside the established combination of trastuzumab, pertuzumab, and a taxane.

The DESTINY-Breast09 trial did not evaluate maintenance therapy regimens, leaving questions about how long patients should remain on trastuzumab deruxtecan. "There's a lot of movement," said Dr. Erika Hamilton of the Sarah Cannon Research Institute in Nashville, Tennessee. "I think the biggest question right now is whether everyone is going to receive trastuzumab deruxtecan in combination with pertuzumab up front, or whether some patients are still appropriate for taxane, trastuzumab, and pertuzumab." Hamilton, who was the principal investigator of the phase III HER2CLIMB-05 trial, noted concerns about indefinite use of trastuzumab deruxtecan, an active drug that patients may take for years.

Hamilton explained that an alternative approach involves limited taxane exposure: "Plus, [there is] the advantage of being able to do something like THP where we do six to eight cycles of the taxane and drop that out, and then the patient's just on maintenance antibodies." She added, "That's very tolerable for my patient -- my patient gets to be cytotoxic free." Interstitial lung disease is a side effect of special interest associated with trastuzumab deruxtecan, which may influence treatment decisions.

Concurrent advances in maintenance therapy come from the HER2CLIMB-05 trial, which showed that adding the tyrosine kinase inhibitor tucatinib to first-line maintenance therapy with trastuzumab and pertuzumab significantly improved progression-free survival compared with placebo plus trastuzumab and pertuzumab. In that trial, progression-free survival was 24.9 months in the tucatinib group versus 16.3 months in the placebo group, with a p-value of less than 0.0001. This benefit was also observed regardless of hormone receptor status.

For patients with hormone receptor-positive disease, palbociclib is another option, as evaluated in the PATINA study. "We also have palbociclib [Ibrance] for the HR-positive subset [evaluated in the PATINA study]," Hamilton said. Beyond first-line treatment, options for patients who progress include trastuzumab emtansine and the HER2CLIMB regimen of tucatinib, trastuzumab, and capecitabine. Dr. Mariana Chavez MacGregor of the University of Texas MD Anderson Cancer Center in Houston noted that treatment options after first-line therapy with the DESTINY-Breast09 regimen have not been formally evaluated. "But, again, this regimen was evaluated in a different setting," she said.

Chavez MacGregor emphasized individualized care: "We're taking into account patients' condition, performance status, comorbidities, and, of course, preferences." She added, "And we have to take into account the tolerance to side effects." The HER2CLIMB trial previously demonstrated that adding tucatinib to trastuzumab and capecitabine improved both progression-free and overall survival in heavily pretreated patients, including those with brain metastases. That regimen is now listed as a preferred second- or third-line option in National Comprehensive Cancer Network guidelines.

Older tyrosine kinase inhibitors like lapatinib and neratinib are less commonly used now. "The reality is that if a patient already was treated with tucatinib -- which is a much more effective tyrosine kinase inhibitor -- the chances of us using some of these other molecules are less," Chavez MacGregor said. She described the standard treatment path as continuing to target the HER2 pathway while combining chemotherapy: "We will continue to try to target the HER2 pathway, and then combine the chemotherapy. That would be kind of the more standard journey."

Why It Matters

HER2-positive breast cancer accounts for about 15% to 20% of all breast cancer cases and historically carried a poor prognosis before the advent of targeted therapies. The DESTINY-Breast09 results, alongside findings from HER2CLIMB-05 and earlier trials like DESTINY-Breast03, are reshaping first-line treatment standards. Trastuzumab deruxtecan, an antibody-drug conjugate consisting of the monoclonal antibody trastuzumab linked to the topoisomerase I inhibitor deruxtecan, has already replaced trastuzumab emtansine as the default second-line therapy based on prior trial data.

These developments offer more effective options earlier in treatment, potentially delaying disease progression and improving quality of life. However, unanswered questions remain about optimal sequencing, long-term tolerability, and post-progression strategies, highlighting the need for ongoing research and personalized clinical decision-making.