compared to standard chemotherapy in patients with inoperable or metastatic HR+/HER2‒ breast cancer [1], according to results from the TROPION-Breast01 (NCT05104866) study, a global, phase 3, open-label, randomised study [2]. Prof. Marc Thill shared his perspective on the trial design, key outcomes, and the clinical implications of these findings. Could you briefly outline the design of TROPION-Breast01?
“TROPION-Breast01 enrolled adult patients with inoperable or metastatic HR+/HER2‒ breast cancer, who had progressed following endocrine or endocrine-based therapy. All participants had received one or two prior lines of chemotherapy and/or another ADC, making this a second-line treatment breast cancer population that you typically see in daily practice. A total of 732 participants were randomised 1:1 to either Dato-DXd or investigator’s choice of chemotherapy (ICC). The primary endpoints were PFS and overall survival (OS).”
How would you interpret the efficacy results?
“After a median follow-up of 10.8 months, Dato-DXd reduced the risk of disease progression or death by 37% compared to ICC. Mean PFS was 6.9 months vs 4.9 months (HR 0.63; 95% CI 0.52-0.76; P<0.0001), a statistically significant and clinically meaningful improvement. This benefit was consistent across prespecified subgroups. While OS data are not yet mature, there was a numerical trend favouring Dato-DXd: median OS was 18.6 versus 18.3 months (HR, 0.84; 95% CI 0.62-1.14).”
“We must consider that many patients in the control arm received innovative therapies rather than conventional chemotherapy, which could reduce the observed OS difference. In fact, 14.2% of patients in the ICC arm received a subsequent ADC, compared to only 4.1% in the Dato-DXd arm. Additionally, nearly 2.5 times more patients remained on treatment with Dato-DXd compared with ICC at data cut-off.”
“If Dato-DXd was compared to conventional chemotherapy options alone, there would certainly have been a difference in OS survival. All in all, it is good to have Dato-DXd as an extra option for patients who do not qualify for another endocrine-based therapy.”
What can you say about the safety profile of Dato-DXd?
“The safety and tolerability of Dato-DXd were manageable, with a longer median treatment duration for Dato-DXd (6.7 months vs 4.1 months). Treatment-related AEs (TRAEs) occurred in 93.6% and 86.3% of patients in the Dato-DXd and ICC group, respectively. However, serious TRAEs were lower with Dato-DXd (5.8% vs 9.1%).
“Common TRAEs included nausea (51.1% vs 23.6%), stomatitis (50% vs 13.1%), and alopecia (36.4% vs 20.5%). Importantly, neutropenia occurred less frequently in the Dato-DXd arm (10.8% vs 42.5%). Dry eyes, seen in about 20% of participants on Dato-DXd, were impactful but generally manageable with artificial tears. Stomatitis also responded well to prophylactic mouthwashes, such as dexamethasone-based rinses. Proactive management of these adverse events was key, and once patients and clinical teams gained experience with the treatment, tolerability proved to be predictable and acceptable”
How did the participants respond to the dosing schedule?
“Participants appreciated the once-every-3-weeks (Q3W) schedule and the ease of administration. Less frequent hospital visits improve patient quality-of-life, particularly for those living far from treatment centres. This is an advantage over sacituzumab govitecan (Trodelvy®), which is administered on days 1 and 8 of each 3-week cycle, and has a higher incidence of neutropenia.”
How would you compare Dato-DXd to sacituzumab govitecan?
“In our practice, we often consider Dato-DXd as the preferred first option due to its tolerability and simpler schedule, especially in patients who are not suitable for further endocrine therapy. Sacituzumab govitecan remains an important alternative, particularly for those with more extensive prior chemotherapy. However, its more intensive schedule and higher rates of neutropenia can make it more demanding for both patients and physicians.”
“We sometimes use Dato-DXd first, then follow with sacituzumab govitecan if needed. The choice also depends on prior toxicities like peripheral neuropathy, which may guide us toward Dato-DXd to avoid worsening of symptoms. As more data become available, particularly on ADC sequencing, these decisions will become more refined.”
What do you see for the future of Dato-DXd?
“Dato-DXd has also shown promise not only in HR+/HER2-disease but also in triple-negative breast cancer (TNBC). Several ongoing phase 3 trials are evaluating its role in adjuvant, neoadjuvant, and post-neoadjuvant settings. Sequencing strategies will become increasingly important as more ADCs are approved. Differences in efficacy, toxicity, and quality-of-life will help guide decisions. For now, Dato-DXd is a valuable new option for patients who are no longer candidates for endocrine-based therapy.”
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