DESTINY-Breast09 and Ongoing Trials Underscore Shifting ADC Landscape in HER2+ Breast Cancer

Hope S. Rugo, MD

Results from the phase 3 DESTINY-Breast09 trial (NCT04784715) highlight the increasing push to bring antibody-drug conjugate (ADC)–based regimens into earlier lines of HER2-positive breast cancer management, with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) plus pertuzumab (Perjeta) emerging from DESTINY-Breast09 as a new potential first-line standard of care (SOC), according to Hope S. Rugo, MD. However, she added that data read out thus far from this potentially practice-changing study have prompted critical questions around sequencing strategies, the necessity of pertuzumab, the role of maintenance therapy, and integration with endocrine and CDK4/6 inhibitor therapies to further optimize patient outcomes.

At the 2025 ASCO Annual Meeting, interim findings from DESTINY-Breast09 showed that patients with HER2-positive advanced or metastatic breast cancer treated with first-line T-DXd plus pertuzumab (n = 383) achieved a median progression-free survival (PFS) of 40.7 months (95% CI, 36.5-not calculable [NC]) vs 26.9 months (95% CI, 21.8-NC) with trastuzumab (Herceptin) plus pertuzumab and a taxane (THP; n = 387; HR, 0.56; 95% CI, 0.44-0.71; P < .00001). Notably, this PFS benefit with T-DXd was consistent across all prespecified subgroups.

“Patients [receiving T-DXd plus pertuzumab] had a better response, and patients had a remarkably longer relative improvement in PFS,” Rugo stated in an interview with OncLive®. “Is this how we want to use T-DXd in clinical practice? For which patients? My guess is that the majority of patients we're going to be treating in the metastatic setting will have de novo metastatic disease.”

In the interview, Rugo shared questions and avenues for future investigation generated by the DESTINY-Breast09 trial, discussed key considerations for the potential integration of T-DXd plus pertuzumab into clinical practice, and spotlighted several upcoming or ongoing trials with T-DXd and other ADCs that could bring further change to the treatment paradigm in both early- and later-line settings.

Rugo is a professor in the Department of Medical Oncology & Therapeutics Research, division chief of Breast Medical Oncology, and director of the Women's Cancers Program at City of Hope in Duarte, California.

OncLive: What questions or avenues for future investigation do findings from the DESTINY-Breast09 trial generate?

Rugo: We had already seen that T-DXd was superior to ado-trastuzumab emtansine [Kadcyla; T-DM1] in the [phase 3 DESTINY-Breast03 trial (NCT03529110)], so we had an ADC that was better than our previous, great ADC for HER2-positive disease. We also saw that T-DXd after T-DM1 was superior to our prior standards. Therefore, we all believed that T-DXd would beat THP in DESTINY-Breast09. That wasn’t a surprise.

I still don’t completely understand why [data from] the T-DXd alone arm [from DESTINY-Breast09] are not able to be reported yet. It has to do with events in the different arms. We won’t know that [the addition of] pertuzumab [to T-DXd] is necessary until we see data from that T-DXd [monotherapy] arm, because this was a blinded analysis. A placebo for pertuzumab was given in the T-DXd alone arm. [At the 2025 ASCO Annual Meeting], they reported data for [only] T-DXd plus pertuzumab vs THP. Paclitaxel or docetaxel could be used in THP.

However, exposure to cytotoxic therapy was very different between the arms, and that’s an important differential that we need to understand more about. We didn’t get a lot of data on that in the [ASCO] presentation. We're definitely [going to] look for that in the future.

One of the [things] that we look at is why patients come off [of therapy]. If you look at patients who discontinued trastuzumab in DESTINY-Breast09, more patients [discontinued] due to progressive disease [(52.5%) compared with adverse effects (AEs; 3.4%)]. For T-DXd, [21.3%] stopped T-DXd due to AEs, and [25.8%] discontinued [treatment with a] taxane due to AEs [in the THP arm. Only 3.4% stopped trastuzumab [due to AEs].

What we really want to know is how long patients stayed on T-DXd, because they were allowed to drop that agent and continue on trastuzumab and pertuzumab [if they discontinued for reasons other than progressive disease]. Also, patients were allowed to take endocrine therapy; however, in patients with hormone receptor–positive disease, 38% of patients in the THP arm and only 13.5% in the T-DXd plus pertuzumab arm used endocrine therapy, which is bizarre, because that is our SOC. We’ve seen with data from the [phase 3] AFT-38 PATINA trial [NCT02947685] that showed if you add the CDK4/6 inhibitor palbociclib [(Ibrance) to anti-HER2 therapy and endocrine therapy], you further improve outcomes [for patients with hormone receptor–positive, HER2-positive disease]. Only 8.7% of patients who received T-DXd plus pertuzumab switched to trastuzumab plus pertuzumab after stopping T-DXd for reasons other than progressive disease.

The other part that's important is to look at the patients who received prior trastuzumab. All [patients in DESTINY-Breast09 were] treated in the first-line setting; however, if patients recurred after early-stage disease, you would assume they’d have gotten both trastuzumab and pertuzumab. In actuality, less than 30% of patients in both arms had received prior trastuzumab, less than 10% of patients had ever received pertuzumab, and very few patients had received T-DM1 as adjuvant therapy. That’s fascinating. If you look at how many patients had de novo disease, it was a little over 50% [in both arms].

Based on the data read out thus far from DESTINY-Breast09, what are the potential implications of the findings?

We know how to administer T-DXd, and the mortality [due to interstitial lung disease (ILD)] was 0.5%, which was very encouraging. Two patients died from ILD, and we'd like to make that 0, but this is a small number.

We recently saw a press release from [the phase 3] DESTINY-Breast11 trial [NCT05113251] evaluating T-DXd followed by THP compared with an anthracycline- and THP-based regimen. The press release said they improved pathologic complete response [pCR] rate with [the T-DXd] sequential regimen, which is going to be very appealing in terms of managing AEs and avoiding anthracyclines.2 If the pCR rate translates into an improvement in disease-free survival, [T-DXd followed by THP] will become a SOC for bigger tumors in the neoadjuvant setting. Hopefully, we'll cure more patients.

I suspect that we're going to be adding CDK4/6 inhibitors [to treatment regimens] for patients [with hormone receptor–positive disease], based on the PATINA trial, and moving them to the early-stage setting.

Regarding patients with de novo [metastatic disease], are we going to give them T-DXd plus pertuzumab forever? The next step is to [evaluate] how long we need to treat patients with this regimen. Could we treat them until best response—say, 6 months or so—and then drop T-DXd, substitute trastuzumab, and give endocrine therapy to everybody who has estrogen receptor [ER]–positive disease, potentially with palbociclib? Through that, we may cure more patients with the only curable subset of metastatic breast cancer that we treat. This is an exciting advancement.

How we apply it to clinical practice—other than starting with T-DXd plus pertuzumab if and when it's approved—remains to be seen. The [phase 2] DEMETER trial [NCT06172127] is assessing maintenance therapy with trastuzumab, pertuzumab, and endocrine therapy. What about adding palbociclib [to T-DXd and pertuzumab] in the ER-positive [patient] subset? Hopefully, we'll see those trials opening in the next year, which will help us a lot in both improving outcomes and maintaining quality of life for our patients.

How do you envision the role T-DXd and other ADCs evolving in the management of HER2-positive breast cancer, particularly considering sequencing strategies, the impact of emerging clinical trial data, and the incorporation of newer agents into the paradigm?

Everything's going to change in the next year because we'll see the data from the [phase 3 DESTINY-Breast05 trial (NCT04622319)], which is evaluating T-DM1 vs T-DXd for patients who have residual disease after neoadjuvant therapy, including trastuzumab plus pertuzumab. We know that T-DM1 not only reduced recurrence but improved survival for those patients, although it took a long time to see that [in the phase 3 KATHERINE trial (NCT01772472)]. We suspect that [the adjuvant benefit with] T-DM1 will be inferior to T-DXd; if so, we're going to switch over to give T-DXd to these patients. How that's going to work along with DESTINY-Breast11 remains to be seen; I think T-DM1 will be pushed to the later-line setting.

What happens if a patient has recurrent disease in the metastatic setting? Say they have de novo disease, [then] received T-DXd; if they're on maintenance therapy, which is what I suspect we're all going to do, we would rechallenge with T-DXd. If they then develop progressive disease, we will give T-DM1, but I think it's going to be relegated to at least the third-line setting, because we also have the [phase 2] HER2CLIMB trial [NCT02614794] regimen of capecitabine, trastuzumab, and tucatinib [Tukysa] that we would use next.

[The choice of therapy] is going to be influenced in patients with brain metastases. We know that both T-DXd and tucatinib worked well in patients who didn't need immediate radiation therapy, where we saw shrinkage of brain lesions and better disease control. [If the HER2CLIMB regimen] is going to be our second line, T-DM1 would be [relegated] to the third line or later.

We also have some other HER2-targeted ADCs that are being tested in the later-line setting. Additionally, a new antibody for HER2-positive disease—zanidatamab-hrii [Ziihera]—seems to be very effective and is being tested after T-DXd in the [phase 3] EmpowHER-303 trial [NCT06435429].

There are going to be a lot of changes as we go forward and see the results of these ongoing trials. Will maintenance change in the ER-negative population to trastuzumab plus pertuzumab with tucatinib? That's an ongoing study. Will we treat patients with HER2-positive disease and PIK3CA mutations with alpelisib [Piqray] in the maintenance setting? There are a lot of ongoing studies that may impact what we do in the future after induction with T-DXd plus pertuzumab, if it ends up being the superior arm [to T-DXd monotherapy].

References

1. Tolaney S, Jiang Z, Zhang Q, et al. Trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for first-line (1L) treatment of patients (pts) with human epidermal growth factor receptor 2–positive (HER2+) advanced/metastatic breast cancer (a/mBC): interim results from DESTINY-Breast09. J Clin Oncol. 2025;43(suppl 17):LBA1008. doi:10.1200/JCO.2025.43.17_suppl.LBA1008
2. Enhertu (fam-trastuzumab deruxtecan-nxki) followed by THP before surgery showed statistically significant and clinically meaningful improvement in pathologic complete response in patients with high-risk HER2-positive early-stage breast cancer in DESTINY-Breast11 Phase III trial. Astra Zeneca. News Release. May 7, 2025. Accessed June 9, 2025. https://www.astrazeneca-us.com/media/press-releases/2025/ENHERTU-fam-trastuzumab-deruxtecan-nxki-followed-by-THP-before-surgery-showed-statistically-significant-and-clinically-meaningful-improvement-in-pathologic-complete-response-in-patients-with-high-risk-HER2-positive-early-stage-breast-cancer-in-DESTINY-Breast11-Phase-III-trial.html