Breakthrough Clinical Results
Corcept Therapeutics announced the submission of a New Drug Application (NDA) to the FDA for relacorilant, a selective cortisol modulator, in combination with nab-paclitaxel for treating platinum-resistant ovarian cancer. The NDA is supported by positive Phase 3 ROSELLA and Phase 2 trial data showing improved progression-free and overall survival compared to nab-paclitaxel alone. Relacorilant was well-tolerated, and the combination therapy did not increase the safety burden. This is Corcept's second NDA before the FDA, with another for relacorilant in hypercortisolism. The FDA has assigned a PDUFA target action date of December 30, 2025, for relacorilant in hypercortisolism.
Key Highlights
- NDA submitted to the FDA for relacorilant (with nab-paclitaxel) in platinum-resistant ovarian cancer.
- Positive Phase 3 ROSELLA and Phase 2 trial data demonstrated improved survival outcomes.
- Relacorilant showed a favorable safety profile in combination with nab-paclitaxel.
- This is Corcept's second NDA before the FDA.
Incidence and Prevalence
Global Incidence and Prevalence of Ovarian Cancer
According to the most recent data from 2022, ovarian cancer ranks as the seventh leading cause of death in women and represents the fifth most frequent disease worldwide. This significant global health concern shows no signs of abating, as a 2015 Ukrainian study reported that the level of ovarian carcinoma in Ukraine and most other countries remains high with no signs of decrease during the last 20 years.
Epidemiological Patterns
The disease predominantly affects women in their middle age, with a 2022 Saudi Arabian study of 252 women with ovarian tumors finding that the predominant age group was 41-50 years (25.0%). However, age distribution can vary by region and tumor type. A 2013 Nigerian study reported that approximately 60% of women with epithelial ovarian cancer were aged 50 years or below.
When examining tumor types, the Saudi Arabian study found that benign tumors were most common (55.2%), followed by malignant (34.5%) and borderline (9.9%) tumors. In Nigeria, epithelial ovarian cancer constituted 68% of ovarian cancer cases, while sex cord and germ cell tumors constituted 16% each.
Disease Staging and Mortality
Ovarian cancer is particularly lethal due to late diagnosis. The Nigerian study revealed that over 84% of ovarian cancer cases presented in stages 3 and 4 of the disease. This late presentation significantly impacts survival rates, as early diagnosis is associated with a favorable 5-year survival prognosis. Unfortunately, ovarian cancer is typically asymptomatic in early stages and becomes symptomatic only in advanced stages.
Risk and Protective Factors
Several factors influence ovarian cancer risk. Protective factors include the use of oral contraceptives, multiparity, and breastfeeding. The 2022 Saudi Arabian study confirmed that breastfeeding/parity were significant protective factors (39.3%).
Conversely, risk factors include obesity, nulliparity, smoking, and genetic changes. The Saudi Arabian study specifically identified nulliparity as a notable risk factor (12.3%).
Clinical Presentation and Biomarkers
When symptoms do appear, the most common initial symptoms include abdominal pain (41.7%) and abdominal masses (25.8%) according to the 2022 Saudi Arabian study. In terms of diagnostic markers, the most frequently elevated tumor marker was cancer antigen 125 (CA-125) (36.9%).
Challenges in Management
A 2016 study highlighted that ovarian cancer is one of the most lethal malignancies with a population at risk continually rising due to several factors, including acquired drug resistance, high relapse rate, incomplete knowledge of etiology, cross-talk with other gynecological malignancies, and diagnosis at advanced stages.
These factors collectively contribute to ovarian cancer's status as a major global health concern with significant mortality and morbidity worldwide.
Mechanism of Action
Common Mechanisms of Action in Unsuccessful Ovarian Cancer Drug Trials
PI3K/AKT/mTOR Pathway Inhibition
The PI3K/AKT/mTOR pathway inhibition represents one of the most common mechanisms pursued in ovarian cancer trials. A notable example is the combination of anastrozole and everolimus, which was investigated in patients with metastatic estrogen and/or progesterone receptor-positive gynecologic tumors including ovarian cancer. This combination demonstrated activity in heavily-pretreated patients with ovarian cancer, with 2 of 10 (20%) ovarian cancer patients achieving stable disease ≥6 months/partial response/complete response. Additionally, six of 22 patients (27%) with molecular alterations in the PI3K/AKT/mTOR pathway achieved stable disease ≥6 months/PR/CR. Interestingly, responses were observed in patients with multiple molecular aberrations.
PARP Inhibition
PARP inhibition is another frequently investigated mechanism. While some PARP inhibitors have gained approval, many trials in this category have not led to FDA approval. Olaparib was approved by European Medicines Agency as maintenance therapy post-response to platinum-based chemotherapy for recurrent ovarian cancer in women with deleterious BRCA1/2 mutation. Niraparib received approval as maintenance treatment for patients with recurrent epithelial ovarian cancer who are in complete or partial response to platinum-based chemotherapy, independently of BRCA mutation. Rucaparib, which inhibits PARP-1, 2 and 3, PARP-4, -12, -15 and -16, as well as tankyrase 1 and 2, received accelerated FDA approval for patients with deleterious, germline and/or somatic BRCA mutation-associated advanced ovarian cancer who have been treated with two or more lines of chemotherapy.
Growth Factor Receptor and Angiogenesis Inhibition
Inhibitors of growth factor receptors such as epidermal growth factor receptor and inhibitors of angiogenesis are of particular interest based on promising data from preclinical and early clinical studies. However, the rapid evaluation of these target-specific non-cytotoxics is limited by the lack of accurate information on the expression of target in ovarian tumors. Olaparib in combination with bevacizumab (an angiogenesis inhibitor) demonstrated a 67% reduction in the risk of disease progression or death compared with bevacizumab alone in homologous recombination deficient-positive tumors.
Endocrine/Hormone Therapy
Endocrine/hormone therapy represents another prevalent approach. Anti-estrogens (tamoxifen and fulvestrant) and aromatase inhibitors (letrozole, anastrazole and exemestane) have been evaluated in phase II clinical trials for epithelial ovarian cancer. The efficacy of endocrine therapy in epithelial ovarian cancer is likely to be confined to histological subtypes with the highest ER expression. Low grade serous ovarian cancer appears to be one subgroup with good sensitivity to these agents. Overall, Summary Clinical Benefit Rate (SCBR) was 41% for any endocrine treatment, 43% for tamoxifen, 39% for aromatase inhibitors and 37% for progestins. The SCBR for ER+ and/or PgR+ tumors was 46% versus 37% in tumors with unknown receptors.
Receptor-Based Targeting Approaches
Several receptor-based targeting approaches have been investigated:
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Androgen receptor (AR) targeting: ARs may be a potential therapeutic target in endometrial cancer due to reported anti-proliferative activities of androgens. By contrast, androgens may promote growth of some ovarian cancers and anti-androgen therapy has been proposed.
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G protein-coupled receptor (GPCR) targeting: GPCRs are involved in numerous physio-pathological processes, including the stimulation of cancer progression. Pro-malignancy effects mediated by GPCRs are counteracted by small molecules and peptides that function as receptor antagonists or inverse agonists. GPR30 has been identified as a potential target in ovarian clear cell carcinoma.
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Estrogen receptor pathways: These are involved in the etiology and progression of epithelial ovarian cancer, but only a subset of patients responds to antiestrogens including tamoxifen. GPER signaling is implicated in ovarian cancer, with GPER agonist G1 increasing migration of SKOV3 and OVCAR5 cells.
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Gonadotropin-releasing hormone (GnRH) receptor: This receptor is found in ovarian tissue, including epithelial ovarian cancer, suggesting GnRH agonists may have direct action on EOC.
Drug used in other indications
Relacorilant and Nab-Paclitaxel Clinical Trials
Based on a thorough review of the available information, there is no data regarding clinical trials of Relacorilant in combination with albumin-bound paclitaxel (nab-paclitaxel, Abraxane) for indications other than ovarian cancer.
The only documented clinical investigation involving this combination therapy is the ROSELLA trial, which specifically focuses on platinum-resistant ovarian cancer.
No information is available about: - Additional disease indications beyond ovarian cancer - Intervention models for other clinical trials - Dosing regimens for other indications - Alternative trial designs
The current evidence only supports the investigation of this combination therapy in the context of ovarian carcinoma treatment.