seviteronel + dexamethasone

Seviteronel + dexamethasone is a combination therapy investigated in clinical trials for various androgen receptor (AR) positive cancers. This combination pairs seviteronel, a selective CYP17 17,20-lyase inhibitor and androgen receptor antagonist, with dexamethasone, a corticosteroid. ## Background and Development Seviteronel (also known as INO-464 or VT-464) was initially developed by Innocrin Pharmaceuticals as a selective cytochrome P450c17a (CYP17) 17,20-lyase inhibitor and androgen receptor antagonist. Early clinical trials of seviteronel alone in metastatic castration-resistant prostate cancer (mCRPC) patients showed significant toxicity issues, particularly central nervous system (CNS) side effects, when administered without steroids. The addition of dexamethasone to seviteronel appears to be a strategy to improve tolerability while maintaining efficacy. Current clinical investigations are exploring this combination (referred to as SEVI-D in some trials) in androgen receptor-positive tumors, including triple-negative breast cancer (TNBC). ## Clinical Development The seviteronel + dexamethasone combination is being studied in several contexts: 1. **As a single therapy**: Seviteronel (450 mg once daily) with low-dose dexamethasone (0.5 mg) has been investigated in patients with AR-positive tumors. 2. **In combination with chemotherapy**: A clinical trial is evaluating seviteronel (450 mg once daily) with dexamethasone (0.5 mg) in combination with docetaxel (75 mg/m²) for AR-positive triple-negative breast cancer. This combination is administered in 28-day cycles with docetaxel given intravenously every 3 weeks. According to the search results, early data suggests that "seviteronel with 0.5mg dexamethasone in combination with docetaxel or nab-paclitaxel chemotherapy is well tolerated with early efficacy signals". ## Mechanism of Action The combination leverages two distinct mechanisms: 1. **Seviteronel**: Acts as both a selective CYP17 17,20-lyase inhibitor and an androgen receptor antagonist. This dual mechanism targets androgen synthesis and signaling, which is important in AR-positive cancers. 2. **Dexamethasone**: Likely serves to mitigate the side effects associated with seviteronel while potentially providing additional anti-tumor effects through its anti-inflammatory properties, mediated by its activity as a corticosteroid. ## Toxicity and Tolerability When seviteronel was administered alone without steroids in mCRPC patients, significant toxicity was observed, including concentration impairment, fatigue, tremor, and nausea. These toxicity issues led to the premature closure of a Phase 2 study of seviteronel monotherapy. The addition of low-dose dexamethasone (0.5 mg) appears to improve the tolerability profile of seviteronel, allowing for continued clinical development of this combination in AR-positive tumors. ## Current Status As of 2025, seviteronel + dexamethasone continues to be investigated in clinical trials, particularly in combination with chemotherapy for AR-positive cancers. The combination appears to show better tolerability than seviteronel alone, with promising early efficacy signals in certain patient populations.

Other names

SEVI-D