Platinum-resistant ovarian cancer poses a significant treatment challenge, as most patients with recurrent disease will develop resistance to standard-of-care (SOC) chemotherapy. Activation of the glucocorticoid receptor (GR) pathway, which is driven by cortisol binding, has been implicated in the development of chemoresistance. Moreover, high GR expression, which is common in ovarian tumors, has been linked with worse patient prognosis.

“It was a clinical observation for me that patients [who were] more stressed had worse outcomes,” Domenica Lorusso, MD, PhD, explained in an interview with 

. “This is a clinical observation that accompanied me over most of my career, but I was unable to find a scientific reason why this happened. When we discovered this pathway, it was evident that the higher levels of cortisol were implicated in worsened outcomes…so the possibility to block this pathway is of particular interest.” Lorusso serves as director of the Gynecological Oncology Unit at Humanitas Hospital San Pio X in Milan, Italy, as well as a full professor of obstetrics and gynecology at Humanitas University in Rozzano.

The oral, selective GR modulator relacorilant (CORT125134) is currently in development to address this resistance mechanism. Through antagonism of the GR pathway, relacorilant could block cortisol’s antiapoptotic effects in GR-overexpressing solid tumors, providing a novel strategy for overcoming chemoresistance in a challenging disease setting. Accordingly, the phase 3 ROSELLA study (NCT05257408) has been initiated to confirm and expand on prior data showcasing the ability of this agent to improve responses with standard nab-paclitaxel (Abraxane) in platinum-resistant ovarian cancer.

“I love that we’re looking at a novel mechanism,” Premal Thaker, MD, MS, added in another interview.“A lot of the drugs that we combine with chemotherapy are antiangiogenics, or immunotherapy, or maybe specific agents such as [those targeting] folate receptor alpha (FRα). [These agents] can’t always be used as broadly. All of us have a cortisol pathway in our bodies as part of our coping mechanisms. Cortisol is what helps us in acute stress…but cancer is a much more chronic disease, so it’s interesting that we’re finally looking at different pathways that may affect cancer biology.” Thaker is a surgeon, the David G. and Lynn Mutch Distinguished Professor of Obstetrics and Gynecology, director of gynecologic oncology clinical research, and interim chief of the Division of Gynecologic Oncology at Siteman Cancer Center in St. Louis, Missouri. 

Early Investigations of Relacorilant Provide Proof-of-Concept for GR Pathway Inhibition

Therapeutic options for patients with platinum-resistant/refractory ovarian cancer have historically been limited. SOC approaches primarily comprise sequential single-agent chemotherapy—such as paclitaxel, pegylated liposomal doxorubicin, topotecan, or gemcitabine—with or without bevacizumab (Avastin). In FRα-expressing tumors, the antibody-drug conjugate mirvetuximab soravtansine-gynx (Elahere) provides patients with an additional option.

Overall, response rates with single-agent chemotherapy remain low, at approximately 15% or less; responses increase to only 30% with the addition of bevacizumab, underscoring the need for active therapies that address this limitation.

A potential contributor to poorer outcomes in platinum-resistant disease is GR pathway activation. Endogenous cortisol can bind to and activate GRs, suppressing apoptotic pathways. Data from preclinical and clinical studies suggest that antagonism of GR activation with relacorilant can reverse cortisol’s antiapoptotic effects, potentially enhancing the efficacy of chemotherapy in platinum-resistant ovarian cancer.

“We have several preclinical [studies] and early clinical evidence suggesting that there is overexpression of the GR in solid tumors,” Lorusso noted. “It seems that GR overexpression is involved in chemoresistance and epithelial-mesenchymal transition. This creates a more chemoresistant and worse prognostic phenotype in [select] solid tumors, including ovarian cancer.”

For example, in vitro studies showed that the addition of relacorilant to paclitaxel reversed the deleterious effects of glucocorticoids on paclitaxel’s efficacy (

 < .001) in OVCAR5 cells. Furthermore, relacorilant plus paclitaxel decreased tumor growth and slowed time to progression in several xenograft models vs paclitaxel alone (both 

“[This preclinical research is] really important, because we don’t really understand resistance,” Thaker said. “One of the mechanisms we think [drives] resistance to chemotherapy in cancer is [the prevention of] continued cell death. [The question is:] how do we resensitize cells? This is what has been seen preclinically. There has also been some data showing that [relacorilant] may modulate the androgen receptor, which is not as key in ovarian cancer or gynecologic cancers, but could be important for prostate cancer, as there might be some benefit in even immune cell activation.” 

Early-phase research has corroborated such preclinical findings. In a phase 1 dose escalation study (NCT02762981) evaluating relacorilant plus nab-paclitaxel in a heavily pretreated population of patients with advanced or metastatic solid tumors, 33% of response-evaluable patients (n = 57) achieved durable disease control of 16 weeks or greater, with 28.6% of patients (n = 42) achieving longer duration of benefit than they did on a prior taxane. Durable disease control was observed in 25.9% of patients with pancreatic ductal adenocarcinoma (n = 27), 38.5% of patients with ovarian cancer (n = 13), and 41.2% of patients with other solid tumors (n = 17).

“[Relacorilant] is the first molecule that actually works on the GR that can help modulate the downstream effects of cortisol,” Thaker said. She added that, “Glucocorticoids are very important, and talked about much more in… other noncancerous diseases, but this the first time that we’ve looked at it in a cancer cohort.”

Phase 2 Data Support Further Development of Relacorilant in Platinum-Resistant Ovarian Cancer

Findings from a phase 2 trial (NCT03776812) demonstrated that intermittent dosing of relacorilant plus nab-paclitaxel (n = 60) improved progression-free survival (PFS) and duration of response (DOR), with a trend towards superior overall survival (OS), compared with nab-paclitaxel alone (n = 60) in patients with platinum-resistant/refractory ovarian cancer treated with no more than 4 prior chemotherapeutic lines. A third arm consisting of continuous relacorilant plus nab-paclitaxel was also evaluated.

At a median follow-up of 11.1 months, intermittent relacorilant nab-paclitaxel produced a median PFS of 5.6 months vs 3.8 months with nab-paclitaxel alone (HR, 0.66; 95% CI, 0.44-0.98; 

 = .038). Overall response rates (ORR) were similar across arms, at 35.7% (two-sided 95% CI, 23.4%-49.6%) in the intermittent arm vs 35.8% (two-sided 95% CI, 23.1%-50.2%) in the monotherapy arm. The median DOR was 5.55 months (95% CI, 3.75-5.88) and 3.65 (95% CI, 2.89-5.09) in these respective arms (HR, 0.36; 95% CI, 0.16-0.77;

In the preplanned OS analysis, at a median follow-up of 22.5 months, OS events were reported in 61.7% of patients in the intermittent arm vs 81.7% of patients in the nab-paclitaxel monotherapy arm. The median OS was 13.9 months (95% CI, 11.1-18.4) vs 12.2 months (95% CI, 7.7-15.3) in the intermittent vs monotherapy arms, respectively, (HR, 0.67; 95% CI, 0.43-1.03; 

Notably, PFS and OS benefit was consistent across subgroups in the intermittent vs nab-paclitaxel monotherapy arms.

Adverse effects (AEs) were similar across study arms, with the intermittent regimen demonstrating greater tolerability than the continuous regimen. The most common AEs in the intermittent arm included fatigue/asthenia (55.0%), nausea (51.7%), anemia (48.3%), abdominal discomfort (41.7%), peripheral neuropathy (36.7%), alopecia (36.7%), constipation (30.0%), neutropenia (20.0%), and vomiting (28.3%).

Regarding safety, Thaker emphasized that “The big thing is that the AE profile [for intermittent relacorilant] was a bit more manageable. The intermittent patients didn’t have as much abdominal bloating or diarrhea. There’s always going to be some myelosuppression when you combine [other agents] with chemotherapy, but there seemed to be a bit more with the continuous dosing as well….There was also a low discontinuation rate with the use of relacorilant in combination with nab-paclitaxel. In patients who have platinum-resistant ovarian cancer, it is important for us not to make their quality of life worse, because we’re dealing with a palliative situation.”

Among patients who received continuous dosing of relacorilant plus nab-paclitaxel achieved a median PFS of 5.3 months (HR vs nab-paclitaxel, 0.83; 95% CI, 0.56-1.22; 

 = .329). Although a numerical improvement in PFS was achieved, after multiplicity adjustment, these results were not deemed statistically significant (

 < .025). The median OS was 11.3 months (95% CI, 7.5-16.4), the ORR was 35.2% (two-sided 95% CI, 22.7%-49.4%), and the median DOR was 3.79 months (95% CI, 2.33-5.55).

“These preliminary data, which seem to be very interesting, supported the randomized phase 3 [ROSELLA] trial,” Lorusso said. “[However], the data with the continuous dosing [of relacorilant show that] it seems to be less effective with respect to the intermittent [dosing schedule]. This is why we chose the intermittent schedule for the randomized phase 3 trial.”

The randomized, 2-arm, open-label, multicenter, global ROSELLA study was designed to confirm these phase 2 findings in a larger patient population (

). Patients at least 18 years of age with confirmed high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancers will be enrolled onto the study. Platinum-resistant disease, defined as progression less than 6 months after completion of a platinum-containing therapy; prior exposure to between 1 and 3 systemic anticancer therapies; at least 1 prior line of platinum-based chemotherapy and bevacizumab; an ECOG performance status of 0 or 1; and adequate organ function are also required.

Those with low-grade endometroid, clear cell carcinoma, mucinous or sarcomatous histology, mixed tumors with any of these histologies, or low-grade borderline ovarian tumors are not eligible for the study. Other key exclusion criteria include primary platinum-refractory disease, previous exposure to chemotherapy and other therapies within 28 days of the first study dose; and clinically relevant toxicity from prior systemic therapy or radiotherapy that has not resolved to grade 1 or lower.

Upon enrollment, patients are randomly assigned 1:1 to receive 150 mg of oral relacorilant the day before, day of, and day after infusion with 80 mg/m

 of nab-paclitaxel, which will be administered on days 1, 8, and 15 of each 28-day cycle; or 100 mg/m

 of nab-paclitaxel monotherapy on days 1, 8, and 15 of each 28-day cycle. Relacorilant will not be administered on day -1 of cycle 1.

Lorusso explained that, “In particular, nab-paclitaxel was chosen because it does not require corticosteroid premedication. Considering that this is a GR pathway, if we [administer] premedication with the glucocorticoid, the risk is that it will impair the efficacy of relacorilant. From this point of view, nab-paclitaxel seems to be the best companion [drug].”

Treatment will continue until confirmed progressive disease or unacceptable toxicity.

“In the phase 2 trial, we mandated prophylaxis. In the phase 3 study we left the [decision up to the] clinician,” Lorusso noted. “In my experience, as I enrolled several patients onto this trial, dermatological toxicities are manageable without [the use of] granulocyte colony–stimulating factor.”

The study’s primary end point is PFS by blinded independent central review (BICR) per RECIST v1.1. Key secondary and exploratory end points include OS per RECIST v1.1, investigator-assessed PFS, ORR by BICR, best overall response, DOR, clinical benefit rate at 24 weeks, and cancer antigen 125 response. Safety and patient-reported outcomes will also be assessed.

ROSELLA is being conducted at 117 locations across North America and Europe, in collaboration with the Gynecologic Oncology Group Foundation, the European Network for Gynaecological Oncological Trial groups, the Asia-Pacific Gynecologic Oncology Trials Group, and the Latin American Cooperative Oncology Group. The study was initiated in June 2022, with a planned enrollment of approximately 360 patients, and completed recruitment as of April 8, 2024.

“We’re always looking for options for our patients,” Thaker concluded. “I believe that, since this doesn’t have overlapping, common AEs that we see with other agents…that we are going to see patients enjoy some benefit [who have been] enrolled.” 

Olawaiye AB, Kim JW, Bagameri A, et al. Clinical trial protocol for ROSELLA: a phase 3 study of relacorilant in combination with nab-paclitaxel versus nab-paclitaxel monotherapy in advanced platinum-resistant ovarian cancer. 

. 2024;35(4):e111. doi:10.3802/jgo.2024.35.e111

Munster PN, Greenstein AE, Fleming GF, et al. Overcoming taxane resistance: preclinical and phase 1 studies of relacorilant, a selective glucocorticoid receptor modulator, with nab-paclitaxel in solid tumors. 

. 2022;28(15):3214-3224. doi:10.1158/1078-0432.CCR-21-4363

Colombo N, Van Gorp T, Matulonis UA, et al. Relacorilant + nab-paclitaxel in patients with recurrent, platinum-resistant ovarian cancer: a three-arm, randomized, controlled, open-label phase II study.

. 2023;41(30):4779-4789. doi:10.1200/JCO.22.02624

Olawaiye AB, Van Gorp T, Monk BJ, et al. GOG-3073, ENGOT-OV72/MITO: a phase 3 study of relacorilant + nab-paclitaxel vs nab-paclitaxel in advanced, platinum-resistant ovarian cancer. Presented at: Society of Gynecologic Oncology 2023 Annual Meeting on Women’s Cancer; March 25-28, 2023; Tampa, Florida. Poster 1241.

Relacorilant in combination with nab-paclitaxel in advanced, platinum-resistant, high-grade epithelial ovarian, primary peritoneal, or fallopian-tube cancer. ClinicalTrials.gov. Updated August 5, 2024. Accessed October 28, 2024. https://clinicaltrials.gov/study/NCT05257408 

Corcept completes enrollment in pivotal phase 3 ROSELLA trial of relacorilant in patients with platinum-resistant ovarian cancer. News release. Corcept Therapeutics. April 8, 2024. Accessed October 28. 2024. https://ir.corcept.com/news-releases/news-release-details/corcept-completes-enrollment-pivotal-phase-3-rosella-trial

Articles

Domenica Lorusso, MD, PhD, and Premal Thaker, MD, highlight the upcoming phase 3 ROSELLA trial of relacorilant in platinum-resistant ovarian cancer.

ROSELLA Trial of Relacorilant Targets Stress Response to Overcome Chemoresistance in Ovarian Cancer

Relacorilant (CORT-125134), a selective glucocorticoid receptor modulator, has been shown to restore chemosensitivity and enhance the efficacy of nab-paclitaxel (Abraxane) in patients with recurrent, platinum-resistant, high-grade serous ovarian cancer, in whom high levels of endogenous cortisol have been shown to promote tumor progression, according to Domenica Lorusso, MD, PhD. She emphasized that further research with this combination could add to the evidence supporting the role of glucocorticoid receptor modulators in managing this disease.

In a phase 2 trial (NCT03776812), the combination of intermittent relacorilant plus nab-paclitaxel improved progression-free survival (PFS) and duration of response (DOR) compared with nab-paclitaxel monotherapy in patients with recurrent, platinum-resistant or refractory, high-grade serous or endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer, or those with ovarian cancer who had received a maximum of 4 prior chemotherapeutic regimens. The median PFS was 5.6 months with the combination (n = 56) vs 3.8 months with nab-paclitaxel alone (n = 53; HR, 0.66; 95% CI, 0.44-0.98; 

 The median DORs were 5.55 months (95% CI, 3.75-5.88) and 3.65 months (95% CI, 2.89-5.09) in these respective arms.

Based on the positive findings from the phase 2 trial, the phase 3 ROSELLA trial (EudraCT 2022-000662-18) was initiated to confirm the benefit of adding intermittent relacorilant to nab-paclitaxel in a larger patient population. This randomized, 2-arm, open-label, multicenter study is investigating intermittent relacorilant plus nab-paclitaxel vs nab-paclitaxel monotherapy in patients with confirmed high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer.

“This class of agents is interesting,” Lorusso said in an interview with 

®. “We [look forward to] the final results of the [ROSELLA] trial.”

In the interview, Lorusso discussed the rationale for investigating the activity of glucocorticoid receptor modulation in solid tumors, key findings from the phase 2 trial in ovarian cancer, and the importance of conducting the phase 3 trial to confirm prior findings with relacorilant plus nab-paclitaxel in this population.

Lorusso is the director of the Gynaecological Oncology Unit at Humanitas Hospital San Pio X in Milan, Italy, as well as a full professor of obstetrics and gynaecology at Humanitas University in Rozzano.

: What has preclinical research shown about the operation of selective glucocorticoid receptor modulators?

: We have preclinical and early clinical evidence suggesting that glucocorticoid receptors are overexpressed in several solid tumors. When [glucocorticoid receptors] are overexpressed, unfortunately, the prognosis is worse. It seems that overexpression of glucocorticoid receptors is involved in chemoresistance, as well as epithelial-mesenchymal transition and acceleration. This creates a more chemo-resistant and worse prognostic phenotype in several solid tumors, including ovarian cancer.

What was the rationale for investigating relacorilant plus nab-paclitaxel in patients with ovarian cancer?

There was a phase 1 trial [NCT02762981] combining relacorilant with nab-paclitaxel, and we discovered that there was at least an additive effect in terms of efficacy when we combined the 2 agents. Nab-paclitaxel was chosen because it does not require corticosteroid premedication. Considering [these diseases use the] glucocorticoid receptor pathway, if we use premedication with glucocorticoid [agents], we risk impairing the efficacy of relacorilant. From this point of view, nab-paclitaxel seems to be the best companion, according to the data we have right now.

The phase 1 trial reported signals of efficacy, and based on this, we performed a randomized phase 2 trial with nab-paclitaxel in combination with relacorilant. The randomized phase 2 [trial included a standard comparator arm of] single-agent nab-paclitaxel, as well as 2 experimental arms, in which relacorilant was given intermittently or continuously. According to the data we have in the intermittent arm, significant increases in PFS, overall survival, overall response rate, and DOR were reported with a good toxicity profile. These preliminary data, which seem to be interesting, supported the randomized phase 3 [ROSELLA] trial.

The trial is ongoing, but recruitment [for ROSELLA] is closed, and we are waiting for the final results. In this randomized, phase 3, potentially registrational trial, nab-paclitaxel is being compared with nab-paclitaxel in combination with intermittent relacorilant in a population of patients with platinum-resistant ovarian cancer who have received no more than 3 prior lines of therapy and have already received bevacizumab. [This is] the [population] of patients in which the randomized phase 2 exploratory analysis reported the higher benefit [with the combination].

What was seen regarding the efficacy with continuous dosing of relacorilant in the phase 2 trial?

We have the data with the continuous dosing, but [that schedule] seems to be less effective [than] intermittent [dosing]. This is the reason why we chose the intermittent schedule for the randomized phase 3 trial.

Is the ROSELLA trial mandating prophylaxis to reduce the incidence of the grade 3 or greater hematologic toxicities that were seen in the phase 2 study?

In the phase 2 trial, we mandated prophylaxis. In the phase 3 trial, we left the [investigating] clinicians more freedom [to determine the necessity of prophylaxis]. I enrolled several patients in this trial. In my experience, the hematologic toxicity is well manageable without granulocyte colony-stimulating factor.

What is your hope regarding the continued development of relacorilant, this class of agents, and ongoing research in this area?

It was a clinical observation for me that patients who were more stressed had worse outcomes. This was a clinical observation that accompanied me over most of my career, but I was unable to find a scientific reason why this happened. When we discovered this pathway, it was evident that higher levels of cortisol were implicated in worse outcomes through an activation of this pathway of more chemoresistance, which is the epithelial-mesenchymal transition. The possibility to block this pathway is interesting.

Colombo N, Van Gorp T, Matulonis UA, et al. Relacorilant + nab-paclitaxel in patients with recurrent, platinum-resistant ovarian cancer: a three-arm, randomized, controlled, open-label phase II study. 

Olawaiye A, Monk BJ, Herzog TJ, et al. ROSELLA: a phase 3 study of relacorilant in combination with nab-paclitaxel versus investigator’s choice in advanced, platinum-resistant, high-grade epithelial ovarian, primary peritoneal, or fallopian-tube cancer. 

 2022;40(suppl_16):TPS5620. doi:10.1200/JCO.2022.40.16_suppl.TPS5620

Domenica Lorusso, MD, PhD, discusses the investigation of the glucocorticoid receptor modulator relacorilant plus nab-paclitaxel in ovarian cancer.

Glucocorticoid Receptor Targeting With Relacorilant May Improve Ovarian Cancer Outcomes 

Dr Lorusso on the Use of Selective Glucocorticoid Receptor Modulators in Recurrent Ovarian Cancer

Domenica Lorusso, MD, PhD, director, Gynaecological Oncology Unit, Humanitas Hospital San Pio X, Milan; full professor, Obstetrics and Gynaecology, Humanitas University, discusses the rationale for investigating the selective glucocorticoid receptor modulator relacorilant (CORT125134) alongside nab-paclitaxel (Abraxane) in recurrent, platinum-resistant ovarian cancer.

Emerging preclinical and early clinical evidence has revealed that the overexpression of the glucocorticoid receptor in solid tumors correlates with poor prognosis, Lorusso begins. This overexpression is believed to contribute to chemoresistance and the promotion of epithelial-mesenchymal transition, a process that accelerates tumor progression and resistance to chemotherapy, she explains. Notably, this phenomenon has been observed in various solid tumors, including ovarian cancer, Lorusso adds.

Selective glucocorticoid receptor modulation with relacorilant has shown potential for reversing chemoresistance and improving the efficacy of chemotherapy, Lorusso continues. A phase 1/2 trial (NCT02762981) evaluated the safety and efficacy of relacorilant in combination with nab-paclitaxel in patients with solid tumors as did a phase 2 trial (NCT03776812) in patients with recurrent, platinum-resistant ovarian cancer. Nab-paclitaxel was chosen because it does not require prior treatment with a glucocorticoid, which could undermine the therapeutic effectiveness of relacorilant, Lorusso notes. The latter trial demonstrated that the use of relacorilant plus nab-paclitaxel had an additive effect on treatment efficacy, suggesting that this combination may improve patient outcomes, she reports.

These early results suggest that this combination could help restore chemosensitivity and enhance the overall response to chemotherapy in patients with glucocorticoid receptor–overexpressing tumors, Lorusso concludes. The phase 3 ROSELLA trial (NCT05257408) is underway to further assess the efficacy of this combination therapy in a larger population of patients with platinum-resistant ovarian cancer. If successful, this strategy could offer a novel approach to overcoming chemoresistance in ovarian cancer.

Videos

Domenica Lorusso, MD, PhD, discusses the rationale for investigating relacorilant combined with nab-paclitaxel in recurrent, platinum-resistant ovarian cancer.

Integrating the Glucocorticoid Receptor Pathway Into Ovarian Cancer Management | Supplements and Featured Publications

ROSELLA Trial of Relacorilant Targets Stress Response to Overcome Chemoresistance in Ovarian Cancer

Glucocorticoid Receptor Targeting With Relacorilant May Improve Ovarian Cancer Outcomes

Dr Lorusso on the Use of Selective Glucocorticoid Receptor Modulators in Recurrent Ovarian Cancer