Overall survival with relacorilant and nab-paclitaxel in patients with platinum-resistant ovarian cancer (ROSELLA): a phase 3 randomised controlled trial

Author(s): Prof Domenica Lorusso, MD^a,b; Laurence Gladieff, MD^c,d; David M O’Malley, MD^e; Prof Jae-Weon Kim, MD^f; Gabriel Garbaos, MD^g; Prof Anna Fagotti, MD^h; Lucy Gilbert, MDⁱ; Linda Mileshkin, MBBS^j; Stanislas Quesada, MD^d,k; Elizabeth Hopp, MD^l; Prof Yong Jae Lee, MD^m; Prof Ana Oaknin, MDⁿ; Mariana Scaranti, MD^o; Prof Byoung-Gie Kim, MD^p; Andrew Clamp, BMBCh^q,r; Christina Prillaman, MD^s; Connie Diakos, MBBS^t; Andrea Bagaméri, MD^u; Aliza L Leiser, MD^v; Vanda Salutari, MD^w; Prof Bradley J Monk, MD^x; Philippe Follana, MD^d,y; Emily McClung, MD^z; Vittoria Carbone, MD^aa; Brian Slomovitz, MD^ac; Elena Giudice, MD^ad; Maria Chiara Cannizzaro, MD^ab; Laurène Gavoille, MD^ae; Alix Devaux, MD^af,ag; Prof Paolo Scollo, MD^ah; Prof Giuseppa Scandurra, MD^ai,aj; Chiara Cassani, MD^ak,al; Grazia Artioli, MD^am; Prof Toon Van Gorp, MD^ag,an; Prof Ana Santaballa, MD^ao; Lyndah K Dreiling, MD^ap; Amanda Kesner-Hays, PhD^ap; Iulia Cristina Tudor, PhD^ap; Adrian M Jubb, FRCPath^ap; Nicoletta Colombo, MD^aq; Alexander B Olawaiye, MD^ar

Source: Volume 407, Issue 10538p1513-1524

Dr. Maen Hussein's Thoughts

Relacorilant is a selective glucocorticoid receptor antagonist that increases the sensitivity of many cancer cell types to chemotherapy. Adding it to nab-paclitaxel in platinum resistant ovarian cancer pateints had18-m overall survival was 46% and 27%. The median overall survival in the relacorilant combination group was extended by 4·1 months compared with the nab-paclitaxel monotherapy group (16· vs 11·9 months

BACKGROUND

Relacorilant is a selective glucocorticoid receptor antagonist that increases the sensitivity of many cancer cell types to chemotherapy. The efficacy and safety of relacorilant plus nab-paclitaxel were assessed in the phase 3 ROSELLA (GOG-3073, ENGOT-ov72, APGOT-Ov10, and LACOG-0223) trial; the combination showed significant improvement in progression-free survival among patients with platinum-resistant ovarian cancer compared with nab-paclitaxel monotherapy. Results of the final overall survival analysis are reported here.

METHODS

In this open-label phase 3 trial, patients were randomly assigned 1:1 to receive relacorilant (150 mg orally the day before, day of, and day 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). Patients, aged 18 years or older, with one to three lines of previous anticancer therapy and platinum-resistant disease (progression <6 months from their last dose of platinum) were eligible. The trial was conducted at 117 hospitals and community oncology centres in 14 countries across Australia, Europe, Latin America, North America, and South Korea. Progression-free survival, assessed by blinded independent central review, and overall survival (time from randomisation to death from any cause) were dual primary endpoints. Additional prespecified endpoints included safety, second progression-free survival (time from randomisation to disease progression on subsequent anticancer therapy or death due to any cause, whichever occurred first), and patient-reported outcomes. This trial is registered at ClinicalTrials.gov, NCT05257408, and is ongoing.

FINDINGS

Between Jan 5, 2023, and April 8, 2024, 381 patients were randomly assigned to the relacorilant combination group (n=188) or the nab-paclitaxel monotherapy group (n=193). All patients had received bevacizumab; 167 (44%) had received three previous lines of therapy, and 234 (61%) had received a poly(ADP-ribose) polymerase inhibitor. At a median follow-up of 24·8 months (95% CI 23·6–25·7), the addition of relacorilant to nab-paclitaxel resulted in a statistically and clinically significant improvement in overall survival compared with nab-paclitaxel monotherapy (hazard ratio for death 0·65 [95% CI 0·51–0·83]; p=0·0004); 18-month overall survival was 46% and 27%, respectively. The median overall survival in the relacorilant combination group was extended by 4·1 months compared with the nab-paclitaxel monotherapy group (16·0 [95% CI 13·0–18·3] vs 11·9 months [10·0–13·8]). Subsequent anticancer treatments were similar across study groups. Adverse events were similar in both groups when adjusted for duration of study treatment. Neutropenia (121 [64%]), anaemia (115 [61%]), fatigue (101 [54%]), and nausea (82 [44%]) were the most common adverse events in the relacorilant combination group. No new safety signals were observed with additional follow-up since the primary analysis.

INTERPRETATION

The addition of relacorilant to nab-paclitaxel led to significantly longer overall survival in patients with platinum-resistant ovarian cancer, without the need for biomarker selection. The findings support relacorilant plus nab-paclitaxel as a potential new standard treatment option for patients with platinum-resistant ovarian cancer.

FUNDING

Corcept Therapeutics.

Author Affiliations

^aDepartment of Biomedical Science, Humanitas University, Pieve Emanuele, Italy; ^bHumanitas San Pio X Hospital, Milan, Italy; ^cOncopole Claudius Regaud IUCT-Oncopole, Toulouse, France; ^dGINECO, Paris, France; ^eJames Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; ^fDepartment of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, South Korea; ^gInstituto Médico de la Fundación Estudios Clínicos, Santa Fe, Argentina; ^hGynecologic Oncology Unit, Fondazione Policlinico Universitario A Gemelli, IRCCS, Rome, Italy; ⁱDivision of Gynecologic Oncology, Research Institute, McGill University Health Centre, Gerald Bronfman Department of Oncology,; McGill University, Montreal, QC, Canada; ^jDepartment of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australi; ^kMontpellier Cancer Institute, Montpellier, Franc; ^lDepartment of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, US; ^mYonsei University College of Medicine, Seoul, South Kore; ⁿMedical Oncology Department, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spai; ^oRede Américas Oncologia, Hospital 9 de Julho, São Paulo, Brazil; ^pSamsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; ^qThe Christie NHS Foundation Trust, Manchester, UK; ^rUniversity of Manchester, Manchester, UK; ^sVirginia Oncology Associates, Norfolk, VA, USA; ^tRoyal North Shore Hospital, St Leonards, NSW, Australia; ^uDepartment of Gynecology, Hungarian National Institute of Oncology, Budapest, Hungary; ^vRutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA; ^wDepartment of Woman, Child, and Public Health, Fondazione Policlinico Universitario Agostino Gemelli, Rome, Italy; ^xFlorida Cancer Specialists and Research Institute, West Palm Beach, FL, USA; ^yCentre Antoine Lacassagne, Nice, France; ^zStanford University, Palo Alto, CA, USA; ^aaGynecologic Oncology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; ^abDepartment of Women and Children’s Health Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; ^acMount Sinai Comprehensive Cancer Center, Miami Beach, FL, USA; ^adHumanitas San Pio X Hospital, Milan, Italy; ^aeGentilly Oncology Center, Interregional Institute of Oncology, Nancy, France; ^afOncology Department of Grand Hôpital de Charleroi, Charleroi, Belgium; ^agBelgium and Luxembourg Gynaecological Oncology Group, Leuven, Belgium; ^ahDepartment of Medicine and Surgery, Kore University of Enna, Enna, Italy; ^aiDipartimento di Medicina, Kore University of Enna, Enna, Italy; ^ajMedical Oncology Unit, Cannizzaro Hospital, Catania, Italy; ^akDepartment of Clinical, Surgical, Diagnostic, and Pediatric Sciences, University of Pavia, Pavia, Italy; ^alUnit of Obstetrics and Gynecology, IRCCS San Matteo Foundation, Pavia, Italy; ^amAzienda ULSS2 Marca Trevigiana, Treviso, Italy; ^anUniversity Hospital Leuven, Leuven Cancer Institute, Leuven, Belgium; ^aoDepartment of Medical Oncology, La Fe University Hospital, IIS La Fe, Valencia, Spain; ^apCorcept Therapeutics, Redwood City, CA, USA; ^aqGynecologic Oncology Program, European Institute of Oncology, IRCCS, Milan, Italy; ^arUniversity of Pittsburgh School of Medicine and UPMC Magee–Women’s Hospital, Gynecologic Oncology Group, Pittsburgh, PA, USA

Pembrolizumab plus weekly paclitaxel in platinum-resistant recurrent ovarian cancer (ENGOT-ov65/KEYNOTE-B96): a multicentre, randomised, double-blind, phase 3 study

Participants (who received one to two previous systemic therapies including at least one platinum regimen and who progressed 6 months or less after the last platinum) regime were randomly assigned 1:1 to intravenous pembrolizumab 400 mg every 6 weeks for up to 18 cycles plus open-label intravenous paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 21-day cycle or intravenous placebo every 6 weeks for up to 18 cycles plus open-label intravenous paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 21-day cycle; intravenous bevacizumab 10 mg/kg every 2 weeks was permitted per investigator. Overall survival (OS) was significantly improved in the PD-L1 CPS 1 or higher population (median 18·2 months vs 14·0 months; HR 0·76
OS was significantly improved in the overall population (median 17·7 m vs 14·0 m, hazard ratio (HR) 0·82

Atezolizumab With Bevacizumab and Nonplatinum Chemotherapy for Recurrent Ovarian Cancer: Final Results From the Placebo-Controlled AGO-OVAR 2.29/ENGOT-ov34 Phase III Trial

This is another well-done study that, frankly, confirms what we’ve seen elsewhere—PDL1 inhibition does not seem to meaningfully change outcomes in platinum-resistant ovarian cancer, even when added to chemo + bev.

Efficacy and Safety of Avutometinib ± Defactinib in Recurrent Low-Grade Serous Ovarian Cancer: Primary Analysis of ENGOT-OV60/GOG-3052/RAMP 201

The ENGOT-OV60/GOG-3052/RAMP 201 phase II trial evaluated avutometinib (a RAF/MEK clamp) plus defactinib (FAK inhibitor) in recurrent low-grade serous ovarian cancer (LGSOC), showing a confirmed objective response rate (ORR) of 31% (44% in KRAS-mutant, 17% in KRAS wild-type) and a median progression-free survival (PFS) of 12.9 months (22.0 vs 12.8 months for KRAS-mutant vs wild-type). The median duration of response was notably long at 31.1 months, and the disease control rate was 88%. The most common grade ≥3 AEs were elevated creatine phosphokinase (CPK) (24%), diarrhea (8%), and anemia (5%), with a 10% discontinuation rate due to adverse events (AEs); so management of AE’s is key for using this new drug combo. This combination looks like a real contender for a new standard in recurrent LGSOC, especially for KRAS-mutant patients.

Atezolizumab Combined With Bevacizumab and Platinum-Based Therapy for Platinum-Sensitive Ovarian Cancer: Placebo-Controlled Randomized Phase III ATALANTE/ENGOT-ov29 Trial

Adding Atezo to combination chemotherapy with bevacizumab did not meet the primary end point of PFS. Regardless of the PDL-1 status it was also more toxic. It seems that ovarian cancer is still immune to immunotherapy.

Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy in patients with advanced ovarian cancer (OVHIPEC-1): final survival analysis of a randomised, controlled, phase 3 trial

The final results from the OVHIPEC1 study confirm a survival benefit in stage III epithelial ovarian cancers. The OS benefit was about 12 months, and the PFS benefit was four months in favor of CRS + HIPEC compared to CRS alone. This should be offered to patients in the context of definitive surgery.