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 investigator’s choice of chemotherapy 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. 

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

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

Articles

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

Glucocorticoid Receptor Targeting With Relacorilant May Improve Ovarian Cancer Outcomes

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