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

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.¹

“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 OncologyLive. “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.^1,2

“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 (P < .001) in OVCAR5 cells. Furthermore, relacorilant plus paclitaxel decreased tumor growth and slowed time to progression in several xenograft models vs paclitaxel alone (both P < .0001).²

“[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.³

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; P = .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; P = .006).

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; P = .066).

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

ROSELLA Trial Overview

The randomized, 2-arm, open-label, multicenter, global ROSELLA study was designed to confirm these phase 2 findings in a larger patient population (Figure^1,5). 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.^1,4,5

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/m² of nab-paclitaxel, which will be administered on days 1, 8, and 15 of each 28-day cycle; or 100 mg/m² 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, 2024.⁶

“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.”

References

1. 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. J Gynecol Oncol. 2024;35(4):e111. doi:10.3802/jgo.2024.35.e111
2. 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. Clin Cancer Res. 2022;28(15):3214-3224. doi:10.1158/1078-0432.CCR-21-4363
3. 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. J Clin Oncol. 2023;41(30):4779-4789. doi:10.1200/JCO.22.02624
4. 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.
5. 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
6. 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