Two breast cancer drugs match on progression control, but only one shows a survival benefit

Two antibody-drug conjugates targeting Trop-2 are now approved for overlapping use in chemotherapy-pretreated hormone receptor-positive, HER2-negative metastatic breast cancer, yet no head-to-head trial has ever compared them, and none is currently registered. A new systematic review and indirect treatment comparison, published in BMC Cancer, set out to answer the question clinicians face at the bedside: when both options are available, which drug should be prioritized?

The research team, led by Xiang Lv, followed PRISMA 2020 guidance and searched PubMed and Cochrane CENTRAL from January 2012 to December 2025 for phase III randomized trials comparing sacituzumab govitecan (SG) or datopotamab deruxtecan (Dato-DXd) with investigator’s choice chemotherapy in this patient population. Eligibility was restricted to chemotherapy-pretreated patients; trials in chemotherapy-naive cohorts were excluded because prior chemotherapy exposure may modify treatment effects and violate exchangeability. Only peer-reviewed full reports were included, so that every value entering the analysis could be traced to a source stating the denominator, analysis population, and ascertainment method.

Three trials covering 1606 patients met the inclusion criteria. The researchers assessed bias risk with the Cochrane RoB 2 tool, derived indirect estimates through the Bucher method using the common chemotherapy comparator, and rated certainty pairwise with GRADE. Sensitivity analyses addressed three analytic decisions capable of changing the conclusion: the use of crossover-adjusted Dato-DXd overall survival, investigator-assessed SG progression-free survival, and fixed-effect pooling. All analyses used trial-level summary data, and the study was not prospectively registered.

On progression-free survival, the two drugs proved remarkably similar. Both ADCs improved PFS versus chemotherapy: pooled SG achieved a hazard ratio of 0.66 (95% CI 0.56–0.79; GRADE high certainty), while Dato-DXd reached 0.63 (0.52–0.76; moderate certainty). The indirect comparison showed no difference between the drugs, with a hazard ratio of 1.05 (0.82–1.36; p = 0.68), and substituting investigator-assessed PFS did not alter the conclusion (HR 1.08).

Overall survival told a different story. SG showed a benefit, with a pooled hazard ratio of 0.74 (0.61–0.90; p = 0.002; GRADE moderate certainty), whereas the final analysis of the TROPION-Breast01 trial showed no Dato-DXd benefit, with a hazard ratio of 1.01 (0.83–1.22; p = 0.94). Notably, the final TROPION-Breast01 analysis reversed the direction of its overall survival conclusion relative to the interim estimate, a shift the authors highlight as a caution for interpreting interim data.

The indirect overall survival comparison, however, hinged on a single analytic decision. Using the unadjusted Dato-DXd estimate, the comparison nominally favored SG (HR 0.73; 0.56–0.96; p = 0.024), but with the crossover-adjusted estimate the result was nonsignificant (HR 0.86; 0.65–1.14; p = 0.29). The GRADE certainty for this indirect overall survival comparison was rated very low, underscoring how fragile the apparent ranking is.

Toxicity profiles largely did not overlap, and the differences were striking. SG was associated with grade 3 or higher neutropenia in 58.2% of patients and grade 3 or higher diarrhea in 8.8%, versus 1.1% and 0% for Dato-DXd. In the opposite direction, Dato-DXd produced grade 3 or higher stomatitis in 6.4% of patients and any-grade ocular-surface events in 43.9%. Because the source reports differed in adverse-event scope and ophthalmology monitoring requirements, the authors caution that these safety comparisons represent upper bounds on the true differences.

The authors conclude that the two drugs are comparable in progression control, and that the overall survival difference is an evidence-level difference rather than a demonstrated ranking: SG has direct randomized evidence supporting an overall survival benefit, Dato-DXd does not, and the indirect overall survival comparison is insufficient to rank the two against each other. Until head-to-head data become available, they recommend that drug choice be driven by toxicity susceptibility.

Specifically, the review suggests selecting Dato-DXd when myelosuppression risk is dominant and G-CSF prophylaxis is unavailable or contraindicated, and selecting SG when mucosal or ocular vulnerability dominates. The authors add an important caveat: SG trials did not systematically assess stomatitis and ocular events, so its apparent safety advantage applies only to the measured range of outcomes. The findings arrive as clinicians continue to weigh two agents with no direct comparative trial in sight, making structured indirect evidence a practical, if imperfect, guide for treatment sequencing.

Subject of Research: An indirect comparison of sacituzumab govitecan and datopotamab deruxtecan in chemotherapy-pretreated HR-positive, HER2-negative metastatic breast cancer

Article Title: Sacituzumab govitecan versus datopotamab deruxtecan for chemotherapy-pretreated HR-positive, HER2-negative metastatic breast cancer: a systematic review and indirect treatment comparison

Article References: Lv, X., Cao, B., Yang, X., & Yang, Y. (2026). Sacituzumab govitecan versus datopotamab deruxtecan for chemotherapy-pretreated HR-positive, HER2-negative metastatic breast cancer: a systematic review and indirect treatment comparison. BMC Cancer. https://doi.org/10.1186/s12885-026-16936-w

Image Credits: AI Generated

DOI: 10.1186/s12885-026-16936-w

Keywords: metastatic breast cancer, sacituzumab govitecan, datopotamab deruxtecan, antibody-drug conjugates, systematic review, indirect treatment comparison, progression-free survival, overall survival, TROPION-Breast01, drug toxicity, HR-positive, HER2-negative