Abstract
Background
Ovarian cancer has the highest mortality among gynecologic cancers, primarily because it typically is diagnosed at a late stage and because of the development of chemoresistance in recurrent disease. Improving outcomes in women with platinum-resistant ovarian cancer is a substantial unmet need. Activation of the glucocorticoid receptor (GR) by cortisol has been shown to suppress the apoptotic pathways used by cytotoxic agents, limiting their efficacy. Selective GR modulation may be able to counteract cortisol’s antiapoptotic effects, enhancing chemotherapy’s efficacy. A previous phase 2 study has shown that adding intermittently dosed relacorilant, a selective GR modulator, to nab-paclitaxel improved outcomes, including progression-free survival (PFS) and overall survival (OS), with minimal added toxicity, in women with recurrent platinum-resistant ovarian cancer. The ROSELLA study aims to confirm and expand on these findings in a larger population.
Methods
ROSELLA is a phase 3, randomized, 2-arm, open-label, global multicenter study in women with recurrent, platinum-resistant, high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer. Eligible participants have received 1 to 3 lines of prior systemic anticancer therapy, including ≥1 prior line of platinum therapy and prior treatment with bevacizumab, with documented progressive disease or intolerance to the most recent therapy. There is no biomarker-based requirement for participant selection. Participants are randomized 1:1 to receive intermittently dosed relacorilant in combination with nab-paclitaxel or nab-paclitaxel monotherapy. The study’s primary efficacy endpoint is PFS as assessed by blinded independent central review. Secondary efficacy endpoints include OS, investigator-assessed PFS, objective response rate, best overall response, duration of response, clinical benefit rate at 24 weeks, and cancer antigen 125 response. The study is also evaluating safety and patient-reported outcomes.
Trial Registration
ClinicalTrials.gov Identifier: NCT05257408; European Union Drug Regulating Authorities Clinical Trials Database Identifier: 2022-000662-18
Keywords: Relacorilant, Glucocorticoid Receptor, Nab-paclitaxel, Ovarian Neoplasms, Neoplasm Drug Resistance
Synopsis
Intermittently dosed relacorilant, a selective glucocorticoid receptor modulator, plus nab-paclitaxel improved progression-free and overall survival versus nab-paclitaxel alone in a phase 2 study in platinum-resistant ovarian cancer. Here we describe the protocol of the phase 3 ROSELLA study that aims to confirm these findings.
Graphical Abstract
INTRODUCTION
In the United States in 2022, ovarian cancer was the second most common gynecologic malignancy, the leading cause of gynecologic cancer death, and the fifth leading cause of cancer-related deaths in women overall [1]. In the vast majority of cases, ovarian cancer is diagnosed at an advanced stage [2,3]. Despite improvements in treatment, survival rates over the last 30 years have been poor [4], with 10-year survival rates of 10% to 30% for women who have advanced disease [5]. Despite initial responses to therapy, the disease relapses in most women, with 5-year relapse rates of >70% for stage III or IV disease [5,6]. Individuals who develop disease recurrence <6 months after completing platinum-based therapy are considered to have platinum-resistant disease [5,7]. Those with disease that does not respond to or has progressed during or within 1 month of completion of first-line platinum-based therapy are considered to have platinum-refractory disease [7]. Treatment options for individuals with platinum-resistant/refractory disease are limited. The standard approach involves sequential, single-agent chemotherapy (e.g., paclitaxel, pegylated liposomal doxorubicin, topotecan, gemcitabine), with or without bevacizumab [8,9]. In addition, the antibody-drug conjugate (ADC) mirvetuximab soravtansine-gynx is an option for tumors that express folate receptor α (FRα) [10]. However, the response rates to single-agent chemotherapy treatments are generally low, with objective response rates (ORRs) of ≤15%, reaching up to 30% with the addition of bevacizumab [5,11], highlighting the need for additional treatment options to address this significant challenge.
Relacorilant is an investigational, orally administered, selective glucocorticoid receptor (GR) modulator in development to treat platinum-resistant ovarian cancer [12,13]. Even at physiologic levels, endogenous cortisol binding to and activating the GR can suppress the apoptotic pathways used by cytotoxic agents, thus reducing the efficacy of chemotherapies [14,15,16]. The GR is abundantly expressed in ovarian tumors, and high GR expression correlates with poor prognosis [17]. Nonclinical and clinical data suggest that modulation of GR signaling (such as that provided by relacorilant) can enhance chemotherapy efficacy by reversing the antiapoptotic effects of cortisol [12,13,14,15,18,19]. In a recent phase 2 study of 178 women with recurrent platinum-resistant or primary platinum-refractory ovarian cancer, intermittently dosed relacorilant in combination with nab-paclitaxel demonstrated meaningful improvements in progression-free survival (PFS) (hazard ratio [HR]=0.66; 95% confidence interval [CI]=0.44–0.98), duration of response (DOR) (HR=0.36; 95% CI=0.16–0.77), and overall survival (OS) (HR=0.67; 95% CI=0.43–1.03), with minimal added toxicity compared with nab-paclitaxel monotherapy [13]. In an ad hoc analysis of these data, greater improvements were observed in the subgroup of 83 participants who did not have primary platinum-refractory disease and who had received 1 to 3 prior lines of therapy, including prior treatment with bevacizumab. In these patients, adding intermittent relacorilant to nab-paclitaxel improved PFS (HR=0.40; 95% CI=0.21–0.77) and OS (HR=0.38; 95% CI=0.17–0.82) over nab-paclitaxel monotherapy [13]. The findings of this ad hoc analysis of the phase 2 study data helped determine the patient population for further clinical investigations.
ROSELLA (GOG-3073, ENGOT-ov72/MITO, APGOT-ov10, LACOG 0223, ANZGOG2221/2023) is a phase 3 study of intermittently dosed relacorilant in combination with nab-paclitaxel versus nab-paclitaxel monotherapy that aims to confirm and expand on the findings from the phase 2 study in a larger participant population. Here we describe the protocol of this currently ongoing study.
MATERIALS AND METHODS
1. Study design
ROSELLA is a phase 3, randomized, 2-arm, open-label, global multicenter study that began recruiting in June 2022 and completed enrollment in April 2024. In the study, women with recurrent, platinum-resistant, high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer are being randomized 1:1 to receive either intermittently dosed relacorilant in combination with nab-paclitaxel or nab-paclitaxel monotherapy (Fig. 1). The study is being conducted in collaboration with the Gynecologic Oncology Group (GOG) Foundation, the European Network for Gynaecological Oncological Trial groups (ENGOT), the Asia-Pacific Gynecologic Oncology Trials Group (APGOT), and the Latin American Cooperative Oncology Group (LACOG). Planned enrollment is approximately 360 participants, and the study is being conducted at approximately 125 sites globally.
Fig. 1. Study schema.
30-d FU, 30-day follow-up visit (phone); EOT, end-of-treatment visit; LTFU, long-term follow-up visit (phone).
*For patients who discontinue treatment at the time of disease progression, or decline further radiographic tumor assessments, LTFU is every 3 months after last study treatment. For patients who discontinue treatment before disease progression, follow-up is every 8 weeks for 40 weeks, then every 12 weeks until disease progression.
2. Objectives
This study is evaluating the efficacy and safety of relacorilant in combination with nab-paclitaxel compared with nab-paclitaxel monotherapy. The primary objective is PFS as assessed by blinded independent central review (BICR). Secondary efficacy objectives include OS, investigator-assessed PFS, ORR, best overall response (BOR), DOR, and clinical benefit rate (CBR). Exploratory objectives include the relationship between baseline and pharmacodynamic markers and treatment response, pharmacodynamic effects of intermittent relacorilant, resistance mechanisms, and relacorilant pharmacokinetics for participants receiving relacorilant in combination with nab-paclitaxel. Changes from baseline and differences between treatment arms in patient-reported outcomes (PRO) and quality of life (QOL) will be assessed in all participants.
3. Endpoints
The ROSELLA study’s primary efficacy endpoint is PFS by BICR according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) [20]. Secondary efficacy endpoints are OS, PFS as determined by the investigator or local radiologist, ORR, BOR, DOR, CBR at 24 weeks, cancer antigen 125 (CA-125) response per Gynecologic Cancer Intergroup (GCIG) criteria [21], and combined response according to RECIST v1.1 plus GCIG criteria. Unless otherwise noted, assessments for response and disease progression are according to RECIST v1.1 and assessed by BICR. Tumor assessments using computed tomography or magnetic resonance imaging and blood draws for CA-125 assessment are performed prior to the first dose of study treatment, then every 8 weeks from Cycle 1 Day 1 of treatment for the first 40 weeks, and then every 12 weeks thereafter irrespective of any treatment delays. Tumor assessments are performed until documented disease progression, including in participants who prematurely discontinue treatment. Once best CA-125 response is determined, a sample for confirmatory CA-125 assessment is drawn in ≤28 days. Tumor and CA-125 assessments are also done at the end-of-treatment visit, occurring <21 days after the last dose of study treatment.
Safety endpoints are adverse events (AEs), serious AEs, treatment-related AEs, AEs by severity (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0), deaths due to AEs, all deaths, changes in laboratory values and vital sign parameters, and treatment discontinuation and study withdrawal due to AEs. Assessments of AEs are performed at screening; on Days 1, 8, and 15 of all treatment cycles; and at the end-of-treatment and 30-day follow-up visits.
Pharmacodynamic and biomarker exploratory endpoints include assessment of tumor GR expression and salivary cortisol at baseline and change from baseline in expression of GR-regulated genes in whole blood. Between the screening and Cycle 1 Day 1 visits, saliva is collected from all participants for cortisol diurnal rhythm assessment. Immunohistochemistry for GR and other exploratory markers is performed at screening for participants with available tissue samples, either archival (preferably collected within 12 months of screening) or obtained with an optional on-study tumor biopsy collected before Cycle 1 Day 1. To assess glucocorticoid-related pathways and exploratory biomarkers, pre-dose blood samples are collected from all participants at screening, Cycle 1 Days 1 and 15, Cycle 3 Day 1, at the visit following observation of response, and upon disease progression or end of treatment, as well as on Cycle 1 Day 17 for a subset of participants receiving relacorilant in combination with nab-paclitaxel. Additional blood samples collected using this schedule are being used to help identify potential mechanisms associated with lack of response to relacorilant and nab-paclitaxel through longitudinal analysis of resistance-related genes/biomarkers and baseline GR expression. Sparse pharmacokinetic sampling (1 sample at 0 hours pre-dose and 1 sample between 0.5 and 4 hours post-dose) is conducted on Cycle 1 Day 15 to assess plasma concentrations of relacorilant.
Additional exploratory endpoints are changes from baseline in PRO and QOL assessment scores evaluated using the European Organization for Research and Treatment of Cancer (EORTC) ovarian cancer–specific QOL questionnaire (EORTC QLQ-OV28), EORTC core QOL questionnaire (EORTC QLQ-C30), and EuroQol-5 Dimension 5-Level questionnaire (EQ-5D-5L). Participants will also complete a healthcare resource utilization (HRU) questionnaire. Initial PRO, QOL, and HRU assessments will be performed at any time from the screening visit until prior to administration of the first dose of study treatment. Post-baseline assessments will be completed on the first day of treatment for each cycle for Cycles 2 through 4 and then for every other cycle beginning on Cycle 6 Day 1 through the end-of-treatment visit. These assessments will be administered prior to any discussions of tumor assessments or disease-related clinical changes with the patient. The primary PRO is the number of participants with a ≥15-point absolute improvement at Week 8 or 9 in the abdominal/gastrointestinal scale of the EORTC QLQ-OV28.
4. Treatment
Within 28 days of screening, ROSELLA participants are randomized to receive relacorilant in combination with nab-paclitaxel or nab-paclitaxel monotherapy (Fig. 1). Participants in the relacorilant plus nab-paclitaxel arm receive relacorilant 150 mg orally once daily with food for 3 consecutive days: 1 dose the day before (excluding Cycle 1 Day −1), 1 dose the day of, and 1 dose the day after each nab-paclitaxel infusion. Nab-paclitaxel 80 mg/m2 intravenous (IV) infusion is administered on Days 1, 8, and 15 of each 28-day cycle. Participants in the nab-paclitaxel monotherapy arm receive nab-paclitaxel 100 mg/m2 IV infusion on Days 1, 8, and 15 of each 28-day cycle. Participants will continue receiving treatment until they reach a protocol-defined event of disease progression, experience unmanageable toxicity, or fulfill other criteria for treatment discontinuation, such as patient refusal, investigator decision, or pregnancy.
The nab-paclitaxel dose in combination with relacorilant for this phase 3 study is well founded from prior clinical pharmacology to safely and effectively evaluate the combination compared with monotherapy. Because relacorilant is a strong inhibitor of cytochrome P450 3A4 (CYP3A4), which partially mediates nab-paclitaxel elimination, coadministration results in higher nab-paclitaxel exposures [12,22]. Clinical experience from phase 1 [12] and phase 2 [13] studies demonstrated that a nab-paclitaxel 80 mg/m2 dose in combination with relacorilant approximates exposures achieved with 100 to 125 mg/m2 of single-agent nab-paclitaxel based on the CYP3A4-mediated pharmacologic profile. For these earlier clinical evaluations and ROSELLA, nab-paclitaxel was chosen over paclitaxel based on its more favorable safety profile and to avoid the need for corticosteroid premedication [13].
5. Eligibility criteria
The ROSELLA study is enrolling women aged ≥18 years with recurrent, platinum-resistant, histologically confirmed high-grade (grade 3) serous epithelial ovarian, primary peritoneal, or fallopian-tube carcinoma; high-grade (grade 3) endometrioid epithelial carcinoma; or carcinosarcoma with a ≥30% epithelial component. Eligible participants have received 1 to 3 lines of prior systemic anticancer therapy, including ≥1 prior line of platinum therapy and prior treatment with bevacizumab, with documented progressive disease or intolerance to the most recent therapy. Platinum resistance is defined as disease progression <6 months from completion of platinum-containing therapy. Other key inclusion criteria include having ≥1 measurable lesion by RECIST v1.1; Eastern Cooperative Oncology Group performance status 0 or 1; and adequate organ function based on laboratory test criteria that include absolute neutrophil count ≥1,500 cells/mm3, platelet count ≥100,000/mm3, and serum creatinine ≤1.5 times the upper limit of normal or calculated creatinine clearance ≥35 mL/min (Cockroft-Gault). Key exclusion criteria include primary platinum-refractory disease, defined as disease that did not respond to or progressed ≤1 month from completion of platinum-containing therapy in first-line treatment; clinically relevant and reversible toxicity from prior systemic anticancer therapies or radiotherapy that remains unresolved to grade ≤1 before randomization; low-grade serous or endometrioid histology other than epithelial, clear cell or mucinous histology, sarcomatous with <30% epithelial histology component, or mixed tumors containing any of these histologies, or borderline ovarian tumor; untreated or symptomatic central nervous system metastases; and chronic or frequent use of oral corticosteroids. A complete list of inclusion and exclusion criteria can be found in Table 1.
Table 1. Inclusion/exclusion criteria.
| Criteria | Details | |
|---|---|---|
| Inclusion criteria | • Signed and dated IRB/IEC–approved informed consent form prior to study-specific screening procedures | |
| • Female patients ≥18 yr of age at time of consent | ||
| • Confirmed histologic diagnosis of high-grade (grade 3) serous, epithelial ovarian, primary peritoneal, or fallopian tube carcinoma | ||
| • Platinum-resistant disease (defined as progression <6 mo from platinum-containing therapy completion) | ||
| • Consent to provide archival tumor tissue block or slides; may consent to an optional tumor biopsy if archival tumor tissue is unavailable | ||
| • Life expectancy of ≥3 mo | ||
| • ≥1 lesion that meets the RECIST v1.1 definition of measurable disease | ||
| • ECOG performance status 0 or 1 | ||
| • Ability to comply with protocol requirements | ||
| • Ability to swallow and retain oral medication | ||
| • Received prior systemic anticancer therapy (1–3 lines), including ≥1 line of platinum therapy and prior bevacizumab treatment | ||
| • Adequate organ function based on laboratory test criteria: | ||
| - ANC: ≥1,500 cells/mm3 | ||
| - Platelet count ≥100,000/mm3 | ||
| - Hemoglobin ≥9 g/dL | ||
| - AST or ALT ≤2.5 × ULN, or ≤5 × ULN with liver metastases | ||
| - Total bilirubin ≤1.5 × ULN or ≤ 3 × ULN in patients with Gilbert’s syndrome | ||
| - Albumin ≥2.5 g/dL | ||
| - Serum creatinine ≤1.5 ULN or calculated CrCl ≥35 mL/min (Cockroft-Gault equation) if serum creatinine >1.5 × ULN | ||
| • Negative pregnancy test for patients of childbearing potential; use of highly effective contraception for patients of childbearing potential; hormonal contraceptives are not allowed | ||
| • COVID-19 approved vaccines accepted as concomitant medications when investigator recommended | ||
| Exclusion criteria | • Clinically relevant toxicity from prior systemic anticancer therapies or radiotherapy unresolved to grade ≤1 before randomization | |
| • Major surgery within 4 wk prior to randomization | ||
| • Low-grade serous or endometrioid histology other than epithelial, clear cell or mucinous histology, or sarcomatous with <30% epithelial histology component; mixed tumors containing these histologies; or borderline ovarian tumor | ||
| • Primary platinum-refractory disease, defined as disease that did not respond to or has progressed during or within ≤1 mo of the last dose of first-line platinum-containing chemotherapy | ||
| • No prior bevacizumab treatment | ||
| • Treated with the following prior to randomization: | ||
| - Chemotherapy, immunotherapy, investigational agent treatments for the disease under study within 28 days, before first dose of study drug | ||
| - Radiotherapy that was not completed ≥2 wk prior to first dose of study drug | ||
| - Hormonal anticancer therapies within 7 days of first dose of study drug | ||
| - Systemic, inhaled, or prescription strength topical corticosteroids within a period equivalent to 5 times the half-life of the corticosteroid used prior to first dose of study drug | ||
| • Wide-field radiation to >25% of marrow-bearing areas | ||
| • Toxicities of prior therapies that have not resolved to grade ≤1 per NCI CTCAE v5.0 | ||
| • Chronic or frequent use of oral corticosteroids | ||
| • History of severe hypersensitivity or severe reaction to any of the study drugs | ||
| • Concurrent treatment with mifepristone or other GR modulators | ||
| • Peripheral neuropathy grade >1 (any cause) | ||
| • Pregnant or lactating patients or those expecting to conceive children within the projected study duration, starting with the screening visit through ≥6 mo after the last dose of study treatment | ||
| • Clinically significant, uncontrolled condition(s) that in the investigator’s opinion may confound the results of the study or interfere with the patient's safety or participation | ||
| • Chronic/acute active infection with HIV, HCV, or HBV | ||
| • Untreated or symptomatic CNS metastases | ||
| • History of other malignancy within 3 years prior to randomization | ||
| • Concomitant medications that are strong CYP3A inhibitors/inducers or that are substrates of CYP3A prohibited for use with strong CYP3A inhibitors, and moderate and strong CYP2C8 inhibitors | ||
| • Concurrent treatment on other investigational studies for the treatment of ovarian, fallopian tube, or primary peritoneal cancer | ||
| • Receipt of live vaccine within 30 days before study start date | ||
ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; COVID-19, coronavirus disease 2019; CNS, central nervous system; CrCl, creatinine clearance; CYP, cytochrome P450; ECOG, Eastern Cooperative Oncology Group; GR, glucocorticoid receptor; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IRB/IEC, Institutional Review Board/Independent Ethics Committee; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; RECIST, Response Evaluation Criteria in Solid Tumors; ULN upper limit of normal.
6. Sample size
Planned total sample size and number of events needed in the study were informed by median PFS results from previous studies in this patient population. Based on 1:1 randomization allocation ratio, a total of 244 events ensure the study has 90% power for a 2-sided log-rank test with an α=0.05 level of significance to detect a 50% increase in median PFS (HR=0.66). This target HR is similar to the results observed in the phase 2 study of intermittent relacorilant in combination with nab-paclitaxel [13].
7. Randomization and stratification
Randomization is centrally assigned using an interactive response system. Patient randomization is being stratified by region (North America vs. Europe vs. the rest of the world) and number of prior lines of therapy (1 vs. >1).
8. Statistical methods
The primary and all secondary efficacy endpoints will be analyzed using the intent-to-treat population, defined as all randomized study participants. Analyses of safety endpoints will be done using the safety population, composed of all randomized participants receiving ≥1 dose of study treatment. All statistical analyses will be performed using SAS v9.4 or later (SAS Institute, Cary, NC, USA).
Median PFS by BICR (primary endpoint) and median OS (key secondary endpoint) and associated 95% CIs for each treatment arm will be estimated using the Kaplan-Meier method. The HRs and associated 95% CIs will be estimated using a stratified Cox regression model. A stratified log-rank 2-sided test with an α=0.05 significance level will be used for comparison of the 2 treatment arms for the primary endpoint. To preserve experiment-wise 2-sided type 1 error at 0.05, a hierarchical testing procedure for comparisons between treatment arms for the primary endpoint and key secondary endpoint of OS will be used such that hypothesis testing of the difference in OS will only proceed if there is a statistically significant difference (p<0.05 and observed HR <1) between treatment arms for the primary endpoint. Hypothesis testing for all other secondary efficacy endpoints will be done at a nominal 2-sided α=0.05 level of significance with no adjustment for multiplicity.
9. Ethics
This study is being conducted in accordance with Institutional Review Board or Independent Ethics Committee (IRB/IEC) and applicable local regulations. The protocol, investigator’s brochure, informed consent forms, recruitment materials, and all patient materials were approved by the IRB/IEC at each investigative site. The clinical protocol follows Standard Protocol Items: Recommendations for Interventional Trials guidelines, as appropriate.
The study adheres to ethical principles that are based on the Declaration of Helsinki and are consistent with International Council for Harmonisation/Good Clinical Practice and applicable regulatory requirements. Written informed consent is being obtained from all study participants before initiation of study-mandated procedures. An independent data monitoring committee has been established to conduct periodic reviews of data to ensure the safety of study participants.
10. Trial registration
ClinicalTrials.gov Identifier: NCT05257408
European Union Drug Regulating Authorities Clinical Trials Database Identifier: 2022-000662-18
DISCUSSION
Development of platinum resistance is one of the fundamental challenges to treating ovarian cancer. Although the majority of women with ovarian cancer have disease that initially is sensitive to platinum-based chemotherapy, most patients will develop platinum resistance and eventually succumb to the disease [7,8,9]. The primary treatment goal for women with platinum-resistant ovarian cancer is to improve symptoms and prolong survival [8,9]. An ideal agent for this population would have a convenient dosing schedule, could be synergistically combined with existing therapies, and would have little or no cumulative toxicity or cross-resistance.
Several treatment modalities have been evaluated for women with recurrent platinum-resistant ovarian cancer, including immune checkpoint inhibitors, antiangiogenic agents, AXL inhibitors, tumor-treating fields, and ADCs. These treatment options have been tested individually or in combination with each other and with chemotherapy [7,11,23,24]. However, the FRα-targeted ADC mirvetuximab soravtansine-gynx (Elahere [ImmunoGen, Inc., Waltham, MA, USA]) is the only agent since the US Food and Drug Administration approval in 2014 of bevacizumab in combination with chemotherapy to show improvement in PFS and OS in these individuals [10,23,25,26]. Although this agent has been shown to increase OS compared with chemotherapy, it is associated with well-documented ocular AEs and is limited to tumors with high FRα expression [27,28]. There remains a need for agents with a more favorable safety profile that do not rely on biomarker selection.
In the randomized, open-label, phase 2 study, intermittently dosed relacorilant in combination with nab-paclitaxel showed meaningful improvements compared with nab-paclitaxel alone in women with recurrent platinum-resistant/refractory, high-grade serous or endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancer or ovarian carcinosarcoma [13]. Even greater improvements were observed in women with platinum-resistant but not primary platinum-refractory disease who had received 1 to 3 lines of previous anticancer therapy including bevacizumab, establishing the rationale for participant selection for the phase 3 ROSELLA study. The frequency and nature of AEs were similar across all study arms, with the most common AEs of grade ≥3 being neutropenia, anemia, peripheral neuropathy, and fatigue/asthenia. Notably, this study had no requirement for biomarker-based participant selection. Similarly, no biomarker criteria are required for enrollment in ROSELLA.
In conclusion, platinum-resistant ovarian cancer is a lethal disease with limited treatment options. With its novel mechanism of action, relacorilant added to nab-paclitaxel has shown promising results in extending survival rates, with minimal added toxicity compared with nab-paclitaxel monotherapy. The ROSELLA phase 3 study aims to generate additional, high-quality evidence supporting intermittently dosed relacorilant in combination with chemotherapy in a population of women with platinum-resistant ovarian cancer regardless of biomarker status, addressing a significant unmet need.
Footnotes
Funding: This study is funded by Corcept Therapeutics, Inc. (Menlo Park, CA, USA). Editorial support in the preparation of this manuscript was provided by Mary Smith, PhD, of R&R Healthcare Communications and funded by Corcept Therapeutics, Inc.
Presentation: This protocol was presented at the Society of Gynecologic Oncology 2023 Annual Meeting on Women’s Cancer, the 2023 European Society of Gynaecological Oncology Congress, and the 2023 Annual Global Meeting of the International Gynecologic Cancer Society.
Conflict of Interest: Alexander B. Olawaiye: Grants/research support, Corcept Therapeutics, AstraZeneca; Honoraria or consultation fees, AstraZeneca, GSK, Merck, Genentech.
Andrea Bagameri: Honoraria or consultation fees, AstraZeneca.
Laurence Gladieff: Honoraria or consultation fees, AstraZeneca, GSK, MSD, Eisai; Participation in a company sponsored speaker’s bureau, AstraZeneca, GSK, MSD, Eisai.
Linda Mileshkin: Grants/research support, BeiGene/funding for investigator-initiated trial.
Shibani Nicum: Grants/research support, AstraZeneca, GSK; Honoraria or consultation fees, AstraZeneca, GSK, Clovis Oncology, MSD; Participation in a company sponsored speaker’s bureau, AstraZeneca, GSK; Spouse/partner, AstraZeneca and GSK shares.
Angélica Nogueira-Rodrigues: Honoraria or consultation fees, AstraZeneca, Roche, Daiichi, Eisai, MSD, Pfizer, Libbs; Participation in a company sponsored speaker’s bureau, AstraZeneca, Roche, Daiichi, Eisai, MSD, Pfizer, Libbs, Gilead.
Ana Oaknin: Honoraria or consultation fees, Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Eisai, F. Hoffmann-L; Other support - travel and accommodation, AstraZeneca, PharmaMar, Roche.
David M. O’Malley: Grants/research support, AbbVie, Advaxis, Agenus Inc., Alkermes, Aravive Inc, Arcus Biosciences Inc., AstraZeneca, BeiGene USA Inc., Boston Biomedical, Bristol Myers Squibb, Clovis Oncology, Deciphera Pharmaceuticals, Eisai, EMD Serono Inc., Exelixis, Genentech Inc, Genmab, GlaxoSmithKline, GOG Foundation, Hoffman-La Roche Inc., ImmunoGen Inc., Incyte Corporation, Iovance Biotherapeutics, Karyopharm, Leap Therapeutics Inc., Ludwig Institute for Cancer Research, Merck & Co, Merck Sharp & Dohme Corp., Mersana Therapeutics Inc., NCI, Novartis, Novocure, NRG Oncology, OncoC4 Inc., OncoQuest Pharmaceuticals Inc., Pfizer Inc., Precision Therapeutics Inc., Prelude Therapeutics, Regeneron Pharmaceuticals Inc., RTOG, Rubius Therapeutics, Seattle Genetics (Seagen), Sutro Biopharma, SWOG, TESARO, Verastem Inc.; Honoraria or consultation fees (advisory boards), AbbVie, Adaptimmune, Agenus Inc., Arquer Diagnostics, Arcus Biosciences Inc., AstraZeneca, Atossa Therapeutics, Boston Biomedical, Cardiff Oncology, Celcuity, Clovis Oncology, Corcept Therapeutics, DualityBio, Eisai, Elevar Therapeutics, Exelixis, Genentech Inc., Genelux, GlaxoSmithKline, GOG Foundation, Hoffmann-La Roche Inc., ImmunoGen Inc., Imvax, InterVenn Biosciences, InxMed, Iovance Biotherapeutics, Janssen, Jazz Pharmaceuticals, Laekna, Leap Therapeutics Inc., Luzsana Biotechnology, Merck & Co, Merck Sharp & Dohme Corp., Mersana Therapeutics Inc., Myriad, Novartis, Novocure, OncoC4 Inc., Onconova Therapeutics, Regeneron Pharmaceuticals Inc., Replimune, R-Pharm, Roche Diagnostics, Seattle Genetics (Seagen), Sorrento Therapeutics, Sutro Biopharma, Tarveda Therapeutics, Toray, Trillium Pharmaceuticals, Umoja Biopharma, Verastem Inc., VBL Therapeutics, Vincerx Pharma, Xencor, Zentalis.
Lyndah Dreiling: Other support, Corcept Therapeutics stock/stock options; Employee, Corcept Therapeutics.
Iulia C. Tudor: Employee, Corcept Therapeutics.
Domenica Lorusso: Grants/research support, Clovis Oncology, GSK, MSD, Pharmal; Honoraria or consultation fees, Clovis Oncology, GSK, MSD, Pharmal; Participation in a company sponsored speaker’s bureau, Seagen, ImmunoGen, Genmab, AstraZeneca; Other support - travel expenses, AstraZeneca, Clovis Oncology.
- Conceptualization: B.E.
- Writing - review & editing: O.A.B., K.J.W., B.A., B.E., C.A., D.A., G.L., G.M.E., K.J., M.M.E., M.L., M.B., N.S., N.A., O.A., O.D.M., O.M., D.L., T.I.C., L.D.
References
- 1.Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7–33. doi: 10.3322/caac.21708. [DOI] [PubMed] [Google Scholar]
- 2.Doubeni CA, Doubeni AR, Myers AE. Diagnosis and management of ovarian cancer. Am Fam Physician. 2016;93:937–944. [PubMed] [Google Scholar]
- 3.National Cancer Institute. SEER cancer stat facts: ovarian cancer [Internet] Bethesda, MD: National Cancer Institute; 2023. [cited 2024 Feb 23]. Available from: https://seer.cancer.gov/statfacts/html/ovary.html. [Google Scholar]
- 4.Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, et al. Ovarian cancer statistics, 2018. CA Cancer J Clin. 2018;68:284–296. doi: 10.3322/caac.21456. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Atallah GA, Kampan NC, Chew KT, Mohd Mokhtar N, Md Zin RR, Shafiee MNB, et al. Predicting prognosis and platinum resistance in ovarian cancer: role of immunohistochemistry biomarkers. Int J Mol Sci. 2023;24:1973. doi: 10.3390/ijms24031973. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Kurnit KC, Fleming GF, Lengyel E. Updates and new options in advanced epithelial ovarian cancer treatment. Obstet Gynecol. 2021;137:108–121. doi: 10.1097/AOG.0000000000004173. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Havasi A, Cainap SS, Havasi AT, Cainap C. Ovarian cancer-insights into platinum resistance and overcoming it. Medicina (Kaunas) 2023;59:544. doi: 10.3390/medicina59030544. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.González-Martín A, Harter P, Leary A, Lorusso D, Miller RE, Pothuri B, et al. Newly diagnosed and relapsed epithelial ovarian cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34:833–848. doi: 10.1016/j.annonc.2023.07.011. [DOI] [PubMed] [Google Scholar]
- 9.Colombo N, Sessa C, du Bois A, Ledermann J, McCluggage WG, McNeish I, et al. ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease. Ann Oncol. 2019;30:672–705. doi: 10.1093/annonc/mdz062. [DOI] [PubMed] [Google Scholar]
- 10.ImmunoGen, Inc. Elahere [package insert] Waltham, MA: ImmunoGen, Inc.; 2024. [Google Scholar]
- 11.Eskander RN, Moore KN, Monk BJ, Herzog TJ, Annunziata CM, O’Malley DM, et al. Overcoming the challenges of drug development in platinum-resistant ovarian cancer. Front Oncol. 2023;13:1258228. doi: 10.3389/fonc.2023.1258228. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Munster PN, Greenstein AE, Fleming GF, Borazanci E, Sharma MR, Custodio JM, 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;28:3214–3224. doi: 10.1158/1078-0432.CCR-21-4363. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Colombo N, Van Gorp T, Matulonis UA, Oaknin A, Grisham RN, Fleming GF, 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;41:4779–4789. doi: 10.1200/JCO.22.02624. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Skor MN, Wonder EL, Kocherginsky M, Goyal A, Hall BA, Cai Y, et al. Glucocorticoid receptor antagonism as a novel therapy for triple-negative breast cancer. Clin Cancer Res. 2013;19:6163–6172. doi: 10.1158/1078-0432.CCR-12-3826. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Greenstein AE, Hunt HJ. Glucocorticoid receptor antagonism promotes apoptosis in solid tumor cells. Oncotarget. 2021;12:1243–1255. doi: 10.18632/oncotarget.27989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Prekovic S, Zwart W. Inhibiting the glucocorticoid receptor to enhance chemotherapy response. J Clin Oncol. 2023;41:4790–4793. doi: 10.1200/JCO.23.01195. [DOI] [PubMed] [Google Scholar]
- 17.Veneris JT, Darcy KM, Mhawech-Fauceglia P, Tian C, Lengyel E, Lastra RR, et al. High glucocorticoid receptor expression predicts short progression-free survival in ovarian cancer. Gynecol Oncol. 2017;146:153–160. doi: 10.1016/j.ygyno.2017.04.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Stringer-Reasor EM, Baker GM, Skor MN, Kocherginsky M, Lengyel E, Fleming GF, et al. Glucocorticoid receptor activation inhibits chemotherapy-induced cell death in high-grade serous ovarian carcinoma. Gynecol Oncol. 2015;138:656–662. doi: 10.1016/j.ygyno.2015.06.033. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Greenstein AE, Habra MA, Wadekar SA, Grauer A. Adrenal tumors provide insight into the role of cortisol in NK cell activity. Endocr Relat Cancer. 2021;28:583–592. doi: 10.1530/ERC-21-0048. [DOI] [PubMed] [Google Scholar]
- 20.Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45:228–247. doi: 10.1016/j.ejca.2008.10.026. [DOI] [PubMed] [Google Scholar]
- 21.Rustin GJ, Vergote I, Eisenhauer E, Pujade-Lauraine E, Quinn M, Thigpen T, et al. Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG) Int J Gynecol Cancer. 2011;21:419–423. doi: 10.1097/IGC.0b013e3182070f17. [DOI] [PubMed] [Google Scholar]
- 22.Custodio JM, Donaldson KM, Hunt HJ. An in vitro and in vivo evaluation of the effect of relacorilant on the activity of cytochrome P450 drug metabolizing enzymes. J Clin Pharmacol. 2021;61:244–253. doi: 10.1002/jcph.1731. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Tavares V, Marques IS, Melo IG, Assis J, Pereira D, Medeiros R. Paradigm shift: a comprehensive review of ovarian cancer management in an era of advancements. Int J Mol Sci. 2024;25:1845. doi: 10.3390/ijms25031845. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.NovoCure Ltd. Effect of tumor treating fields (TTFields, 200 kHz) concomitant with weekly paclitaxel for the treatment of recurrent ovarian cancer (ENGOT-ov50/GOG-3029/INNOVATE-3) [Internet] Bethesda, MD: National Library of Medicine; 2024. [cited 2024 Apr 11]. Available from: https://clinicaltrials.gov/study/NCT03940196. [Google Scholar]
- 25.US Food and Drug Administration. FDA grants accelerated approval to mirvetuximab soravtansine-gynx for FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or peritoneal cancer [Internet] Silver Spring, MD: US Food and Drug Administration; 2022. [cited 2024 Feb 13]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-mirvetuximab-soravtansine-gynx-fra-positive-platinum-resistant. [Google Scholar]
- 26.Richardson DL, Eskander RN, O’Malley DM. Advances in ovarian cancer care and unmet treatment needs for patients with platinum resistance: a narrative review. JAMA Oncol. 2023;9:851–859. doi: 10.1001/jamaoncol.2023.0197. [DOI] [PubMed] [Google Scholar]
- 27.Hendershot A, Slabaugh M, Riaz KM, Moore KN, O’Malley DM, Matulonis U, et al. Strategies for prevention and management of ocular events occurring with mirvetuximab soravtansine. Gynecol Oncol Rep. 2023;47:101155. doi: 10.1016/j.gore.2023.101155. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Bogani G, Coleman RL, Vergote I, van Gorp T, Ray-Coquard I, Oaknin A, et al. Mirvetuximab soravtansine-gynx: first antibody/antigen-drug conjugate (ADC) in advanced or recurrent ovarian cancer. Int J Gynecol Cancer. 2024;34:469–477. doi: 10.1136/ijgc-2023-004924. [DOI] [PubMed] [Google Scholar]