How is antibody-drug conjugate sequencing changing treatment for metastatic breast cancer?

How much benefit does a second ADC actually provide?

The blunt answer: a second ADC is less effective than the first. Across multiple real-world studies, the median progression-free survival (PFS) on the first ADC is consistently longer than on the second. For example, in a 2023 single-institution study of 32 patients, median PFS on the first ADC was 7.55 months versus 2.53 months on the second [7]. A larger 2024 multi-institution study of 68 patients found that 59% had progressive disease at the first restaging scan on the second ADC [1]. Similarly, a 2024 MSKCC study of 85 patients reported median PFS on the second ADC of only 2.8–3.5 months [2]. The takeaway: while a second ADC can still help some patients, the odds of a durable response are much lower than with the first.

This pattern holds regardless of hormone receptor status or tumor subtype. A 2025 multicenter study of 84 HER2-low patients found that time to treatment failure was longer for the first ADC than the second, irrespective of HR status, age, or presence of visceral disease [9]. Even when patients received an intervening therapy between ADCs, the second ADC still performed poorly—in a 2025 Cedars-Sinai study, median PFS on the second ADC was 3.4 months, and cross-resistance (progression at first scan) occurred in 55% of patients [4]. So, the benefit of a second ADC is real but modest, and it shrinks with each subsequent line.

Does the order of SG and T-DXd make a difference?

The evidence is mixed, but several studies suggest that starting with sacituzumab govitecan (SG) and then using trastuzumab deruxtecan (T-DXd) may yield slightly better progression-free survival than the reverse order. In a 2025 study of 164 HER2-low patients, the SG→T-DXd sequence had a median PFS on the second ADC of 6.3 months versus 4.3 months for T-DXd→SG [5]. A 2025 City of Hope study of 100 patients found that each ADC worked better when used first, but the combined PFS (first + second) was similar regardless of order (11.1 months for ET vs 8.2 months for TE, p=0.7) [3]. However, a 2025 Henry Ford study of 33 patients found the opposite—T-DXd followed by SG appeared more effective, regardless of receptor status [6].

Why the discrepancy? The studies differ in patient populations (e.g., HR+ vs TNBC), prior treatment lines, and small sample sizes. Notably, the largest study [5] and the MSKCC study [2] both found that later treatment line (more prior therapies) was associated with worse PFS on the second ADC, which may confound sequence comparisons. Overall survival did not differ significantly between sequences in any study [4][5]. So, while SG→T-DXd may be a reasonable default, the evidence is not strong enough to mandate a specific order—clinicians often choose based on tumor subtype, prior therapies, and toxicity profiles.

Why does the second ADC stop working? The role of payload and target

Resistance to the second ADC is driven by two main factors: the antibody target (the protein on the cancer cell) and the payload (the chemotherapy drug attached to the antibody). Both SG and T-DXd carry a topoisomerase-I inhibitor payload, so if a tumor becomes resistant to that payload, it may not respond to the other ADC. In the 2024 multi-institution study, cross-resistance was more common when the second ADC targeted the same antigen (78.5%) than when it targeted a different one (53.1%) [1]. However, the payload also matters—in the same study, cross-resistance was similar whether the payload was identical (60%) or different (52.4%) [1].

Emerging biomarker data point to TOP1 mutations as a key mechanism. A 2024 study found TOP1 mutations in 6% of patients who progressed on an ADC, compared to 0.5% in primary breast cancer, and these mutations were associated with rapid progression on a second ADC (median 52 days vs 455 days on the first) [10]. This suggests that tumors can evolve to resist the payload, not just the antibody. Other genomic alterations, such as amplifications in cell cycle genes, have also been linked to worse outcomes on HER2-targeted ADCs [8]. These findings highlight the need for biomarker-driven sequencing—for example, using an ADC with a different payload after a topo-I inhibitor fails, or testing for TOP1 mutations to guide treatment choice.

About These Sources

This answer is built on 10 peer-reviewed studies — published from 2023 to 2026, 9 from 2024 or later, 10 in Q1 journals, collectively cited 117 times — selected as the most relevant from 11 studies that passed quality screening, drawn from 37 papers retrieved from a database of over 500 million.

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