ASCENT-GYN-01 Trial of Sacituzumab Govitecan Aims to Validate Clinical Utility of TROP2 ADCs in Pretreated Endometrial Cancer

Despite recent therapeutic advances, the association between recurrent or metastatic endometrial cancer continues and poor outcomes persists, with a 5-year survival rate of approximately 19% and a median overall survival (OS) of less than 1 year.1 Attempts to address this historically poor prognosis have led to a slew of recent approvals for PD-L1 inhibitors following frontline treatment; however, the movement of these immunotherapies into earlier lines of treatment has translated into a lack of effective treatment options available for patients whose disease has progressed after receiving both platinum-based chemotherapy and subsequent immunotherapy.2 This therapeutic gap has spurred the investigation of novel targeted therapies designed to deliver clinically meaningful efficacy with a tolerable safety profile.

“If we look at the big picture, we've moved the treatment landscape forward,” Ramez N. Eskander, MD, explained in an interview with OncLive®. “We now have chemotherapy and immunotherapy given in the advanced stage or recurrent population, but then we have a gap in treatment where we still need to identify effective options.” Eskander is an assistant professor in the Departments of Obstetrics, Gynecology, and Reproductive Sciences at the University of California (UC) San Diego School of Medicine; as well as the director for oncology of the Clinical Trials Office at UC San Diego Moores Cancer Center.

Standard chemotherapies in the second line and beyond rarely achieve durable disease control, with response rates historically falling under 15%, a median progression-free survival (PFS) of less than 4 months, and substantial toxicity.1 In contrast, the TROP-2–directed antibody-drug conjugate (ADC) sacituzumab govitecan-hziy (Trodelvy) has demonstrated notable efficacy in heavily pretreated patient populations across several tumor types, and data from the phase 2 TROPiCS-03 trial (NCT03964727) provided proof-of-concept for the agent in previously treated advanced endometrial cancer.2

These data provided the rationale for the ongoing phase 3 ASCENT-GYN-01 trial (NCT06486441), which is comparing sacituzumab govitecan vs investigator’s choice of standard-of-care (SOC) chemotherapy in patients with endometrial cancer whose disease has progressed on both platinum-based chemotherapy and checkpoint inhibitor–based therapy, either in combination or sequentially.1

“The premise of the ASCENT-GYN-01 study, among others, is to figure out whether we can use a TROP-2–targeted ADC to elicit a response and improve upon what we normally see with SOC chemotherapy, which is unfortunately not as effective as we'd like it to be,” Eskander explained.

Could TROP-2–Directed ADCs Be More Effective Alternatives to SOC Chemotherapy in Later-Line Endometrial Cancer?

The current first-line standard for advanced or recurrent endometrial cancer typically involves carboplatin plus paclitaxel, often in combination with checkpoint inhibitors such as dostarlimab-gxly (Jemperli) or pembrolizumab (Keytruda), based on data from the phase 3 RUBY (NCT03981796) and NRG-GY018 (NCT03914612) trials, respectively.2 For patients with recurrent disease, platinum-based chemotherapy remains the foundation, with pembrolizumab or trastuzumab incorporated for select molecular subgroups. For patients with mismatch repair–proficient tumors who progress on platinum chemotherapy, the combination of pembrolizumab and lenvatinib (Lenvima) also is an available option. Beyond these regimens, however, therapeutic choices are scarce.

Sacituzumab govitecan has already demonstrated significant activity in other solid tumors, and it is FDA approved for metastatic triple-negative breast cancer and hormone receptor–positive/HER2-negative metastatic breast cancer following prior systemic therapy.3,4

Early clinical data with sacituzumab govitecan in endometrial cancer have demonstrated activity in this setting. In the phase 1/2 IMMU-132-01 trial (NCT01631552), sacituzumab govitecan generated an objective response rate (ORR) of 22.2% (95% CI, 6.4%-47.6%) and a median OS of 11.9 months (95% CI, 4.7-not reached) in patients with recurrent endometrial cancer refractory to at least 1 prior regimen (n=18).5 More recently, results from an open-label phase 2 trial (NCT04251416) reported an ORR of 33.3%, a median PFS of 5.7 months, and a median OS of 22.2 months in patients with TROP-2–overexpressing persistent or recurrent endometrial carcinoma (n=21).6

“We’ve had prior efficacy, not just with sacituzumab govitecan, but with other TROP-2[–directed] ADCs, showing preliminary activity in endometrial cancer,” Eskander said. “That is predicated on preclinical data suggesting that endometrial cancers often highly express TROP-2. The question is whether we can capitalize on that expression by employing a TROP-2–targeting ADC to elicit clinically meaningful responses.”

He added that although lessons can be drawn from breast cancer, where multiple ADCs with overlapping targets and payloads are already in clinical use, the implications for the endometrial cancer domain remain unknown. “We’re gathering a little bit of data from the breast world, where that’s existed, for example, with [fam-trastuzumab deruxtecan-nxki (Enhertu)] and sacituzumab govitecan, but we don’t yet know in endometrial cancer what that might look like. Is there going to be differential efficacy? Is the expression level of TROP-2 going to be relevant?”

Given the myriad ADCs entering late-stage development, sequencing and potential cross-resistance among TROP-2–directed agents or those sharing camptothecin-based payloads are critical considerations.

“It’s a dynamic time in endometrial cancer,” Eskander observed. “The important question will be: How will the landscape evolve if we have a TROP-2–directed ADC approved, like sacituzumab govitecan, and it becomes a SOC for these patients? What does that mean for other TROP-2–directed ADCs or for other ADCs with a camptothecin payload?”

How Did Data From TROPiCS-03 Support Further Evaluation of Sacituzumab Govitecan?

Although early signals of activity were encouraging, definitive proof-of-concept for sacituzumab govitecan’s efficacy and safety in advanced or metastatic endometrial cancer were needed.2 To address this, investigators launched the multicohort, open-label TROPiCS-03 basket study.

TROPiCS-03 included parallel cohorts of patients with small cell lung cancer, non–small cell lung cancer, head and neck squamous cell carcinoma, and endometrial cancer. The proof-of-concept stage was designed to enroll approximately 40 patients per cohort, with the option for expansion if predefined efficacy thresholds were met.

In the endometrial cancer cohort, patients had advanced or metastatic disease that had progressed following platinum-based chemotherapy. The protocol was later amended to also require prior anti–PD-L1 therapy, either sequentially or in combination with platinum-based chemotherapy, reflecting the evolving SOC. Notably, 6 patients (15%) included in the analysis had not previously received anti–PD-L1 therapy.

Results published in the Journal of Clinical Oncology in 2024 showed that at a median follow-up of 5.8 months (range, 0.7-19.3), patients treated with the TROP-2–directed ADC (n=41) experienced an objective response rate (ORR) of 22% (95% CI, 11%-38%), comprising exclusively partial responses. Patients also experienced stable disease (44%) or progressive disease (20%). Additional efficacy data were as follows:

• Median duration of response (DOR): 8.8 months (95% CI, 2.8-not estimable)
• Median time to response: 2.8 months (range, 1.4-5.8)
• Clinical benefit rate (CBR): 32% (95% CI, 18%-48%)
• Median PFS: 4.8 months (95% CI, 2.8-9.8)
• 6- and 12-month PFS rates: 36% (95% CI, 20%-52%) and 19% (95% CI, 6%-38%), respectively

Notably, 61% of patients experienced a reduction in target lesion diameters from baseline with durable responses. OS data were not mature at the data cutoff for this analysis.

Regarding safety, any-grade treatment-emergent adverse effects (TEAEs) occurred in 98% of patients, with the most common including diarrhea (56%), nausea (54%), and fatigue (51%). Grade 3 or higher TEAEs were reported in 80% of patients. TEAEs led to treatment discontinuation in 2 patients, which were febrile neutropenia and weight loss (n=1 each).

An exploratory analysis of TROP-2 expression confirmed high levels of protein expression within the endometrial cancer cohort, and data indicated a limited association between responses to sacituzumab govitecan and TROP-2 expression. Among 39 evaluable patients, the median TROP-2 H-score was 115 (range, 0-245). The median PFS was similar regardless of expression level, at 4.2 months in patients with scores equal to or above the median vs 5.0 months in those below the median (HR, 0.9; 95% CI, 0.4-2.0; P=.8). In addition, best tumor volume change from baseline did not correlate with TROP-2 H-score (P=.873).

What Is the Design of ASCENT-GYN-01?

ASCENT-GYN-01 is a phase 3, randomized, open-label study designed to examine the efficacy and safety of sacituzumab govitecan vs treatment of physician’s choice (TPC).1,7

The study will enroll approximately 640 patients who are 18 years or older with documented evidence of recurrent or persistent endometrial carcinoma or carcinosarcoma and radiologically evaluable disease as defined by RECIST 1.1 criteria.7 Patients are also required to have the following:

• Prior receipt of up to 3 lines of systemic treatment in any setting, including prior platinum-based chemotherapy and PD-L1 inhibitor therapy, administered either sequentially or in combination
• An ECOG performance status of 0 or 1
• Adequate organ function and tumor tissue

Of note, prior receipt of a PD-L1 inhibitor is not required for a proportion of patients who have comorbidities precluding such treatment or for whom it is not available as standard-of-care therapy per local standard; however, investigators are capping enrollment to this subgroup at approximately 10% of the total trial population.1

Patients are ineligible for the study if they meet any of the following criteria:

• A diagnosis of uterine leiomyosarcoma and/or endometrial stromal sarcomas
• An active second malignancy, active central nervous system metastases, and/or carcinomatous meningitis
• A history of significant cardiovascular disease
• Prior exposure to a TROP-2–directed ADC or any prior treatment containing a chemotherapeutic agent targeting topoisomerase
• Are candidates for curative-intent therapy or are eligible for rechallenge with platinum-based chemotherapy

“In the design of the study, we're enrolling patients irrespective of TROP-2 [expression] levels because of [previously reported] preliminary data,” Eskander noted. “However, we'll be looking at that [expression] as part of the secondary end points of the trial, and that will also inform what that might mean for the future development of other ADCs with a different target and the same payload, or [those with the] same target but a different payload.”

Stratification factors include geographic region (North America and Europe vs Asia and rest of the world), prior PD-L1 inhibitor therapy (yes vs no), and the number of prior lines of systemic therapy (1 line vs 2-3 lines).1

Upon enrollment, patients will be randomly assigned 1:1 ratio receive either sacituzumab govitecan or TPC in the following dosing schedules:

• Experimental arm: intravenous (IV) sacituzumab govitecan at 10 mg/kg on days 1 and 8 of each 21-day cycle
• Control arm: doxorubicin at 60 mg/m² IV on day 1 of each 21-day cycle, with a maximum cumulative dose of 500 mg/m²; or paclitaxel at 80 mg/m² IV on days 1, 8, and 15 of each 28-day cycle

Treatment in both arms will continue until disease progression or unacceptable toxicity, followed by long-term follow-up.

For patients receiving sacituzumab govitecan, the use of granulocyte colony-stimulating factor as primary prophylaxis is recommended for those at increased risk of febrile neutropenia, although it is not required, Eskander noted.

“[Neutropenia] is a very common issue because these patients have been previously treated with systemic therapy, and a proportion of them will have had prior pelvic radiation, which can lead to hematologic AEs. These patients may also be older,” he explained. “For those reasons, they're at risk of developing treatment-related neutropenia. [In accordance with] ASCO guidelines, the implementation of growth factors can help ensure that a patient has a reduced risk of neutropenia or neutropenic fever and subsequent complications, and can stay on treatment and experience clinical benefit.”

The study’s end points are as follows:1,7

• Primary end points: PFS, as assessed by blinded independent central review (BICR) per RECIST 1.1 criteria, and OS
• Secondary end points: investigator-assessed PFS, ORR, DOR, investigator-assessed and BICR-assessed CBR, safety, and quality of life

Enrollment for ASCENT-GYN-01 began in August 2024 and the trial is ongoing at 187 sites worldwide. As of September 26, 2025, multiple sites were active across the United States.1

“Clinical trials are the key to advancing the science and identifying future treatments for our patients,” Eskander emphasized. “We're incredibly excited that the trial is open and enrolling globally. We're eager to see how it reads out, and, of course, are optimistic that we'll be able to have yet another treatment strategy to help our [patients with] endometrial cancer.”

References

1. Columbo N, Corr B, Cibula D, et al. ASCENT-GYN-01 (GOG-3104/ENGOT-en26): a randomized, phase III study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with endometrial cancer (EC) after platinum-based chemotherapy and immunotherapy. Ann Oncol. 2024;10(5):105187. doi:10.1016/j.esmoop.2025.105187
2. Santin AD, Corr BR, Spira A, et al. Efficacy and safety of sacituzumab govitecan in patients with advanced solid tumors (TROPiCS-03): analysis in patients with advanced endometrial cancer. J Clin Oncol. 2024;42(29):3421-3429. doi:10.1200/JCO.23.02767
3. FDA grants accelerated approval to sacituzumab govitecan-hziy for metastatic triple negative breast cancer. April 22, 2020. Accessed September 25, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sacituzumab-govitecan-hziy-metastatic-triple-negative-breast-cancer
4. US FDA approves Trodelvy in pre-treated HR+/HER2- metastatic breast cancer. News release. Gilead Sciences. February 3, 2023. Accessed September 25, 2025. https://www.gilead.com/news/news-details/2023/us-fda-approves-trodelvy-in-pre-treated-hrher2--metastatic-breast-cancer
5. Bardia A, Messersmith WA, Kio EA, et al: Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial. Ann Oncol. 2021;32(6):746-756. doi:10.1016/j.annonc.2021.03.005
6. Santin A, McNamara B, Siegel ER, et al. Preliminary results of a phase II trial with sacituzumab govitecan-hziy in patients with recurrent endometrial carcinoma overexpressing Trop-2. J Clin Oncol. 2023;41(suppl 16):5599. doi:10.1200/JCO.2023.41.16_suppl.5599
7. Study of sacituzumab govitecan versus treatment of physician's choice in participants with endometrial cancer after platinum-based chemotherapy and immunotherapy (ASCENT-GYN-01/​GOG-3104/​ENGOT-en26) (ASCENT-GYN-01). ClinicalTrials.gov. Updated September 2, 2025. Accessed September 25, 2025. https://clinicaltrials.gov/study/NCT06486441