Relacorilant Plus Nab-Paclitaxel Demonstrates OS Advantage in Recurrent, Platinum-Resistant Ovarian Cancer

Relacorilant Plus Nab-Paclitaxel in

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Treatment with intermittent or continuous doses of the investigational selective glucocorticoid receptor modulator relacorilant in combination with nab-paclitaxel (Abraxane) resulted in an overall survival (OS) benefit compared with nab-paclitaxel monotherapy, but failed to demonstrate an improvement in progression-free survival (PFS) in patients with recurrent, platinum-resistant ovarian cancer, missing the primary end point of a phase 2 study (NCT03776812). Findings were published in the Journal of Clinical Oncology.

At a median follow-up of 11.1 months across arms, results from the primary analysis of the 3-arm trial showed that patients who received intermittent relacorilant plus nab-paclitaxel (n = 60) experienced a median PFS of 5.6 months compared with 3.8 months among those who received nab-paclitaxel monotherapy (n = 60; HR, 0.66; 95% CI, 0.44-0.98; P = .038). Moreover, patients who were treated with continuous relacorilant and nab-paclitaxel (n = 58) achieved a median PFS of 5.3 months (HR, 0.83; 95% CI, 0.56-1.22; P = .329). However, the results for the primary end point of PFS did not meet the statistical significance threshold (P < .025) following a multiplicity adjustment.

In terms of OS, at a median follow-up of 22.5 months for the predefined analysis, both intermittent and continuous relacorilant plus nab-paclitaxel provided a benefit over nab-paclitaxel monotherapy, with HRs of 0.67 (95% CI, 0.43-1.03; P = .066) and 0.85 (95% CI, 0.56-1.29; P = .447), respectively. The median OS figures were 13.9 months (95% CI, 11.1-18.4), 11.3 months (95% CI, 7.5-16.4), and 12.2 months (95% CI, 7.7-15.3), respectively.

Objective response rates (ORRs) were similar across the treatment arms; the rates in the intermittent (n = 56), continuous (n = 54), and monotherapy (n = 53) arms were 35.7% (95% CI, 23.4%-49.6%), 35.2% (95% CI, 22.7%-49.4%), and 35.8% (95% CI, 23.1%-50.2%), respectively. The complete response rates were 1.8%, 7.4%, and 3.8%, respectively. The median durations of response (DORs) were 5.55 months (95% CI, 3.75-5.88), 3.79 months (95% CI, 2.33-5.55), and 3.65 months (95% CI, 2.89-5.09), respectively. Compared with nab-paclitaxel monotherapy, the HRs for the intermittent and continuous arms were 0.36 (95% CI, 0.16-0.77; P = .006) and 0.72 (95% CI, 0.33-1.58; P = .423).

The open-label phase 2 trial enrolled adult patients with recurrent, platinum-resistant/refractory, high-grade serous or endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancer, or those with ovarian carcinosarcoma who had received a maximum of 4 previous chemotherapeutic regimens. Additionally, eligible patients needed to have undergone a minimum of 1 previous line of platinum-based chemotherapy with a platinum-free interval lasting 6 months or less or disease progression during or immediately after platinum-based therapy. Patients were also required to have an ECOG performance status of 1 or less and adequate organ/bone marrow function. Those with clear cell, mucinous, and borderline disease were not included.

Following enrollment, patients were randomly assigned 1:1:1 to the intermittent, continuous, or monotherapy arms to receive nab-paclitaxel 80 mg/m2 plus relacorilant 150 mg orally once on the day before, the day of, and the day after nab-paclitaxel; nab-paclitaxel 80 mg/m2 plus relacorilant 100 mg orally once daily; or nab-paclitaxel at 100 mg/m2, respectively. Nab-paclitaxel was given once daily on days 1, 8, and 15 of each 28-day cycle in each arm. Patients were stratified by treatment-free interval from most recent taxane (relapse within 6 months vs > 6 months) and presence of ascites (yes vs no).

The primary end point was investigator-assessed PFS comparing each of the 2 combination arms with the monotherapy arm. Secondary end points included OS, ORR, DOR, safety, and pharmacokinetics. Investigators also evaluated glucocorticoid receptor expression,change from baseline in glucocorticoid receptor–target genes, and patient-reported outcomes (PROs) as exploratory end points.

In the total population (n = 178), the median age was 61 years (range, 38-81). Most patients had measurable disease at baseline (91.6%), high-grade serous histology (93.3%), and underwent prior treatment with bevacizumab (Avastin; 59.0%). The median number of prior systemic anticancer regimens was 3 (range, 1-5) and the median number of prior chemotherapies was 2 (range, 1-4). Baseline patient characteristics were generally similar across the 3 study arms.

Regarding safety, the incidence of adverse effects (AEs) was similar across study arms. The most common any-grade AEs in the intermittent arm were fatigue or asthenia (55.0%), nausea (51.7%), anemia (48.3%), and abdominal discomfort (41.7%). In the continuous arm, any-grade AEs included nausea (75.4%), fatigue or asthenia (71.9%), anemia (64.9%), and peripheral neuropathy (54.4%). In the monotherapy arm, common any-grade AEs consisted of fatigue or asthenia (65.0%), anemia (56.7%), nausea (45.0%), and abdominal discomfort (41.7%).

Serious AEs occurred in the intermittent (n = 60), continuous (n = 57), and monotherapy (n = 60) arms at rates of 26.7%, 54.4%, and 31.7%, respectively. Drug-related serious AEs occurred in 10 patients, with 14 total events. Three patients died due to AEs, 2 in the intermittent arm due tointestinal obstruction and general physical health deterioration, and 1 due to pneumonia in the continuous arm. Investigators noted that no deaths were considered related to the study drug.

In terms of PROs, patients in all arms experienced estimated mean decreases from baseline across all PRO instruments. Larger decreases were observed in patients treated with continuous relacorilant compared with nab-paclitaxel monotherapy (P < .05). Patients in the monotherapy and intermittent arms experienced similar levels of decrease.

Although the study did not meet its primary end point, investigators concluded that relacorilant is an agent with a convenient dosing schedule that has the potential to be synergistically combined with other therapies and provide symptom improvement and extend survival. The combination of relacorilant and nab-paclitaxel is being studied in a phase 3 trial (NCT05257408) that is currently recruiting patients with advanced, platinum-resistant, high-grade epithelial ovarian, primary peritoneal, or fallopian-tube cancer.

Reference

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. Published online June 26, 2023. doi:10.1200/JCO.22.02624