Current and around-the-corner therapies in platinum-resistant ovarian cancer: an insight into the ROSELLA study

Ovarian cancer (OC) is the eighth most common cause of cancer in women worldwide (1). Recent advances in its treatment are mostly in the maintenance setting with the approval of poly (ADP-ribose) polymerase inhibitors (PARPi) with or without bevacizumab in first line (2-5). The antibody-drug conjugates (ADCs) are the rising stars in the treatment of OC with the first positive results in the platinum-resistant setting (6).

Patients affected by platinum-resistant ovarian cancer (PROC) face a poor prognosis, with a median overall survival (OS) typically ranging from 10 to 16 months with the use of the best chemotherapies available (7). Resistance to platinum-based chemotherapy is a significant challenge, and needs novel therapies.

Until recent years, treatment options for patients with PROC included non-platinum chemotherapy administered alone (liposomal doxorubicin, weekly paclitaxel, gemcitabine, topotecan and oral etoposide) (8-13).

After decades of marginal gains, the AURELIA study showed an improvement of progression-free survival (PFS) and quality of life (QoL) in symptomatic patients by adding bevacizumab to non-platinum-based chemotherapy (14,15). Median PFS was 6.7 months in the arm with bevacizumab versus 3.4 months in the chemotherapy arm (hazard ratio, 0.48); unfortunately, bevacizumab did not demonstrate an improvement in OS. The trial was not designed to detect an OS difference because of crossover to bevacizumab that occurred in 40% of patients.

The first trial in PROC demonstrating an improvement of PFS and OS was the MIRASOL trial (6). This phase 3 trial compared the efficacy and safety of mirvetuximab soravtansine-gynx (MIRV), a new antibody-drug conjugate targeting folate receptor α (FRα), with the investigator’s choice of chemotherapy. Median PFS and OS were 5.6 and 16.5 months with MIRV versus 3.9 and 12.8 months with chemotherapy, respectively. MIRV did not affect patient QoL compared with investigator’s choice of chemotherapy (16).

Following the results of the MIRASOL trial, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved MIRV for patients with PROC treated with no more than three previous lines of therapy and with high FRα tumor expression (≥75% of cells with ≥2+ staining intensity).

Surprisingly, since current results of checkpoint inhibitors targeting the PD-L1/PD-1 pathway have been disappointing in ovarian cancer, a press release on the randomized phase III study KEYNOTE B96 announced that adding pembrolizumab to paclitaxel with or without bevacizumab showed a statistically significant improvement in PFS and OS for patients whose tumors express PD-L1 (17). The full results will be likely presented at European Society of Medical Oncology (ESMO) in October 2025.

The use of relacorilant, a selective glucocorticoid receptor (GR) antagonist with nab-paclitaxel has a strong rationale: OC cells frequently express the GR (18). In 133 out of 341 (39.0%) of the tumors from patients who had adjuvant chemotherapy after upfront cytoreduction surgery, GR protein was strongly expressed. Serous tumors, high grade tumors, and advanced stage tumors were more likely to have high GR expression. When GR was high, the median PFS was considerably lower than in those with low GR (20.4 versus 36.0 months, P<0.001). GR signaling reduces sensitivity to chemotheraру and it is specifically implicated in the mechanism of resistance to paclitaxel. Therefore, high expression of GR and elevated cortisol are associated with poor prognosis in patients with OC (19). Cortisol inhibited paclitaxel-induced apoptosis in the MIA PaCa-2 cell line, but relacorilant restored it. In the OVCAR5 cell line, relacorilant increased the efficacy of paclitaxel and the potency of platinum therapy. A test to discover effective combination partners for relacorilant revealed that microtubule-targeted medicines regularly benefit from combination with relacorilant (20).

Relacorilant was previously tested in a randomized phase 2 study in patients with PROC. The trial (NCT03776812) showed that the addition of intermittent relacorilant improved PFS compared with nab-paclitaxel monotherapy (P=0.038), with a median PFS of 5.6 versus 3.8 months in the chemotherapy arm (21).

Recently, the ROSELLA study (22), a multicenter, randomised, controlled, phase 3 trial, demonstrated that the addition of relacorilant prolonged PFS in PROC with at least three prior lines of therapy; moreover, the interim results also showed an improvement in OS. In this study 381 patients were randomly assigned to the relacorilant plus nab-paclitaxel or to the nab-paclitaxel alone arm. The primary endpoint was PFS and OS. Patients were significantly pre-treated, with 39% of the patients receiving at least one line of platinum-resistant therapy, 19% receiving a taxane as their last line of therapy, and 4% receiving a taxane for PROC. Median PFS and OS were 6.5 versus 5.5 months and 15.9 versus 11.5 months in the relacorilant versus chemotherapy-only group respectively. These results were consistent across all subgroups of patients with poor prognosis (older patients, more heavily pre-treated patients, patients with short primary platinum-free intervals, and patients with a high burden of disease). Moreover, a significant reduction in ascites in patients receiving combination therapy was reported. Adverse events (AEs) were similar across study groups when adjusted for nab-paclitaxel exposure and the most common AEs were neutropenia, anaemia, fatigue, and nausea.

At present, QoL data are not yet available, but QoL was only a secondary endpoint of the study.

There is no direct comparison between weekly nab-paclitaxel and weekly paclitaxel in PROC patients. In the studies that used nab-paclitaxel, median PFS were 5.5 months (13), 3.8 months (21), and 4.5 months (23), comparable to median PFS (3.9–5.5 months) in studies that used weekly paclitaxel (24-27).

In order to prevent some of the prevalent toxicities caused by taxanes, such as hypersensitivity reactions and gastrointestinal symptoms that are typically addressed with steroid premedication, weekly nab-paclitaxel was created in place of weekly paclitaxel, which was formerly used in PROC (28). The benefit is that patients with OC may benefit from a combination of these two treatments, GR modulation by relacorilant and a steroid-free taxane (nab-paclitaxel).

The ROSELLA study results position the combination of relacorilant and nab-paclitaxel as another potential standard for patients with PROC.

BRCA and homologous recombination (HR) status testing is essential at the time of diagnosis. However other biomarkers such as FRα and human epidermal growth factor receptor 2 (HER2) may became essential later on (1). The DESTINY-PanTumor02 was a phase II, basket trial that investigated trastuzumab deruxtecan in heavily pre-treated patients expressing HER2. In the cohort of OC, 40 patients were treated. The median number of prior treatments was 3, and 35.0% of patients had five or more prior lines of therapy; the median OS was 13.2 months in all patients and 20.0 months in patients with HER2 IHC 3+ expression. The overall response rate in the HER2 IHC 3+ expression was 63.6% and in the HER2 IHC 2+ expression was 36.8%. The results from this study further support the use of an HER2 ADC for OC (29). Following the results of this study, FDA granted accelerated agnostic approval to trastuzumab-deruxtecan for unresectable or metastatic IHC 3+ HER2 solid tumors.

Although we are in the biomarker-driven era medicine, the possibility to use relacorilant and nab-paclitaxel regardless the absence of a biomarker can be intriguing. In fact, in some instances, the time needed to assess a biomarker driven targeted therapy might be too long especially if we consider that PROC patients are frail and often symptomatic and need to start quickly a new line of therapy.

The recent approval of MIRV in the same setting of relacorilant plus paclitaxel raises the question of which one to choose. No studies of comparison are now available to answer this question, but in this contest, we need urgent strategies for timing and sequencing.

The role of anti-angiogenic agent bevacizumab is well known in the PROC setting, especially in association with paclitaxel. Bevacizumab’s anti-angiogenic properties can create a more favourable environment for immunotherapy by reducing tumor burden and potentially improving immune cell infiltration into the tumor (30).

Given this boosting role of the bevacizumab to immunotherapy, the BELLA study (NCT06906341), a phase 2 ongoing trial, is evaluating the association of relacorilant plus nab-paclitaxel plus bevacizumab in the PROC setting. Bevacizumab is administered 10 mg/kg every 2 weeks.

The schedule of relacorilant is relatively easy to administer for patients: 150 mg three times a week (the day before, the day of nab-paclitaxel and the day after) at the same time with an optimal compliance into the study.

Analyzing the safety profile of relacorilant plus nab-paclitaxel the rate of discontinuations due to AEs was very low: 10% due to relacorilant and 9% due to nab-paclitaxel. The most frequent grade ≥3 AEs were neutropenia 44%, anemia 18% and fatigue 9%. Dose reductions due to AEs occurred in 7% for relacorilant and 48% for nab-paclitaxel.

In this primary publication QoL data were not available lacking, an important point of discussion for this new drug combination. Although a statistically significant improvement in efficacy was seen (1 month for PFS and 4 months for OS), we have to understand if this result is also clinically meaningful for PROC patients. Data on QoL are ready at the time of efficacy analyses, but are often published after many years. Several investigations have demonstrated suboptimal reporting of QoL data and suboptimal inclusion of patient-reported outcomes (PROs) and QoL among research endpoints, even in gynecological oncology randomized controlled trials, despite the significance of QoL in determining therapeutic value.

In oncology, the proportion of trials including QoL among endpoints increased in 2017–2021 compared to 2012–2016. However, the proportion of primary publications reporting QoL results remains suboptimal (31).

In conclusion, considering the likely similar efficacy in comparison with MIRV, the place of relacorilant plus nab-paclitaxel in the algorithm of PROC will be strongly influenced by its effect on QoL.

In Figure 1 we summarized the benchmarks and new options for platinum-resistant OC setting.

Figure 1 Benchmarks and new options for platinum-resistant ovarian cancer (6,8-14,22). *, not yet approved by FDA. FDA, Food and Drug Administration.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-25-91/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-91/coif). V.T. reports consulting fees from GSK, Astrazeneca, MSD, EISAI, and Abbvie; payment or honoraria from GSK, Astrazeneca, MSD, EISAI, and Abbvie; support for attending meetings and/or travel from GSK, Astrazeneca, and Abbvie; participation on a Data Safety Monitoring Board or Advisory Board of GSK and Astrazeneca. G.V. reports consulting fees from GSK, Astrazeneca, MSD, EISAI, and Abbvie; payment or honoraria from GSK, Astrazeneca, MSD, EISAI, Abbvie, Regeneron, and Karyopharm; support for attending meetings and/or travel from GSK, Astrazeneca, Abbvie, and MSD; participation on a Data Safety Monitoring Board or Advisory Board of GSK, Astrazeneca, MSD, Abbvie, Regeneron, and Karyopharm. The authors have no other conflicts of interest to declare.

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