TROPION-Breast02 Data Support Dato-DXd as New First-Line SOC in Triple-Negative Breast Cancer

Datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) significantly improved overall survival (OS) and progression-free survival (PFS) compared with investigator’s choice of chemotherapy (ICC) when used as first-line treatment in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) for whom immunotherapy was not an option.1

The primary results from the phase 3 TROPION-Breast02 trial (NCT05374512), shared during the 2025 European Society for Medical Oncology (ESMO) Congress, showed that the median PFS with Dato-DXd (n = 323) was 10.8 months (95% CI, 8.6-13.0) by blinded independent central review (BICR) vs 5.6 months (95% CI, 5.0-7.0) with ICC (n = 321), translating to a 43% reduction in the risk of disease progression or death (HR, 0.57; 95% CI, 0.47-0.69; P < .0001). The 12-month PFS rates in the respective arms were 45.6% and 25.6%, and the rates at 18 months were 32.7% and 16.8%.

The median OS with the antibody-drug conjugate (ADC) was 23.7 months (95% CI, 19.8-25.6) vs 18.7 months (95% CI, 16.0-21.8) with ICC, translating to a 21% reduction in the risk of death (HR, 0.79; 95% CI, 0.64-0.98; P = .0291). The 12- and 18-month OS rates with Dato-DXd were 75.2% and 61.2%, respectively; with ICC, these respective rates were 67.8% and 51.3%.

“[The trial] met both dual primary end points, [with] first-line Dato-DXd demonstrating statistically significant and clinically meaningful improvement in OS and PFS over ICC,” Rebecca Dent, MD, MSc, said in a presentation of the data. “TROPION-Breast02 results support Data-DXd as the new first-line standard of care for patients with locally recurrent inoperable or metastatic TNBC for whom immunotherapy is not an option.” Dent is head of the Department of Medical Oncology at the National Cancer Centre Singapore at SingHealth.

AstraZeneca announced topline survival data from TROPION-Breast02 earlier this month.2

What Unmet Need Does TROPION-Breast02 Address?

Dent opened her presentation by underscoring that advanced or metastatic TNBC is the most aggressive cancer subtype with the fewest available therapeutic options. As such, the 5-year OS rate for those with metastatic disease is only 14.9%.1 Notably, approximately 70% of patients are not candidates for frontline immunotherapy, and for this group, no new first-line approvals have been made in over a decade. These patients receive chemotherapy in the first line, Dent said, and that approach is linked with poor outcomes. Moreover, approximately 50% of patients do not receive treatment beyond the first-line setting, underscoring the need for first-line options, she added.

What Did TROPION-Breast02 Examine?

The open-label, global, randomized phase 3 TROPION-Breast02 study enrolled patients with histologically or cytologically documented locally recurrent inoperable or metastatic TNBC who had not previously received chemotherapy or targeted systemic treatment in the locally recurrent inoperable or metastatic setting. Patients had an ECOG performance status of no greater than 1, and immunotherapy was not an option for them. No minimum disease-free interval (DFI) was required.

Study participants were randomly assigned 1:1 to receive Dato-DXd at 6 mg/kg on day 1 every 3 weeks (n = 323) or ICC in the form of paclitaxel, nab-paclitaxel (Abraxane), capecitabine, eribulin mesylate/eribulin, and carboplatin (n = 321). Stratification factors included geographic region (US/Canada/Europe vs other regions), PD-L1 status (high vs low), and DFI (0-12 months vs ≥12 months). Treatment continued until progressive disease by investigator assessment and RECIST criteria, intolerable toxicity, or other discontinuation criteria were met. Patients were permitted to receive subsequent treatment after disease progression or discontinuation.

In addition to the dual primary end points of the trial being OS and PFS by BICR and RECIST 1.1 criteria, key secondary end points included investigator-assessed PFS, objective response rate (ORR), duration of response (DOR), and safety.

For the dual primary end points, a multiple testing procedure with an alpha-exhaustive recycling strategy was utilized. The study would be considered positive if PFS and/or OS analysis data were statistically significant. The data cutoff date for the primary PFS and final OS analysis was August 25, 2025. At this time point, PFS was at 63% maturity with 408 events observed, and OS was at 54% maturity with 349 events observed. Moreover, 14% and 3% of patients in the Dato-DXd and ICC arms, respectively, were still receiving treatment. The median follow-up was 27.5 months (range, 13.3-38.7).

What Do We Know About the Demographic and Baseline Characteristics of Patients Enrolled to TROPION-Breast02?

The median patient age was 56 years (range, 27-85) in the ADC arm vs 57 years (range, 23-83) in the ICC arm. Almost all patients were female (100%; 99%), and more than half were from geographic regions beyond the US, Canada, or Europe (63%; 63%), with an ECOG performance status of 0 (60%; 57%). In the Dato-DXd arm, 47% of patients were Asian, 41% were White, 9% were other, and 4% were Black or African American. In the ICC arm, 48% of patients were White, 41% were Asian, 7% were other, and 4% were Black or African American.

In terms of DFI history, in the Dato-DXd arm, 34% had de novo disease, 21% had a prior DFI ranging from 0 to 12 months, 15% had a prior DFI ranging from 0 to 6 months, and 46% had a prior DFI longer than 1 year; in the ICC arm, these rates were 34%, 21%, 16%, and 45%, respectively. Regarding PD-L1 status, in the ADC arm, 89% of patients had a combined positive score (CPS) of 10 or lower, and 11% had a CPS of 10 or higher; in the ICC arm, these rates were 91% and 9%, respectively. Most patients across the Dato-DXd and ICC arms had visceral metastases (78%; 73%), and about one-third had liver metastases (29%; 31%). In the respective arms, 11% and 9% of patients had brain metastases. More than half of patients had fewer than 3 metastatic sites (64%; 67%).

The preselected choice of chemotherapy for the Dato-DXd arm was nab-paclitaxel for 56% of patients, paclitaxel for 25%, eribulin mesylate/eribulin for 13%, carboplatin for 3%, and capecitabine for 2%; in the ICC arm, these rates were 54%, 29%, 11%, 4%, and 2%.

What Additional Efficacy Data Were Reported with Dato-DXd?

The investigator-assessed PFS with the ADC was 9.6 months (95% CI, 7.4-11.2) vs 5.2 months (95% CI, 4.2-5.6) with ICC, consistent with the findings reported by BICR (HR, 0.56; 95% CI, 0.47-0.67). The 12-month PFS rate with Dato-DXd was 40.7% vs 18.5% with ICC; the respective 18-month rates were 27.5% and 9.2%.

Dato-DXd elicited a confirmed ORR of 62.5% compared with 29.3% with ICC, representing a difference of 33.2% between the arms (OR, 4.24; 95% CI, 3.03-5.95). In the ADC arm, 9.0% of patients had a complete response (CR) as their best overall response, 53.6% had a partial response, and 26.9% had stable disease; 8.4% of patients experienced disease progression, and 2.2% were not evaluable. “With Dato-DXd, confirmed ORR was more than double that with ICC, and [the] confirmed CR rate was more than 3 times that with ICC,” Dent said.

The median DOR with Dato-DXd was 12.3 months (95% CI, 9.1-15.9) compared with 7.1 months (95% CI, 5.6-8.9) with ICC, translating to a 5.2-month difference.

What Was the Safety Profile of Dato-DXd in Locally Recurrent Inoperable or Metastatic TNBC?

The median treatment duration with the ADC was 8.5 months (range, 0.7-38.0) vs 4.1 months with ICC (range, 0.1-32.0). Any-grade treatment-related adverse effects (TRAEs) occurred in 93% of patients in the Dato-DXd arm (n = 319) compared with 83% of those in the ICC arm (n = 309); the rates of grade 3 or higher TRAEs were 33% and 29%, respectively. Serious TRAEs were reported in 9% of those who received Dato-DXd and in 8% of those given ICC. In the ADC arm, TRAEs led to dose interruption or reduction for 24% and 27% of patients, and treatment discontinuation for 4% of patients; in the ICC arm, TRAEs resulted in dose interruption, dose reduction, or treatment discontinuation in 19%, 18%, and 7% of patients, respectively.

“Despite more than double the median duration of treatment in the Dato-DXd arm, rates of grade 3 or higher and serious TRAEs were similar, and discontinuations were lower with Dato-DXd [than with] ICC,” Dent underscored.

In the Dato-DXd arm, the most common TRAEs reported in at least 15% of patients included dry eye (any grade, 24%; grade ≥ 3, 1%), stomatitis (57%; 8%), nausea (45%; < 1%), constipation (23%; < 1%), vomiting (20%; 1%), decreased appetite (15%; < 1%), neutropenia (12%; 3%), anemia (15%; 2%), leukopenia (8%; < 1%), peripheral neuropathy (4%; 0%), alopecia (41%; 0%), and fatigue (32%; 3%).

For the ADC, TRAEs of special interest included oral mucositis or stomatitis (grade 1, 24%; grade 2, 27%; grade ≥ 3, 8%). These effects resulted in dose interruption for 3% of patients and dose reduction for 11% of patients. For 90% of patients, grade 2 or higher effects resolved to grade 1 or lower at the time of data cutoff. Other TRAEs of special interest included dry eye (grade 1, 16%; grade 2, 7%; grade 3, 1%), keratitis (7%; 4%; 2%), and conjunctivitis (2%; 4%; <1%). These effects resulted in dose interruption for 6% of patients, dose reduction for 4% of patients, and discontinuation for fewer than 1% of patients. In 67% of patients with grade 2 or higher TRAEs, their toxicities resolved to grade 1 or lower. Adjudicated drug-related interstitial lung disease or pneumonitis (grade 1, <1%; grade 2, 2%; grade 3, <1%) was also reported.

“The Dato-DXd safety profile was manageable and generally consistent with the known profile,” Dent said.

Disclosures: Dent serves in a consulting or advisory role for AstraZeneca, Daiichi Sankyo/AstraZeneca, Eisai, Gilead Sciences, MSD, Novartis, Pfizer, and Roche. She received travel, accommodation, and expense support from AstraZeneca, Daiichi Sankyo/AstraZeneca, Eisai, MSD, Novartis, Pfizer, and Roche. She received honoraria from AstraZeneca, Daiichi Sankyo/AstraZeneca, DKSH, Eisai, Gilead Sciences, MSD, Novartis, Pfizer, and Roche. Research funding to her institution was received by Roche and AstraZeneca.

References

1. Dent RA, Shao Z, Schmid P, et al. First-line datopotamab deruxtecan (Dato-DXd) vs chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) for whom immunotherapy was not an option: primary results from the randomised, phase 3 TROPION-Breast02 trial. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA21.
2. Datroway (datopotamab deruxtecan-dlnk) demonstrated statistically significant and clinically meaningful improvement in overall survival as 1st-line therapy for patients with metastatic triple-negative breast cancer for whom immunotherapy was not an option in TROPION-Breast02. News release. AstraZeneca. October 6, 2025. Accessed October 19, 2025. https://www.astrazeneca-us.com/media/press-releases/2025/DATROWAY-datopotamab-deruxtecan-dlnk-demonstrated-statistically-significant-and-clinically-meaningful-improvement-in-overall-survival-as-1st-line-therapy-for-patients-with-metastatic-triple-negative-breast-cancer-for-whom-immunotherapy-was-not-an-option-in-TROPION-Breast02.html