Intermittent Relacorilant With Nab-Paclitaxel Leads to OS Benefit in Pretreated Ovarian Cancer Population

Nicoletta Colombo, MD, PhD

Relacorilant in combination nab-paclitaxel (Abraxane) demonstrated signs of an improvement in overall survival (OS) in patients with platinum-resistant or platinum-refractory ovarian cancer, according to results from a phase 2 study (NCT03776812) presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

“Cortisol modulation is emerging as a promising novel therapeutic platform in oncology,” said Nicoletta Colombo, MD, PhD, an associate professor of obstetrics and gynecology and associate chair, Obstetrics-Gynecology Clinic, University of Milan-Bicocca; as well as director, Gynecologic Cancer Medical Treatments, European Institute of Oncology, when presenting the updated trial findings. “In this heavily pretreated study population, including patients with primary platinum-refractory disease, sustained benefit was observed with the intermittent dosing schedule of relacorilant without additional [adverse] effect burden.”

Colombo explained that cortisol plays a role in chemotherapy resistance by suppressing apoptotic pathways that cytotoxic agents use. Expression of glucocorticoid receptor (GR), which cortisol binds to, is widely seen in ovarian cancers, and higher expression levels are associated with poor outcomes for patients (HR for progression-free survival [PFS], 1.66; 95% CI, 1.29-2.41; P < .001).²

Treatment with relacorilant, a selective GR modulator, was hypothesized to inhibit the antiapoptotic effects of cortisol and enhance the efficacy of cytotoxic therapy.

Prior analysis of the combination supports this mechanism of action and showed that relacorilant with nab-paclitaxel suppressed more GR target genes than nab-paclitaxel alone (P <.00001).^1,3

In a prior phase 1/2 study (NCT02762981) of relacorilant and nab-paclitaxel in patients with solid tumors, the combination showed disease control lasting at least 16 weeks in 38.5% (n = 5/13) of patients with advanced ovarian cancer.³

The phase 2 study was a 3-arm randomized, open-label trial that enrolled patients with recurrent platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer who had received up to 4 prior chemotherapeutic regimens. Patients were randomly assigned to receive either intermittent relacorilant at 150 mg with nab-paclitaxel at 80 mg/ m² (n=60), continuous relacorilant at 100 mg with nab-paclitaxel at 80 mg/m² (n=58), or nab-paclitaxel alone at 100-mg/m² (n=60). Nab-paclitaxel was administered on days 1, 8, and 15 to participants in each arm. For participants in the intermittent arm, relacorilant was administered on the day before, the day of, and the day after each dose of nab-paclitaxel.

PFS by investigator assessment per RECIST 1.1 criteria was the primary end point of the trial. Secondary end points were objective response rate (ORR), duration of response (DOR), OS, and safety.

Across the 3 arms, patients had a median age of 61 years (range, 38-81), 36.5% were platinum refractory, and 6.2% were refractory to their primary platinum regimen. The median number of prior therapies was 3 (range, 1-5), which included prior taxane therapy in 99.4%, bevacizumab (Avastin) in 59.0%, and PARP inhibition in 36.5%. A total of 12.1% had a BRCA1 mutation, and 6.1% had a BRCA2 mutation.

The primary PFS analysis was presented at the 2021 European Society for Medical Oncology Annual Congress⁴ after a median follow-up of 11.1 months. It showed a median PFS of 5.6 months (95% CI, 3.7-7.2) with intermittent relacorilant plus nab-paclitaxel compared with 3.8 months (95% CI, 3.5-5.4) with nab-paclitaxel alone (HR, 0.66; 95% CI, 0.44- 0.98; P=.038). In the continuous relacorilant arm, the median PFS was 5.3 months (95% CI, 3.8-5.6), with an HR compared with nab-paclitaxel alone of 0.83 (95% CI, 0.56-1.22).

Colombo noted that although ORRs were similar between the intermittent and comparator arms, there was an even greater improvement seen in DOR with the addition of intermittent relacorilant (HR, 0.36; 95% CI, 0.16-0.77; P = .006).

Updated survival findings after a median follow-up of 22.5 months showed a median OS of 13.9 months (95% CI, 11.1-18.4) in the intermittent relacorilant arm compared with 12.2 months (95% CI, 7.7-15.3) in the comparator arm (HR, 0.67; 95% CI, 0.43-1.03; P=.066) (TABLE^1,4).

“The trend toward improved overall survival that was observed at the primary analysis was confirmed,” Colombo said. “Note that the separation in the 2 curves starts at [approximately] 6 months and is sustained over the course of the study....This translates into 27% of patients in the intermittent arm still alive at 2 years compared with 14% in the comparator arm.”

In the continuous relacorilant arm, the median OS was 11.3 months (95% CI, 7.5- 16.5) for an HR vs the comparator arm of 0.85 (95% CI, 0.56-1.29).

The majority of subgroups analyzed favored the addition of intermittent relacorilant over nab-paclitaxel alone, with the exception of patients who were more heavily pretreated, those who were refractory to platinum therapy, and patients refractory to secondary platinum therapy. Patients who received prior bevacizumab seemed to benefit even more from the addition of relacorilant.

In an analysis excluding patients with primary platinum-refractory disease, the median OS with continuous relacorilant improved to 12.3 months (95% CI, 7.6-16.4).

Generally, rates of adverse events of special interest were lower in the intermittent arm or comparable with the control arm. Neutropenia of any grade was reported in 20.0% of patients in the intermittent arm, 38.6% in the continuous arm, and 36.7% in the control arm; grade 3 or higher events were reported in 6.7%, 26.3%, and 15.0%, respectively. Febrile neutropenia of grade 3 was observed only in 1 patient in the control arm. Less than half of all patients (46.7%) received prophylactic granulocyte colony-stimulating factor therapy to reduce the risk of neutropenia.

Anemia was reported in 48.3% of patients in the intermittent arm, 64.9% in the continuous arm, and 56.7% in the control arm; grade 3 or higher events were reported in 13.3%, 19.3%, and 11.7%, respectively. Cases of peripheral neuropathy of any grade were observed in 36.7%, 54.4%, and 35.0% with intermittent relacorilant and nab-paclitaxel, continuous relacorilant and nab-paclitaxel, and nabpaclitaxel alone, respectively; grade 3 or higher cases were observed in 0%, 15.8%, and 5.0%. Fatigue or asthenia was reported in 55.0% of patients in the intermittent arm, 71.9% in the continuous arm, and 65.0% in the control arm; grade 3 or higher events were reported in 11.7%, 8.8%, and 1.7%, respectively.

Colombo noted that a phase 3 trial (ROSELLA; NCT05257408) of intermittent relacorilant and nab-paclitaxel compared with investigator’s choice of chemotherapy in pretreated patients with high-grade serous, endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancer is planned to begin enrolling later in 2022.

_REFERENCES:

_{1. Colombo N, Van Gorp T, Matulonis UA, et al. Overall survival data from a 3-arm, randomized, open-label, phase 2 study of relacorilant, a selective glucocorticoid receptor modulator, combined with nab-paclitaxel in patients with recurrent platinum-resistant ovarian cancer. J Clin Oncol. 2022;40(suppl 17):LBA5503. doi:10.1200/ JCO.2022.40.17_suppl.LBA5503}

_{2. Veneris JT, Darcy KM, Mhawech-Fauceglia P, et al. High glucocorticoid receptor expression predicts short progression-free survival in ovarian cancer. Gynecol Oncol. 2017;146(1):153-160. doi:10.1016/j. ygyno.2017.04.012}

_{3. Munster PN, Sachdev JC, Fleming GF, et al. Relacorilant (RELA) with nab-paclitaxel (NP): safety and activity in patients with pancreatic ductal adenocarcinoma (PDAC) and ovarian cancer (OvCA). J Clin Oncol. 2019;37(suppl 15):4130. doi:10.1200/JCO.2019.37.15_suppl.4130}

_{4. Colombo N, Nguyen DD, Fleming GF, et al. Relacorilant, a selective glucocorticoid receptor modulator, in combination with nab-paclitaxel improves progression-free survival in patients with recurrent platinum-resistant ovarian cancer: a 3-arm, randomized, open-label, phase II study. Ann Oncol. 2021;32(suppl 5):721O. doi:10.1016/j. annonc.2021.08.1164}