Strategies for Platinum-Resistant Ovarian Cancer – Insights from the SGO and ESGO Conferences in 2026

Introduction

Ovarian cancer (OC) is the 8th most common type of cancer in women, with ~325,000 newly diagnosed cases worldwide in 2022. In terms of mortality, it ranked 6th among women, accounting for ~207,000 cancer deaths in the same year [1]. This substantial mortality stems mostly from late diagnoses; most OCs are diagnosed at stage III/IV, when the cancer has often already spread or infiltrated surrounding tissue [2]. Most advanced OCs respond well to treatment initially, but eventually relapse and progress to platinum-resistant (PR) OC [3], defined by only brief (<6 mo) or no response to platinum-based chemotherapy. For these patients, the only available option for a long time was platinum-free chemotherapy (e.g., with pegylated liposomal doxorubicin or (nab‑)paclitaxel, which is sometimes combined with the VEGF inhibitor bevacizumab and offers objective response rates (ORR) of only 10-15%. In 2024, the folate receptor α (FRα) targeting antibody-drug conjugate (ADC) mirvetuximab-soravtansin, which had demonstrated an ORR of 42% in its pivotal phase III trial [4], received FDA and EMA approvals. Still, the outlook for patients with PROC continues to be poor.

The development of new treatments for OC, therefore, has a strong focus on this group of patients with the highest unmet need. In this article, we will highlight new results from ongoing clinical studies of drugs with various new mechanisms of action, published at the congresses of the Society of Gynecological Oncology (SGO) and the European Society of Gynecological Oncology (ESGO) in 2026. We will focus on two new ADCs, the first trial to demonstrate a benefit of checkpoint inhibition in PROC and two novel small molecule drugs with innovative mechanisms of action.

Antibody-drug conjugates

Mirvetuximab-Soravtansin (MIRV) led the way for ADCs in ovarian cancer and was the first drug in a long time to substantially improve outcomes for patients with PROC. However, long-term remissions remain rare, and the unmet need is especially high among those with low or moderate FRα expression who do not qualify for treatment with MIRV.

Sofetabart Mipitecan

Sofetabart Mipitecan is a second-generation FRα-targeting ADC that carries the topoisomerase I-inhibiting payload exatecan at a high drug-to-antibody ratio of 8. The first-in-human phase I study NCT06400472 tested Sofetabart Mipitecan in a variety of FRα-expressing solid tumors, including patients with PROC, some of whom had previously been treated with MIRV [5].

Across all four dose levels (2/3/4/6 mg/kg) and FRα expression levels, the confirmed (c) ORR was 62% (16/26). Excluding the lowest dose level, cORR was 72% (13/18). While the number of patients was low, the data does not indicate that previous MIRV exposure negatively affected response to Sofetabart Mipitecan. Most common adverse events (AEs) were nausea and fatigue (each 55.6%), anemia (48.1%), and decreased appetite (40.7%), which were all low grade (Gr≤2) except for anemia (Gr≥3: 22.2%). Neuropathy, interstitial lung disease, and blurred vision occurred at rates of 7%, 4%, and 4%, respectively, and were all Gr≤2.

In conclusion, Sofetabart Mipitecan is a promising new ADC considering the robust response rates across FRα expression levels (including FRα expression < 75%) irrespective of prior ADC use. The phase III trial FRAmework-01 will evaluate the drug ± bevacizumab vs chemotherapy ± bevacizumab in a larger population.

Raludotatug Deruxtecan

While Sofetabart Mipitecan has the potential to reach patients with tumors expressing only moderate levels of FRα, new targets are needed to make ADCs available to even more patients with advanced OC. Raludotatug Deruxtecan (R-DXd) is an ADC with an exatecan payload targeting cadherin 6 (CDH6), a cell–cell adhesion glycoprotein that is aberrantly expressed in up to 94% of epithelial OCs [6]. REJOICE-ovarian01 is a phase II/III study evaluating R-DXd in patients with previously treated PROC irrespective of tumor CDH6 expression.

In a subgroup analysis of patients with different types and numbers of previous lines of treatment (LOT), ORRs of around 50 % (1 LOT: 50%; 2 LOT: 59.5%; 3 LOT: 43.6%) with no significant differences between subgroups were observed. Similarly, the type of previous treatment and length of the platinum-free interval did not result in different response rates between the study participant subgroups. R-DXd showed a manageable safety profile regardless of the number and type of previous LOT.

Data on progression-free survival (PFS) and overall survival (OS) are currently still immature and will require longer follow-up. The phase III part of REJOICE-ovarian01 is evaluating R-DXd vs treatment of the physician’s choice in a larger cohort of patients with PROC (N~600).

Immunotherapy

Pembrolizumab

Despite their broad applicability and success across solid tumors, the use of checkpoint inhibitors had, for a long time, failed to demonstrate superiority over established therapy options in patients with PROC. ENGOT-ov65/KEYNOTE-B96 is a phase III trial evaluating pembrolizumab vs placebo in addition to chemotherapy with paclitaxel, with or without bevacizumab.

At the ESGO 2026 congress, the final results were presented and revealed significant benefits in terms of 18-month PFS (17.3 % vs 9 %; hazard ratio [HR] = 0.73) and 18-month OS (49.1 % vs 39.1 %; HR = 0.82) in the intention-to-treat population. In the subgroup with a combined positive score (CPS) ≥ 1 (PD-L1-positive), the effect on 18-month OS was slightly more pronounced (51.5 % vs 38.9%, HR = 0.76). The positive effect was seen across all subgroups, including age, race, fitness, and prior treatment. Patients in the pembrolizumab (pembro) arm experienced somewhat higher rates of AEs (Gr≥3: 82.8% vs 70.8%; serious AEs: 56.3% vs 38.7%), but the safety profile was considered manageable and consistent with the known profiles of the individual therapies [7]. Completion and compliance rates were similar between treatment arms according to the QLQ-C30 and QLQ-OV28 instruments. Patients in the pembro arm reported no significant differences in terms of overall health-related quality of life (HRQoL; QLQ-C30) or abdominal disease symptoms (QLQ-OV28) versus the control arm [8].

ENGOT-ov65/KEYNOTE-B96 at its final analysis demonstrated for the first time that the addition of a checkpoint inhibitor, pembrolizumab, can improve outcomes for patients with PROC without significantly affecting QoL in a negative way.

Small molecule drugs

Relacorilant

Glucocorticoid receptor signaling contributes to chemoresistance by inhibiting apoptosis in tumor cells. Relacorilant is a novel selective glucocorticoid receptor antagonist that restores sensitivity of cancers to cytotoxic chemotherapy.

Relacorilant was tested as an addition to therapy with nab-paclitaxel vs nab-paclitaxel only in the phase III ROSELLA trial. At SGO 2026, the final OS results of the study were presented [9]. The primary PFS analysis showed promising results, increasing 6-month PFS vs nab-paclitaxel monotherapy from 42% to 52% and 12-month PFS from 13% to 25% (HR = 0.70). Similarly, OS rates in the +relacorilant arm were markedly better at 12 months (60% vs 50%) and 18 months (46% vs 27%); mOS was 16.0 months vs 11.9 months (HR = 0.65). The combination treatment was well tolerated overall. It was associated with slightly higher rates of Gr≥3 AEs (74.5% vs 59.5%) and serious AEs (35.1% vs 23.7%), but no cases of renal insufficiency or fatal treatment related (TR) AEs were recorded. The most common Gr≥3 AEs were neutropenia (44% vs 25%) and anemia (18% vs 9%).

In the ROSELLA trial, relacorilant met its PFS and OS endpoints and provided a 4.1-month OS extension vs the comparator arm. Importantly, its use is biomarker-independent, which reduces the need for patient selection and expands the group of benefiting patients.

Rezatapopt

The Y220C mutation in the tumor suppressor TP53 destabilizes the p53 protein and causes it to lose its function. This mutation occurs in ~1% of solid tumors overall but is disproportionally found in high-grade serous OC (HGSOC) at a rate of ~3.5%. Rezatapopt is a small molecule p53 reactivator that selectively stabilizes p53 Y220C in its wild type conformation and restores its natural function.

The PYNNACLE phase II trial was designed to assess rezatapopt in patients with advanced solid tumors, including OC, who relapsed under standard therapy or are ineligible for SoC treatment [10]. Among patients with OC (n = 72), the ORR was 44.4%, and the median duration of response (mDOR) was 8.2 months. The substance’s activity was confirmed at the molecular level by changes in allele frequency among tumor cells; 60% of patients had a decrease of ≥90% in cells harboring the Y220C mutation. Results from the total safety population (N = 141) indicate that the treatment was well tolerated. The most common AEs across grades were nausea (41.8%) and fatigue (25.5%). Only few Gr≥3 AEs occurred, most frequently alanine amino transferase (ALT) increase (7.1%), aspartate amino transferase (AST) increase (6.4%) and anemia (5.7%), which were reversible for the most part. Among patients with OC, 5.3% discontinued treatment due to TRAEs, consistent with data in the overall safety population.

Rezatapopt is a first-in-class drug, demonstrated in the PYNNACLE trial that the concept of p53 reactivation is feasible in patients with TP53 Y220C mutated OC. Its availability for oral administration and favorable safety profile may in the future provide substantial QoL benefits for a patient population highly burdened by disease symptoms and treatment side effects.

Conclusion

Patients with platinum-resistant OC are a difficult patient population with limited options despite recent progress. However, a number of novel and 2nd generation treatments are on the horizon, promising further improvements and potentially long-term remissions for an increasing number of patients. As the clinical trials progress and new treatments enter the clinic, more data will be collected, and it will be interesting to see if new combination treatments with even higher efficacy can be established.

References

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