Glucocorticoid modulation, a novel oncologic therapeutic platform in Ovarian Cancer

Ovarian Cancer is of heterogeneous origin. Prognosis of ovarian cancer is bleak, metastases rate of OC cells are majorly attributed. Metastases rate generally depends on types of ovarian tissues, where it primarily originate. Surgeries, chemotherapies, radiation therapies, and chemo radiation therapies are generally considered for OC treatment. Surgeries are preferred treatment options for low grade ovarian cancer, especially in early stages. While platinum based chemotherapies are main stream treatment options in initial lines of therapies for advanced high grade ovarian cancer. Up to 25% of women with ovarian cancer have innately platinum-refractory disease, having diagnosed with clear cell, mucinous cell ovarian cancer subtypes. Most of platinum sensitive high grade OC patients have been treated with platinum based chemotherapies. Carboplatin or Cisplatin remains the backbone of treatment. However, most of those who are initially sensitive to front-line platinum therapy, eventually acquire progressive resistance and over the time develop recurrence. Resistant patients of advanced ovarian cancer are been quite frequent leading to higher recurrence rate. 

The higher expression of glucocorticoids  receptor on tumor cells, and subsequently, glucocorticoids (Cortisol)  binding to GR receptors, majorly attributed in developing resistance against SOC chemotherapy, apart from other resistance mechanism like high expression of e-flux exporter, changing metabolism pathway etc., which tumor  cells adopt. Cortisol activity at the GR reduces chemotherapy efficacy by suppressing apoptic pathways utilized by cytotoxic agents, such as nab-paclitaxel. High GR expression associated with poor prognosis and reduced chemotherapy response in ovarian cancer.

Patients with platinum-resistant ovarian cancer have historically been an underserved pool with few effective treatment options. Depending on the duration of remission, recurrent patients are   re-prescribed with platinum drugs, often in combination with another chemotherapeutic drug or a molecularly targeted agent such as a PARP inhibitors. PARP inhibitors are mostly helpful as a maintenance therapy in initial lines.  So far, introduction of targeted and immunological therapies could not benefitted much to recurrent/registrant patients. So moving ahead in advanced lines of treatment for OC management, Care givers are left with keep changing combinations of treatment agents, which are already prescribed in the initial lines of treatment schedule. It reflects huge void in treatment landscape of platinum-resistant/recurrent ovarian cancer patients.

Orally available relacorilant, a glucocorticoid receptor antagonist, upon administration, competitively binds to and blocks GRs. Thereby, inhibits the activity of GRs, and prevents both the translocation of the ligand-GR complexes to the nucleus and gene expression of GR-associated genes. It decreases the negative effects, that result from excess levels of endogenous glucocorticoids and helps in reversing chemo resistance for cytotoxic agents. In addition, by binding to GRs and preventing their activity, inhibition with relacorilant also inhibits the proliferation of GR-overexpressing cancer cells. The Corcept Therapeutics Presented updated results of Phase II clinical study, evaluating glucocorticoid receptor modulator relacorilant in Combination with Nab-Paclitaxel in patients with recurrent platinum-resistant ovarian cancer, at ESMO 2022: 

Median progression-free survival (PFS) were found to be in,

• Intermittent relacorilant arm 5.6 months (HR=0.66; P = 0.038) 
• Continuous relacorilant arm 5.3 months ( HR=0.83, P=0.329)
• Nab-paclitaxel arm 3.8 months

Median Overall survival (OS) in were found to be in,

• ​​​​​Intermittent relacorilant arm 13.9 months (HR=0.63; P = 0.045)
• Continuous relacorilant arm 12.3 months ( HR=0.84 )
• Nab-paclitaxel arm 12.2 months

​​​​​HR & P-value were recorded in control arm vs. comparator arm.

• Over all response rate (ORR) in high tumor GR expression patient pool 
• In relacorilant + nab-paclitaxel arm was found to be 40.4% (p=0.037)
• In nab-paclitaxel only arm 18.8%
• Over all response rate (ORR) in low tumor GR expression patient pool
• In relacorilant + nab-paclitaxel arm was found to be 32.4% 
• In nab-paclitaxel only arm 47.1%
• P value for ORR were found to be,  P=0.037 and P>0.05 (non-significant) in high and low tumor  GR expression, respectively

The Corcept Therapeutics’ updated Phase II clinical study results, in intermittent relacorilant + nab-paclitaxel arm showed improved efficacy (PFS and OS) compared to the continuous relacorilant + nab-paclitaxel arm and comparator arm without the additional burden of side effects, in patients with recurrent platinum-resistant ovarian, fallopian Tube, or primary peritoneal cancer. ORR data clearly reflecting superioriority of relacorilant + nab-paclitaxel. Moreover, ORR was excellent in high tumor GR expression patient pool, with clinical significance, which are more prone to be platinum resistant.  Encouraged by Phase II results, Corcept Therapeutics plans for pivotal Phase III trial in the second half of 2022.

As of now, mainstream treatment modalities have shown weaker efficacy, and caregivers feel a huge unmet need in platinum-refractory or resistant OC patients. So far, updated clinical results of novel GR modulators has been proved, that it has potential to challenge heavily pretreated, platinum resistance and recurrent OC. It could be a breakthrough treatment option going forward and will address a huge unmet need with a noticeably more acceptable pharmacodynamics and pharmacokinetic profile in the second or later line of therapy. 

Get more detailed insights, at: Ovarian Cancer Market Outlook