Background

Relacorilant, a first-in-class selective glucocorticoid receptor antagonist, increases a tumour's sensitivity to chemotherapy by reducing cortisol signalling. This study aimed to show whether the addition of relacorilant to nab-paclitaxel improves progression-free and overall survival in females with platinum-resistant ovarian cancer.

Methods

This randomised, controlled, open-label phase 3 trial (ROSELLA [GOG-3073/ENGOT-ov72]) was done at 117 hospitals and community oncology treatment centres in 14 countries across Australia, Europe, Latin America, North America, and South Korea. Patients had to be aged 18 years or older and had to have a confirmed diagnosis of platinum-resistant, epithelial (ie, high-grade serous, endometrioid, or carcinosarcoma with a ≥30% epithelial component) ovarian, primary peritoneal, or fallopian tube cancer; up to three previous lines of anticancer therapy and previous bevacizumab and disease progression or intolerance to the most recent therapy; measurable disease according to the Response Evaluation Criteria in Solid Tumours (RECIST; version 1.1); an Eastern Cooperative Oncology Group performance status of 0 or 1; and adequate organ function. Patients were assigned (1:1) to relacorilant (150 mg orally the day before, of, and after nab-paclitaxel infusion) plus nab-paclitaxel (80 mg/m² intravenously on days 1, 8, and 15 of each 28-day cycle) or nab-paclitaxel monotherapy (100 mg/m² intravenously on the aforementioned schedule). The dual primary endpoints were progression-free survival assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumours (version 1.1) and overall survival, and were assessed in all randomly assigned patients by intention to treat. The safety population included all randomly assigned patients who received at least one dose of the assigned treatment. This trial was registered at ClinicalTrials.gov, NCT05257408, and is ongoing.

Findings

Between Jan 5, 2023, and April 8, 2024, 381 patients were randomly assigned to the combination group (n=188) or to the nab-paclitaxel monotherapy group (n=193). Patients receiving relacorilant plus nab-paclitaxel had a statistically significant improvement in progression-free survival assessed by blinded independent central review compared with those receiving nab-paclitaxel monotherapy (hazard ratio 0·70 [95% CI 0·54–0·91]; median 6·54 months [95% CI 5·55–7·43] vs 5·52 months [3·94–5·88]; stratified log-rank p=0·0076). At the planned interim analysis, there was a clinically meaningful difference in overall survival with the addition of relacorilant to nab-paclitaxel (0·69 [95% CI 0·52–0·92]; 15·97 months [95% CI 13·47–not reached] vs 11·50 months [10·02–13·57]; log-rank p=0·0121). Adverse events were similar across study groups when adjusted for nab-paclitaxel exposure; no new safety signals were observed.

Interpretation

The addition of relacorilant to nab-paclitaxel prolonged progression-free survival and interim results also showed an improvement in overall survival. Together, the results position the combination of relacorilant and nab-paclitaxel as a potential new standard treatment for patients with platinum-resistant ovarian cancer.

Funding

Corcept Therapeutics.

中文翻译：

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Relacorilant 和白蛋白结合型紫杉醇治疗铂耐药卵巢癌患者 （ROSELLA）：一项开放标签、随机、对照的 3 期试验

  背景

Relacorilant 是一种一流的选择性糖皮质激素受体拮抗剂，通过减少皮质醇信号传导来增加肿瘤对化疗的敏感性。本研究旨在显示向白蛋白结合型紫杉醇中添加 relacorilant 是否能改善铂类耐药卵巢癌女性患者的无进展生存期和总生存期。

  方法

这项随机、对照、开放标签的 3 期试验 （ROSELLA [GOG-3073/ENGOT-ov72]） 在澳大利亚、欧洲、拉丁美洲、北美和韩国 14 个国家的 117 家医院和社区肿瘤治疗中心进行。患者必须年满 18 岁，并且必须确诊为铂类耐药、上皮癌（即高级别浆液性、子宫内膜样癌或癌肉瘤，具有 ≥30% 上皮成分）卵巢癌、原发性腹膜癌或输卵管癌;最多三线既往抗癌治疗和既往贝伐珠单抗和疾病进展或对最新治疗不耐受;根据实体瘤反应评估标准（RECIST;1.1 版）的可测量疾病;Eastern Cooperative Oncology Group 体能状态为 0 或 1;以及足够的器官功能。患者被分配 （1：1） 至 relacorilant （在白蛋白结合型紫杉醇输注前一天、输注时和输注后一天口服 150 mg） 加白蛋白结合型紫杉醇 （80 mg/m² 在每个 28 天周期的第 1 天、 8 天和第 15 天静脉注射）或白蛋白结合型紫杉醇单药治疗 （100 mg/m² 静脉注射，按上述时间表）。双重主要终点是盲法独立中央审查根据实体瘤反应评估标准 （1.1 版） 评估的无进展生存期和总生存期，并按意向治疗在所有随机分配的患者中进行评估。安全人群包括所有随机分配的患者，他们接受了至少一剂指定治疗。该试验于 NCT05257408 ClinicalTrials.gov 注册，目前正在进行中。

  发现

在 2023 年 1 月 5 日至 2024 年 4 月 8 日期间，381 例患者被随机分配到联合治疗组 （n=188） 或白蛋白结合型紫杉醇单药治疗组 （n=193）。与接受白蛋白结合型紫杉醇单药治疗的患者相比，接受 relacorilant 联合白蛋白结合型紫杉醇治疗的患者通过盲法独立中心审查评估的无进展生存期有统计学意义改善（风险比 0·70 [95% CI 0·54–0·91];中位 6·54 个月 [95% CI 5·55–7·43] vs 5·52 个月 [3·94–5·88];分层对数秩 p=0·0076）。在计划的中期分析中，在白蛋白结合型紫杉醇基础上加用 relacorilant 后，总生存期存在临床意义差异（0·69 [95% CI 0·52–0·92];15·97 个月 [95% CI 13·47–未达] vs 11·50 个月 [10·02–13·57];对数秩 p=0·0121）。当调整白蛋白结合型紫杉醇暴露时，研究组之间的不良事件相似;未观察到新的安全信号。

  解释

在白蛋白结合型紫杉醇中加入 relacorilant 延长了无进展生存期，中期结果也显示总生存期有所改善。总之，研究结果将 relacorilant 和白蛋白结合型紫杉醇的组合定位为铂类耐药卵巢癌患者的潜在新标准治疗方法。

  资金

  Corcept Therapeutics。