Emerging Agents and Paradigm Shifts in Gynecologic Cancer: Expert Takeaways From ESMO 2025

The 2025 ESMO Congress concluded on October 21 after 5 days of data-driven scientific exchange focused on evolving treatment paradigms, novel therapeutics, and meaningful advancements across tumor types.

OncLive® asked experts in gynecologic oncology to spotlight the most important research and conclusions in their field to come out of the meeting. We gathered insights from:

• Vicky Makker, MD, an attending physician, section head of the Endometrial Cancer Program, and director of the Hematology-Medical Oncology Fellowship Training Program at Memorial Sloan Kettering Cancer Center
• Antonio Gonzalez-Martin, MD, principal investigator of the Translational Oncology Group, director of the Department of Medical Oncology, and director of the Cancer Center Clínica Universidad de Navarra.
• Vanda Salutari, MD, an oncologist in the Department of Health of Woman and Child at the Catholic University of Sacred Heart
• Dana M. Chase, MD, a professor of obstetrics and gynecology in the Division of Gynecologic Oncology at the University of California, Los Angeles.

Collectively, these experts agreed that the datasets presented at the meeting signal meaningful forward momentum in gynecologic oncology. Top takeaways included the continued expansion of the antibody-drug conjugate (ADC) treatment armamentarium in platinum-resistant ovarian cancer, a renewed interest in checkpoint inhibitor–based strategies in molecularly defined disease states, and the identification of potential biomarkers to refine treatment selection.

For those who missed the meeting in Berlin, watch the video above to hear meeting takeaways directly from our experts, and read on for additional details on each highlighted study, summarized below.

What do new data for ADCs signal for ovarian cancer management?

LBA43 - NAPISTAR 1-01: A phase I dose escalation study of TUB-040, a novel NaPi2b-targeting exatecan antibody-drug conjugate (ADC) in patients with platinum-resistant ovarian (PROC) high grade serous carcinoma (HGSC)

Makker began by emphasizing the strength of readouts in the ADC space, particularly for patients with heavily pretreated, recurrent gynecologic malignancies.

“The most compelling data that we saw at this year's ESMO were in the ADC category,” Makker stated. “A number of ADCs are being evaluated across the board in recurrent endometrial cancers, and it's really been heartening to see the robust efficacy recapitulated across these trials. It's also great to now have a good bit of safety data regarding these agents. We're going to really see an evolution in the treatment paradigm for advanced recurrent endometrial cancers, with just an emergence of really notable, important ADC molecules.”

One emerging candidate of note is the NaPi2b-targeted ADC TUB-040, which was evaluated in the phase 1/2a NAPISTAR1-01 trial (NCT06303505). This proof-of-concept dose escalation study enrolled 67 patients with ovarian cancer to receive TUB-040 across doses ranging from 0.5 mg/kg to a planned dose as high as 5.3 mg/kg.

Data featured at the 2025 ESMO Congress focused primarily on 46 patients treated at dose levels of 1.67 mg/kg (n = 10), 2.1 mg/kg (n = 12), 2.5 mg/kg (n = 12), and 3.3 mg/kg (n = 12), with supportive information from other cohorts. Objective response rates (ORRs) exceeded 50% at the evaluated dose levels, with responses seen at all doses at and above 1.67 mg/kg; this included a complete response at 2.5 mg/kg. Across the 1.67 mg/kg to 3.3 mg/kg cohorts, the ORR was 59%—including a confirmed ORR of 50%—and the disease control rate was 96%. Responses remained ongoing in 93% of responders at the time of reporting.

“Previously, there was some development using an ADC that targeted the same receptor, but those studies were withdrawn due to toxicity concerns,” Chase noted. “To see another one being developed is interesting, [provided that it shows a] tolerable safety profile and a good efficacy comparable to the other ADCs that we're seeing presented.”

Based on earlier signs of efficacy, the FDA granted TUB-040 fast track designation in June 2024 for platinum-resistant ovarian cancer.2

“Until we see a randomized phase 2 or 3 [trial showing] how they're going to pan out in terms of toxicities and efficacy, it's going to be hard to be completely excited by [these emerging ADCs],” Chase concluded.

Can checkpoint inhibition finally find success in ovarian cancer?

LBA3 - Pembrolizumab vs placebo plus weekly paclitaxel ± bevacizumab in platinum-resistant recurrent ovarian cancer: Results from the randomized double-blind phase III ENGOT-ov65/KEYNOTE-B96 study

Another readout of note was the phase 3 KEYNOTE-B96/ENGOT-ov65 trial (NCT05116189), in which 643 patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma were randomly assigned to receive pembrolizumab (Keytruda; n = 322) or placebo (n = 321), both given in combination with weekly paclitaxel with or without bevacizumab (Avastin).3 Progression-free survival (PFS) by RECIST 1.1 criteria served as the primary end point, and overall survival (OS) in the PD-L1–positive population was a key secondary end point.

Interim results presented at ESMO confirmed that pembrolizumab plus weekly paclitaxel—with or without bevacizumab—significantly improved PFS regardless of PD-L1 status and improved OS in the PD-L1–positive subgroup. In the intention-to-treat population, the median PFS was 8.3 months (95% CI, 7.2-8.6) vs 6.4 months (95% CI, 6.2-8.1) with the pembrolizumab regimen vs placebo regimen, respectively. Grade 3 or higher treatment-related adverse effects (TRAEs) occurred in 67.5% of patients in the pembrolizumab arm vs 55.3% in the placebo arm.

Gonzalez-Martin described this trial as one of the first clearly positive immunotherapy studies in the platinum-resistant ovarian cancer setting, prompting renewed discussion about whether—and how—to integrate checkpoint inhibition into practice.

“[KEYNOTE-B96] is one of the, [if not] the only, real positive studies with checkpoint inhibitor in the platinum-resistant ovarian cancer setting, and it is starting to generate a lot of discussion about [whether to] integrate that into our clinical practice, [and if so] how,” Gonzalez-Martin stated.

Prior to the start of the 2025 ESMO Congress, Merck announced that the study met another key secondary end point, with the pembrolizumab-based regimen generating a statistically significant and clinically meaningful improvement in OS in the ITT population.4 Findings from this analysis will be shared at a future medical meeting.

“There was a lot of hype leading up to the meeting that this could be the one and only ovarian cancer trial that's going to prove [there is] a role of immunotherapy in ovarian cancer, and I do think the results have implications [for practice],” Chase expanded. “Some [of my colleagues] are saying, ‘[We have an] 18-month OS in patients with recurrent platinum-resistant ovarian cancer. That is groundbreaking and new for this patient population.’ Then I've heard other people say that these were potentially lower-risk patients, and the median PFS and OS difference is not that clinically meaningful. [Overall,] because of the OS benefit and the high unmet need [in this patient population], I do think people are going to start using this regimen.”

Do patients with PARP inhibitor–exposed platinum-resistant ovarian cancer still benefit from relacorilant plus nab-paclitaxel?

LBA45 - ROSELLA (GOG3073, ENGOTov72, APGOT-OV10): Relacorilant + nab-paclitaxel in the subgroup of patients with platinum-resistant ovarian cancer (PROC) previously exposed to a PARP inhibitor

The phase 3 ROSELLA trial (NCT05257408) investigated relacorilant plus nab-paclitaxel (Abraxane) in patients with platinum-resistant ovarian cancer who had progressed less than 6 months after their last dose of platinum therapy and had received 1 to 3 prior lines of therapy, including bevacizumab.5

Patients were randomly assigned 1:1 to receive either nab-paclitaxel in combination with relacorilant or nab-paclitaxel monotherapy. The study’s dual primary end points were PFS by blinded independent central review and OS; secondary end points included investigator-assessed PFS, ORR, duration of response, clinical benefit rate, and safety.

In a preplanned subgroup analysis presented at ESMO, relacorilant plus nab-paclitaxel (n = 114) improved PFS compared with nab-paclitaxel alone (n = 120) in patients previously exposed to PARP inhibition, including those whose disease progressed on PARP therapy. In PARP inhibitor–exposed patients, the median PFS was 7.36 months (95% CI, 5.59-8.18) vs 4.63 months (95% CI, 3.55-5.72) with relacorilant plus nab-paclitaxel vs nab-paclitaxel alone, respectively (HR, 0.60; 95% CI, 0.42-0.85; nominal P = .0035). In those who progressed on PARP inhibition, the median PFS with the combination (n = 86) was 7.36 months (95% CI, 5.39-8.44) vs 3.94 months (95% CI, 3.32-5.72) with nab-paclitaxel alone (n = 97; HR, 0.56; 95% CI, 0.37-0.84; nominal P = .0046). The safety profile remained consistent with previously reported data. These findings suggest a potential role for glucocorticoid receptor modulation in overcoming resistance to PARP inhibitor–based regimens.

“To see that these patients, when they were treated with relacorilant plus nab-paclitaxel, didn't seem to [experience] inferior [outcomes compared with] patients who didn't progress on a PARP inhibitor or had never received a PARP inhibitor, was interesting,” Chase stated. “There are a lot of hypotheses out there that patients who progress on PARP are not going to do as well.”

“[Both the KEYNOTE-B96 and ROSELLA] presentations could change our clinical practice,” Salutari stated. “It seems that these results [have caused] some confusion [among] oncologists, but I believe that more options are better than not [enough] options. [With these trials, we could] have more weapons [in our arsenal] and could build the right [strategy for] the right patient.”

How could translational research from phase 3 studies guide future research in endometrial cancer?

LBA40 - WES-derived aneuploidy score (W-AS) identifies MMRd patients with reduced benefit from immunotherapy in endometrial cancer: Multi-omic analysis of the phase III AtTEnd/ENGOT-EN7 trial

LBA41 - Baseline (BL) multiplex cytokine profiling identifies prognostic signatures in the phase III ANITA (ENGOT-Ov41/GEICO 69-O) trial in recurrent ovarian cancer (rOC)

Gonzalez-Martin also highlighted two translational analyses that may help refine patient selection for immunotherapy in gynecologic cancers.

Findings from a biomarker analysis of the phase 3 AtTEnd trial (NCT03603184) showed that high whole-exome sequencing (WES)–aneuploidy scores (W-AS) were associated with poorer outcomes with the addition of atezolizumab (Tecentriq) to chemotherapy in patients with mismatch repair–deficient (dMMR) advanced or recurrent endometrial cancer.6

Data presented at the ESMO Congress demonstrated that 90.9% of patients within the overall evaluable dMMR population (n = 110) had low W-AS vs 9.1% who had high W-AS. In the atezolizumab arm (n = 40), these rates were 85.0% and 15.0%, respectively; respective rates in the placebo arm (n = 70) were 94.3% and 5.7%. Analysis of the non-dMMR population is ongoing.

“[These data may help] identify patients with the dMMR endometrial cancer who do not respond well to [immunotherapy],” Gonzalez-Martin explained.

Similarly, data presented from an analysis of baseline circulating immune-oncology proteins in the phase 3 ANITA trial(NCT03598270) identified several potentially predictive or prognostic biomarkers for poor outcomes with atezolizumab plus platinum-based chemotherapy followed by niraparib (Zejula) maintenance in patients with late-relapsed, recurrent ovarian cancer.7 In a multivariable OS model, VISTA (B7-H5), CA125, VEGF-A, and CD96 (Tactile) were significantly associated with survival outcomes, with the strongest prediction at 6 months. Notably, high levels of VISTA (B7-H5) and VEGF-A were associated with the worst PFS and OS outcomes.

“Translational research from the ANITA study also identified some interesting baseline plasma proteins associated with a worse prognosis that could guide future research in the field,” he added.

References

1. González-Martín A, Sehouli J, Braicu EI, et al. NAPISTAR 1-01: A phase I dose escalation study of TUB-040, a novel NaPi2b-targeting exatecan antibody-drug conjugate (ADC) in patients with platinum-resistant ovarian (PROC) high grade serous carcinoma (HGSC). Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA43.
2. Tubulis receives FDA fast track designation for antibody-drug conjugate candidate TUB-040 in platinum-resistant ovarian cancer. News release. Tubulis. June 27, 2024. Accessed October 27, 2025. https://tubulis.com/news/tubulis-receives-fda-fast-track-designation-for-antibody-drug-conjugate-candidate-tub-040-in-platinum-resistant-ovarian-cancer/
3. Colombo N, Zsiros E, Sebastianelli A, et al. Pembrolizumab vs placebo plus weekly paclitaxel ± bevacizumab in platinum-resistant recurrent ovarian cancer: Results from the randomized double-blind phase 3 ENGOT-ov65/KEYNOTE-B96 study. Presented at: European Society of Medical Oncology Congress 2025; October 17–20, 2025; Berlin, Germany. Abstract LBA3.
4. Merck announces phase 3 KEYNOTE-B96 trial met secondary endpoint of overall survival (OS) in all comers population of patients with platinum-resistant recurrent ovarian cancer. News release. Merck. October 16, 2205. Accessed October 27, 2025. https://www.merck.com/news/merck-announces-phase-3-keynote-b96-trial-met-secondary-endpoint-of-overall-survival-os-in-all-comers-population-of-patients-with-platinum-resistant-recurrent-ovarian-cancer/
5. Lorusso D, Quesada S, Chan JK, et al. ROSELLA (GOG3073, ENGOTov72, APGOT-OV10): relacorilant + nab-paclitaxel in the subgroup of patients with platinum-resistant ovarian cancer (PROC) previously exposed to a PARP inhibitor. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA45.
6. Mazzarella L, Colombo N, Harano K, et al. WES-derived Aneuploidy score (W-AS) identifies MMRd patients with reduced benefit from immunotherapy in endometrial cancer: Multi-omic analysis of the phase III AtTEnd/ENGOT-EN7 trial. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA40.
7. González-Martín A, et al. Baseline (BL) multiplex cytokine profiling identifies prognostic signatures in the Phase 3 ANITA (ENGOT-OV41/GEICO 69-O) trial in recurrent ovarian cancer (ROC). Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA41