ASCENT-03 Data Show Consistent Safety With Sacituzumab Govitecan in Previously Untreated Advanced TNBC

Patients with previously untreated triple-negative breast cancer (TNBC) who received sacituzumab govitecan-hziy (Trodelvy) experienced fewer adverse effects (AEs) resulting in dose reduction or treatment discontinuation than those given chemotherapy, and common AEs like neutropenia and diarrhea resolved quickly with standard management, according to data from a detailed safety analysis of the phase 3 ASCENT-03 study (NCT05382299).¹

The findings, which were shared during the 2025 San Antonio Breast Cancer Symposium, showed that any-grade treatment-emergent AEs (TEAEs) were experienced by 99% of those who received the antibody-drug conjugate (ADC; n = 275) vs 97% of those given chemotherapy (n = 276). Any-grade exposure-adjusted incidence rates (EAIR) for the respective arms were 40.21 (95% CI, 35.58-45.27) and 21.66 (95% CI, 19.14-24.40), respectively. Moreover, of the 7 TEAEs that proved fatal, 6 were because of infections and were determined to be related to treatment. Five infections were secondary to neutropenia in those who were at risk for febrile neutropenia but did not receive granulocyte colony-stimulating factor (G-CSF) as primary prophylaxis.

Moreover, the median time to onset of diarrhea proved shorter for those who received the ADC (any grade, 13 days [range, 1-427]; grade ≥ 3, 67 days [range, 6-356]) vs chemotherapy (26 days [range, 1-296]; 210 days [range, 110-310]). However, the study authors noted that the sample size is small, and these observations should be interpreted with caution. The median duration of diarrhea was comparable between the ADC (any grade, 6 days [range, 1-273]; grade ≥ 3, 6 days [range, 1-370]) and chemotherapy (6 days [range, 1-370; 1 day [range, 1-1]) arms; the same was true for neutropenia with sacituzumab govitecan (9 days [range, 2-49]; 8 days [range, 1-36]) vs chemotherapy (14 days [range, 1-179]; 8 days [range, 1-25]). The frequency of these two AEs was highest early on in treatment with the ADC.

“These results support [sacituzumab govitecan] as an effective treatment that has adverse effects that can be managed for people with metastatic triple-negative breast cancer who are not candidates for PD-L1–targeting treatment,” Sara A. Hurvitz, MD, FACP, of the Department of Medicine at UW Medicine, and the Clinical Research Division at Fred Hutchinson Cancer Center, in Seattle, WA, and colleagues, wrote in a poster.

What was the design of the phase 3 ASCENT-03 trial?

The ASCENT-03 study enrolled patients with previously untreated, locally advanced unresectable or metastatic TNBC whose tumors were negative for PD-L1 defined as a combined positive score (CPS) below 10 or positive for PD-L1 defined as a CPS of 10 or higher who had prior exposure to PD-(L)1 inhibition in the (neo)adjuvant setting or with a comorbidity that prevented them from receiving that therapy.

Study participants were randomly assigned to receive the ADC intravenously at a dose of 10 mg/kg on days 1 and 8 of 21-day treatment cycles or chemotherapy in the form of paclitaxel, nab-paclitaxel (Abraxane), or gemcitabine paired with carboplatin. Treatment continued until progressive disease or intolerable toxicity.

The trial’s primary end point was progression-free survival (PFS) by blinded independent central review (BICR) assessment. Important secondary end points included overall survival, objective response rate (ORR), and duration of response (DOR) by BICR, as well as safety.

What data were previously reported from ASCENT-03 with sacituzumab govitecan?

Prior data from the trial showed that the median PFS with the ADC was 9.7 months (95% CI, 8.1-11.1) vs 6.9 months (95% CI, 5.6-8.2) with chemotherapy (HR, 0.62; 95% CI, 0.50-0.77; P < .001).² Moreover, sacituzumab govitecan elicited an ORR of 48% (95% CI, 42%-54%) vs 46% (95% CI, 40%-52%) with chemotherapy; the median DOR in the respective arms was 12.2 months (95% CI, 9.7-13.8) and 7.2 months (95% CI, 5.7-8.4), respectively.

What did the current safety analysis examine? What additional information was reported?

At this year’s SABCS, investigators reported the first in-depth safety analysis of the study.¹ EAIRs were defined as the number of patients with at least 1 of the specified TEAEs per patient-year of exposure (PYE), and it was calculated as the number of patients with a specific event divided by total PYE in each group. PYE represented the sum of each patient’s time at risk, or exposure duration, in the study. Investigators evaluated incidence, severity, time to onset, duration, and impact of toxicity management.

Demographic and baseline characteristics were noted to be well balanced between the treatment arms. The median patient age across the ADC and chemotherapy arms was 55.5 years (range, 23-86). Almost all patients were female (>99%; 99%), more than half were White (64%; 63%), and had an ECOG performance status of 0 (66%; 67%), and the majority were PD-L1 negative (>99%; >99%). The most common geographic regions were Europe (35%; 38%) and Asia/Pacific (30%; 26%).

The median treatment duration for sacituzumab govitecan was 8.3 months vs 5.8 months for carboplatin, 6.1 months for gemcitabine, and 6.3 months for taxanes. The EAIRs for grade 3 or higher TEAEs in the ADC and chemotherapy arms were 1.85 (95% CI, 1.59-2.14) and 2.02 (95% CI, 1.73-2.35; difference, –0.18; 95% CI, –0.59 to 0.23); for serious TEAEs they were 0.40 (95% CI, 0.31-0.51) and 0.49 (95% CI, 0.38-0.63), respectively (difference, –0.09; 95% CI, –0.25 to 0.06). EAIRs for TEAEs that led to dose interruption (difference, –0.09; 95% CI, –0.54 to 0.36), dose reduction (difference, –0.48; 95% CI, –0.73 to –0.23), or treatment discontinuation (difference, –0.17; 95% CI, –0.26 to –0.09) all favored the ADC over chemotherapy.

Moreover, the EAIR differences between the sacituzumab govitecan and chemotherapy arms for neutropenia, febrile neutropenia, anemia, thrombocytopenia, diarrhea, fatigue, and peripheral neuropathy were 0.47 (95% CI, –0.02 to 0.96), 0.04 (95% CI, 0.00-0.09), –0.74 (95% CI, –1.05 to –0.45), –0.57 (95% CI, –0.73 to –0.43), 1.01 (95% CI, 0.76-1.28), –0.08 (95% CI, –0.38 to 0.21), and –0.18 (95% CI, –0.28 to –0.10), respectively.

Regarding management, primary prophylaxis with G-CSF was linked with less frequent and severe neutropenia in the ADC arm. Of those who received it in the ADC (n = 54) arm, 52% experienced any-grade neutropenia and 28% experienced grade 3 or higher neutropenia; of those who received it in the chemotherapy arm (n = 28), these rates were 75% and 50%, respectively.

Disclosures: Hurvitz reported grants or contracts from Ambrx, Amgen, Arvinas, AstraZeneca, Bayer, Celcuity, Cytomx, Daiichi Sankyo, Dantari, Dignitana, Genentech/Roche, G1-Therapeutics, Gilead Sciences, Inc., Greenwich Life Sciences Inc, GSK, Immunomedics, Jazz Pharmaceuticals, Lilly, LOXO, Macrogenics, Novartis, OBI Pharma, Orinove, Orum, Pfizer, Phoenix Molecular Designs, Ltd., Pieris, PUMA, Radius, Samumed, Sanofi, Seattle Genetics/Seagen, Stemline/Menarini, and Zymeworks. Royalties or licenses were received from Elsevier, McGraw Hill, Sage, and Wolters Kluwer. Consulting feeds were provided by Arvinas/Pfizer, Beigene, Bristol Myers Squibb, Boehringer Ingelheim, Briacell, BridgeBio, Daiichi Sankyo, Jazz Pharmaceuticals/Zymeworks, Gilead Sciences, Inc., Luminate, MedSir, Menarini, Mersana, Novartis, and Roche. Hurvitz disclosed participation on data safety monitoring or advisory boards with Alliance Foundation, InClin/Atossa, and QuantumLeap. Stock or stock options with RomTech were also cited.

References

1. Hurvitz A, Bardia A, Tolaney SM, et al. Safety analysis of ASCENT-03, a phase 3 study of sacituzumab govitecan vs chemotherapy for previously untreated advanced triple-negative breast cancer in patients who are not candidates for PD-(L)1 inhibitors. Presented at: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; Houston, TX. Poster PS1-13-24.
2. Cortés J, Punie K, Barrios C, et al. Sacituzumab govitecan in untreated, advanced triple-negative breast cancer. N Engl J Med. 2025;393(19):1912-1925. doi:10.1056/NEJMoa2511734