Professors Qi Zhou and Li Yuan Discuss Four Studies: ADCs Show Promise in Platinum-Resistant Ovarian Cancer, While New Breakthroughs Emerge in Precision Biomarker Development

Ovarian cancer is often referred to as the "king of gynecologic cancers." Platinum-resistant recurrent ovarian cancer (PROC) remains a major clinical challenge. Once platinum resistance develops, conventional single-agent chemotherapy offers low response rates and poor prognosis, leaving patients with limited treatment options. In recent years, the emergence of antibody-drug conjugates (ADCs) and targeted small-molecule agents has begun to reshape the treatment landscape of platinum-resistant ovarian cancer.

The 2026 Congress of the European Society for Medical Oncology (ESMO) was held in Madrid, Spain, from October 23 to 27. Four rapid oral presentations focusing on platinum-resistant ovarian cancer were featured at this year’s congress. They covered three novel ADCs—FRα-targeted torvu-sam, B7-H4-targeted Mo-Rez, and Cadherin-6-targeted R-DXd in combination with bevacizumab—as well as the novel WEE1 inhibitor azenosertib.

These studies not only demonstrated encouraging antitumor activity but also explored biomarkers capable of predicting treatment efficacy in greater depth. By moving beyond target expression alone to examine the tumor microenvironment and molecular subtypes, they provide new evidence for precision-based treatment stratification in platinum-resistant ovarian cancer.

On the occasion of this year’s congress, Oncology Frontier invited Professor Qi Zhou and Dr. Li Yuan from Chongqing University Cancer Hospital to discuss these four studies. The research findings and their expert commentary are presented below.

Updated Results from the FONTANA Study: FRα-Targeted ADC Torvutatug Samrotecan (Torvu-sam, AZD5335) in Platinum-Resistant Ovarian Cancer

Abstract No.: 1245RO

Torvu-sam is an ADC targeting folate receptor alpha (FRα) and carrying a topoisomerase I inhibitor payload. This presentation reported mature data from the dose-optimization stage of Module 1 of the phase I/IIa FONTANA study (NCT05797168).

The study enrolled patients aged ≥18 years with histologically confirmed platinum-resistant ovarian cancer. Patients were assigned to the dose-escalation cohort M1A, which had no restrictions on FRα expression or the number of prior lines of therapy, or the dose-expansion cohort M1B, which included patients who had received ≤3 prior lines of therapy.

M1B was further divided into two subgroups: M1B1, comprising patients with high FRα expression (≥25% of tumor cells with staining intensity of 1+ or higher), and M1B2, comprising patients with low FRα expression (<25% of tumor cells with staining intensity of 1+ or higher).

Torvu-sam was administered intravenously every three weeks until disease progression or unacceptable toxicity. The primary endpoints were safety and tolerability. Secondary endpoints included preliminary efficacy, while exploratory endpoints included dynamic ctDNA monitoring.

As of March 16, 2026, a total of 223 patients had received treatment: 71 in M1A, 124 in M1B1, and 28 in M1B2. The median duration of exposure was 7.1 months.

Safety: The most common adverse events (AEs) of any grade were nausea (76.7%), fatigue (59.2%), neutropenia (54.3%), vomiting (49.3%), and anemia (47.5%). The most common grade 3–4 AEs were neutropenia (25.6%) and anemia (15.7%). Dose reductions occurred in 26.5% of patients, while 8.1% discontinued treatment because of AEs.

Efficacy: In the M1B cohort receiving torvu-sam at doses of 1.6–2.4 mg/kg, objective responses were observed across all FRα expression subgroups:

High FRα expression (n=60): confirmed objective response rate (cORR), 61.7%.
Low FRα expression (n=63): cORR, 57.1%.
Very low/negative FRα expression (n=20): cORR, 40.0%.
Overall population (n=143): cORR, 56.6%.

Greater drug exposure was associated with more pronounced and more durable tumor shrinkage. Molecular responses based on ctDNA were also observed across different dose levels and FRα subgroups. PFS and duration of response (DOR) data were scheduled to be presented at the congress.

Conclusion: Torvu-sam demonstrated a manageable safety profile and encouraging antitumor activity in patients with platinum-resistant ovarian cancer across different levels of FRα expression. These results support the initiation of the phase III TREVI-OC-01 study (NCT07218809).

BEHOLD-1 Study: Exploratory Analysis of Biomarkers Associated with Response to the B7-H4 ADC Mo-Rez

Abstract No.: 1248RO

Mo-Rez (GSK5733584) is a novel ADC targeting the immunomodulatory molecule B7-H4. It consists of a protease-cleavable linker and a topoisomerase I (TOP1) inhibitor payload. In the dose-expansion stage of the global phase Ib BEHOLD-1 study, the 5.8 mg/kg Q3W regimen achieved a confirmed ORR of 62% in patients with platinum-resistant ovarian cancer. This presentation reported an exploratory analysis of biomarkers associated with treatment response.

Archived or fresh tumor tissue samples collected at screening were assessed using B7-H4 immunohistochemistry (IHC, n=111) and whole-transcriptome sequencing (WTS, n=79). B7-H4 IHC expression was analyzed as a continuous variable and according to prespecified cutoffs. Immune and tumor microenvironment (TME) characteristics were evaluated using fGSEA and GSVA analyses of WTS data. Biomarkers were then correlated with treatment response according to RECIST 1.1. The data cutoff date was November 12, 2025.

Analysis of immune microenvironment characteristics indicated that responders had higher scores for macrophages, Treg/Th2 cell chemotaxis, and myeloid cell infiltration. Stromal remodeling features showed the strongest association with treatment efficacy (P=0.00065). Cathepsin B (CTSB) expression was significantly higher in tumors from responders (P=0.02), and CTSB expression was associated with macrophage and stromal remodeling features.

Conclusion: Response to Mo-Rez was closely associated with the immune microenvironment and CTSB expression. Mechanistic findings suggest that a TME characterized by abundant macrophages, stromal remodeling, and high CTSB expression may facilitate linker cleavage, payload release, and the bystander-killing effect. More than 95% of platinum-resistant ovarian tumors express B7-H4, indicating that target expression alone is insufficient to predict treatment efficacy. Composite biomarker models that incorporate the drug’s mechanism of action are therefore needed.

REJOICE-Ovarian02 Study, Cohort B-1: R-DXd Plus Bevacizumab for Platinum-Resistant Recurrent Ovarian Cancer

Abstract No.: 1247RO

Raludotatug deruxtecan (R-DXd) is an ADC targeting Cadherin-6 and carrying an enzymatically cleavable peptide linker and a cytotoxic TOP1 inhibitor payload. The earlier REJOICE-Ovarian01 study demonstrated that R-DXd monotherapy was safe and effective in platinum-resistant ovarian cancer, with an ORR of 50%. This presentation reported the efficacy and safety of R-DXd in combination with bevacizumab (Bev) in Cohort B-1 of the phase Ib/II REJOICE-Ovarian02 study (NCT06843447).

Eligible patients had high-grade serous epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer with measurable disease. They had received 1–3 prior lines of therapy and experienced disease progression within six months of their most recent platinum-based treatment. Patients with primary platinum-refractory disease were excluded.

Patients received R-DXd at either 4.8 mg/kg (n=10) or 5.6 mg/kg (n=20), in combination with bevacizumab 15 mg/kg every three weeks, until disease progression or unacceptable toxicity. The primary endpoints included dose-limiting toxicities (DLTs), AEs, and AE-related treatment discontinuation. The secondary endpoint was ORR assessed by blinded independent central review (BICR).

As of February 3, 2026, 30 patients had received combination treatment, with a median follow-up of 4.5 months. No DLTs or additive synergistic toxicities were observed, and the overall safety profile was consistent with the known safety characteristics of the two individual agents. Grade ≥3 AEs were manageable with dose modifications and standard supportive care.

One patient in the 4.8 mg/kg group experienced grade 1 treatment-related interstitial lung disease (ILD). In the 5.6 mg/kg group, one patient developed aspiration pneumonia, which was subsequently determined to be grade 5 treatment-related ILD.

Efficacy results were encouraging. In the R-DXd 4.8 mg/kg plus bevacizumab group, the confirmed ORR was 80% (8/10), including one complete response (CR) and seven partial responses (PRs). In the 5.6 mg/kg group, the confirmed ORR was 53% (8/15), with all responses being PRs. All patients achieved disease control and tumor shrinkage. At the data cutoff, 25 patients remained on treatment.

Conclusion: R-DXd plus bevacizumab demonstrated a manageable safety profile and promising preliminary antitumor activity in platinum-resistant ovarian cancer.

Overall Survival Data from Part 1b of the DENALI Study: The WEE1 Inhibitor Azenosertib in Platinum-Resistant Ovarian Cancer

Abstract No.: 1242RO

Nearly all patients with recurrent ovarian cancer eventually develop platinum resistance, leaving them with limited treatment options and a poor prognosis. Azenosertib is a selective oral WEE1 tyrosine kinase inhibitor with best-in-class potential.

Data from Part 1b of the DENALI study were presented at SGO 2025. Among patients with Cyclin E1-positive platinum-resistant ovarian cancer, azenosertib monotherapy achieved an objective response rate of approximately 35%, with a median DOR of 6.3 months. This presentation reported interim overall survival (OS) data from the same cohort.

DENALI (GOG-3066, NCT05128825) is a multi-part, open-label phase II study. Eligible patients had high-grade serous ovarian, fallopian tube, or primary peritoneal cancer; platinum-resistant disease; measurable lesions; and an ECOG performance status of 0–1. Patients had previously received bevacizumab and 1–5 lines of systemic therapy.

Cyclin E1 expression was retrospectively assessed by IHC using a dedicated cutoff. Azenosertib was administered at 400 mg once daily for five days, followed by two days off treatment. The primary endpoint was ORR. Secondary endpoints included DOR, PFS, OS, and safety.

The full analysis set included 102 patients, of whom 94 had evaluable Cyclin E1 status: 48 were Cyclin E1-positive and 46 were Cyclin E1-negative.

As of September 2, 2025, the median OS was:

Cyclin E1-positive subgroup: 15.8 months (95% CI: 8.7–17.8).
Cyclin E1-negative subgroup: 7.5 months (95% CI: 5.8–12.3).
Overall population: 12.3 months (95% CI: 8.7–16.1).

Updated survival data were scheduled to be presented at the congress. No new safety signals were observed.

Conclusion: Cyclin E1 is a highly specific predictive biomarker of response to azenosertib. In patients with Cyclin E1-positive platinum-resistant ovarian cancer, azenosertib monotherapy achieved a median OS superior to that historically observed with conventional single-agent chemotherapy. These findings support continued evaluation in this biomarker-selected population in DENALI Part 2 and the phase III confirmatory ASPENOVA study.

Expert Commentary

I. Moving Beyond Target Expression Toward Biological Stratification: Exploring New Approaches to Precision Treatment for Platinum-Resistant Recurrent Ovarian Cancer

PROC represents a major challenge in the clinical management of gynecologic malignancies. As the disease progresses, tumor heterogeneity continues to evolve and drug resistance becomes increasingly pronounced. The efficacy of chemotherapy remains limited, and patients urgently need novel treatment strategies that offer better efficacy, different mechanisms of action, and preservation of quality of life. The rapid development of ADCs and cell-cycle checkpoint inhibitors has opened up new avenues for precision treatment of PROC.

The four phase I/II studies presented at this year’s ESMO Congress each addressed a different aspect of this challenge while complementing one another. The torvu-sam study explored the relationship between FRα expression and ADC efficacy; the Mo-Rez study focused on the TME and candidate biomarkers associated with payload release; the R-DXd plus bevacizumab study investigated a combination strategy integrating ADCs and antiangiogenic therapy; and the azenosertib study explored the identification of potentially responsive patients based on Cyclin E1-related cell-cycle dysregulation.

Together, these studies suggest that therapeutic development in PROC is moving away from empirical treatment and toward stratified approaches based on tumor molecular characteristics.

1. ADCs: From Target Positivity to Treatment Prediction and Precision Patient Selection

FRα is an important target in ADC development for ovarian cancer, but target expression alone cannot fully determine treatment efficacy. Factors such as intratumoral drug distribution, internalization efficiency, linker cleavage, payload release, and bystander effects may all influence the ultimate treatment response. Therefore, in addition to overall response rates, DOR, PFS, and safety data across different FRα subgroups should be evaluated to further clarify the clinical positioning of these agents in different biomarker-defined populations.

Torvu-sam (FONTANA study): Expanding the Potential Patient Population for FRα-Targeted ADCs

The FONTANA study presented phase I/IIa results showing that torvu-sam achieved an overall cORR of 56.6% in the 1.6–2.4 mg/kg dose groups. The cORRs in the high-, low-, and very low/negative FRα expression subgroups were 61.7%, 57.1%, and 40.0%, respectively.

These findings suggest that torvu-sam has preliminary antitumor activity across different levels of FRα expression, potentially offering a treatment option worthy of further investigation for patients traditionally classified as having low FRα expression. In the low-expression analysis, defined as fewer than 25% of tumor cells with staining intensity of 1+ or higher, the ORR was 47.5%.

The key highlight of this update is that the efficacy signal remained robust following dose expansion, while the additional value lies in the results among patients with very low or negative FRα expression, who still achieved a cORR of 40.0%. Compared with the population that is difficult to cover with mirvetuximab soravtansine, torvu-sam may potentially expand the population eligible for FRα-targeted ADC therapy, moving this possibility from hypothesis toward clinical validation.

Regarding safety, the overall safety profile was consistent with previous findings, with no new safety signals and no maximum tolerated dose (MTD) reached. As drug exposure increased, with median exposure extending from 3.8 to 7.1 months, the incidence of AEs also increased. Hematologic toxicity remained the main burden among grade ≥3 AEs. Neutropenia (grade 3–4, 25.6%) and anemia (15.7%) were the key events requiring management. The dose-reduction rate increased to 26.5%, while the treatment discontinuation rate was 8.1%.

This is a typical toxicity profile for ADCs carrying a topoisomerase I (TOP1) inhibitor payload. Clinical implementation will therefore require appropriate preventive granulocyte colony-stimulating factor (G-CSF) support and regular blood count monitoring.

In summary, the 2026 update confirms the broad activity of torvu-sam in patients with high, low, and very low FRα expression. Together with dose optimization, durable responses, and manageable toxicity, these findings position torvu-sam as one of the most differentiated FRα-targeted ADC candidates this year and provide a rationale for the initiation of the phase III TREVI-OC-01 study (NCT07218809).

It should be noted, however, that the very low/negative FRα subgroup included only 20 patients. The robustness of this finding requires validation in larger populations and in the phase III study.

Mo-Rez (BEHOLD-1 study): Treatment Response May Depend More on Whether the Tumor Microenvironment Permits Payload Release

The exploratory analysis from BEHOLD-1 further broadens the scope of biomarker research for ADCs. Mo-Rez (GSK5733584) is a novel ADC targeting the immunomodulatory molecule B7-H4, incorporating a protease-cleavable linker and a TOP1 inhibitor payload. In the dose-expansion stage of the global phase Ib BEHOLD-1 study, the 5.8 mg/kg Q3W regimen achieved a confirmed ORR of 62% in patients with platinum-resistant ovarian cancer. This year’s congress presented an exploratory analysis of biomarkers associated with treatment response.

Archived or fresh tumor tissue samples collected at screening were assessed using B7-H4 IHC (n=111) and WTS (n=79). B7-H4 IHC was analyzed as a continuous variable and according to prespecified cutoffs. The immune and TME characteristics were evaluated using fGSEA and GSVA analyses of WTS data, and candidate biomarkers were correlated with response according to RECIST 1.1. The data cutoff date was November 12, 2025.

The results showed that B7-H4 was expressed in 96% of ovarian tumors, but B7-H4 expression level alone was not associated with treatment response. Compared with non-responders, responders had significantly greater enrichment of immune-related pathways, with TNFα-NF-κB representing the most highly enriched pathway. Analysis of the immune microenvironment indicated higher scores for macrophages, Treg/Th2 cell chemotaxis, and myeloid cell infiltration among responders.

Stromal remodeling features showed the strongest association with treatment efficacy (P=0.00065). CTSB expression was significantly higher in tumors from responders (P=0.02), and CTSB expression was associated with macrophage and stromal remodeling features.

These findings suggest that ADC efficacy may depend not only on the presence of the target but also on whether the TME facilitates linker cleavage and payload release. However, these conclusions are derived from exploratory transcriptomic analyses involving a limited number of samples. They demonstrate associations rather than causality, and it cannot yet be concluded that CTSB or stromal remodeling features are definitive determinants of treatment response. Independent cohort validation and mechanistic studies will be needed to establish reproducible composite biomarker models with clinical predictive value.

Together, these two studies show how torvu-sam and Mo-Rez are advancing precision ADC research from two complementary perspectives: the range of target expression and the tumor microenvironment. The next critical step is not simply to define broader target-positive populations, but to identify the patients who are most likely to achieve durable and clinically meaningful benefit.

2. R-DXd Plus Bevacizumab: Evaluating Incremental Benefit and Safety of Combination Therapy

Raludotatug deruxtecan (R-DXd) is an ADC targeting Cadherin-6 and carrying an enzymatically cleavable peptide linker and a TOP1 inhibitor payload. The earlier REJOICE-Ovarian01 study demonstrated that R-DXd monotherapy was safe and effective in platinum-resistant ovarian cancer, with an ORR of 50%. This presentation reported the efficacy and safety of R-DXd plus bevacizumab (Bev) in Cohort B-1 of the phase Ib/II REJOICE-Ovarian02 study.

Patients received R-DXd at 4.8 mg/kg (n=10) or 5.6 mg/kg (n=20), in combination with bevacizumab 15 mg/kg every three weeks, until disease progression or unacceptable toxicity. The primary endpoints included DLTs, AEs, and AE-related treatment discontinuation. The secondary endpoint was ORR assessed by BICR.

As of February 3, 2026, 30 patients had received combination treatment, with a median follow-up of 4.5 months. No DLTs were observed, and no additive synergistic toxicities emerged. The overall safety profile was consistent with the known characteristics of the two individual agents. Grade ≥3 AEs were manageable with dose modifications and standard supportive care.

One particularly important safety finding was that one patient in the 4.8 mg/kg group experienced grade 1 treatment-related ILD. In the 5.6 mg/kg group, one patient initially presented with aspiration pneumonia but was subsequently determined to have grade 5 treatment-related ILD.

Efficacy results showed a confirmed ORR of 80% (8/10) in the R-DXd 4.8 mg/kg plus bevacizumab group, including one CR and seven PRs. In the 5.6 mg/kg group, the confirmed ORR was 53% (8/15), with all responses being PRs. All patients achieved disease control and tumor shrinkage.

The REJOICE-Ovarian02 Cohort B-1 study evaluated the feasibility of combining a Cadherin-6-targeted ADC with bevacizumab in PROC. Mechanistically, R-DXd directly kills tumor cells by delivering a cytotoxic payload, while bevacizumab exerts antitumor effects by inhibiting VEGF-mediated angiogenesis. These mechanisms may offer complementary therapeutic effects.

However, this cohort included only 30 patients, with a median follow-up of 4.5 months. The sample sizes in both dose groups were small, and the study did not include a randomized control arm. Therefore, it is not yet possible to conclude that the lower dose is superior to the higher dose, nor can the combination be considered superior to R-DXd monotherapy, which achieved an ORR of 50% in REJOICE-Ovarian01.

ILD is an important class-related toxicity that requires particular attention with DXd-based ADCs. Future studies should further clarify its incidence, risk factors, early detection strategies, and standardized management pathways. Efficacy must be assessed alongside a careful evaluation of the risk-benefit balance.

The value of this study lies in identifying a promising combination strategy for PROC. Randomized controlled studies are needed to determine whether the combination can deliver clinically meaningful incremental benefit and to establish the optimal dose and safety management strategy.

3. Azenosertib: Exploring Precision Treatment Based on Cell-Cycle Dysregulation

The DENALI study offers a therapeutic approach to PROC that differs from ADC-based strategies. Azenosertib is a selective oral WEE1 tyrosine kinase inhibitor with best-in-class potential. By interfering with the G2/M checkpoint and DNA damage response, it may induce synthetic lethality in tumor cells that depend on this checkpoint for survival.

Aberrant Cyclin E1 expression can cause replication stress and increase tumor cell dependence on WEE1, providing a biological rationale for its potential role as a predictive biomarker of treatment response.

The interim OS data from DENALI Part 1b presented at this year’s congress showed a clear biomarker-stratified difference. Median OS was 15.8 months (95% CI: 8.7–17.8) in Cyclin E1-positive patients, compared with 7.5 months (95% CI: 5.8–12.3) in Cyclin E1-negative patients and 12.3 months (95% CI: 8.7–16.1) in the overall population. Median OS in the positive subgroup was nearly twice that in the negative subgroup and also compared favorably with historical outcomes from single-agent chemotherapy.

Together with the previously reported ORR of approximately 35% and median DOR of 6.3 months among Cyclin E1-positive patients, these findings support further investigation in this specific molecular subgroup. For patients with Cyclin E1-positive disease, who account for approximately half of the PROC population, a biomarker-driven, non-chemotherapy approach using an oral WEE1 inhibitor has demonstrated an important efficacy signal.

However, it is important to emphasize that this was a single-arm study. Differences in OS between biomarker subgroups may reflect predictive value, but they may also reflect differences in prognosis. High Cyclin E1 expression itself may be associated with a poor prognosis. Confirmation of its predictive value will require randomized controlled studies comparing the relative treatment benefit across different biomarker-defined populations.

Furthermore, Cyclin E1 testing in this study was performed retrospectively using IHC. The reproducibility and standardization of the positivity threshold and testing method require further validation. The current OS data are also based on an interim analysis, and the confidence intervals for the individual subgroups remain wide.

Therefore, the clinical value of azenosertib still requires confirmation through DENALI Part 2 and the phase III confirmatory ASPENOVA study. These studies should provide PFS, OS, response rate, and safety data to determine whether Cyclin E1 can genuinely guide treatment selection in clinical practice.

II. Establishing a Biomarker-Based Precision Treatment Framework Will Be an Important Direction for PROC

The four studies discussed above reflect three major trends in the development of PROC treatment.

First, ADC research is moving beyond a narrow focus on target expression toward a more comprehensive assessment of target heterogeneity, the tumor microenvironment, and drug mechanisms of action.

Second, the evaluation of combination therapies is shifting from early response rates toward durable clinical benefit and a more balanced assessment of risks and benefits.

Third, cell-cycle regulatory agents are opening up new opportunities for precision treatment by exploiting molecular defects in tumors. However, their clinical translation still depends on reliable predictive biomarkers and confirmatory clinical studies.

Looking ahead, the key to precision treatment for PROC will not simply be the discovery of more novel targets or drugs. Rather, high-quality clinical research must answer three fundamental questions: Which treatment is appropriate for which patients? How substantial and durable is the benefit? And does the expected benefit outweigh the associated treatment risks?

Only by integrating molecular classification, standardized biomarker testing, clinical efficacy assessment, and comprehensive safety management can we gradually establish a more precise, rational, and sustainable treatment framework for PROC—ultimately improving both patient survival and quality of life.

Professor Qi Zhou

Dr. Li Yuan