Advanced Breast Cancer
Each year over 230,000 women and 2,300 men are diagnosed with breast cancer in the United States, with almost 40,000 deaths in women and 440 men are attributable to the disease. ER+ (estrogen receptor positive) patients comprise ~50% of all metastatic breast cancer cases, and triple-negative breast cancer (TNBC) accounts for ~15-20%. TNBC has a more aggressive course than ER+ breast cancer does, but both have poor survival rates post-failure of endocrine and/or chemotherapy.
The current treatment paradigm for advanced breast cancer demonstrates a clear, unmet medical need for an efficacious treatment for ER+ and TNBC subtypes. Approved aromatase inhibitor (AI) and estrogen receptor antagonist drugs block the effects of estrogen in breast cancer cells and resistance to these agents is a growing concern. Androgen receptor (AR)-mediated effects have been reported to be important to the progression of certain breast cancer subtypes with androgens and not just estrogens driving their growth. Seviteronel combines two distinct mechanisms to decrease androgen stimulation of the AR: selective CYP17 lyase and direct AR inhibition. Seviteronel also decreases activation of the ER through the action of estrogens, which are also decreased due to CYP17 lyase inhibition. Seviteronel may provide a new therapeutic approach for the treatment of AR+ TNBC and ER+ breast cancer that has progressed following exposure to AIs or estrogen receptor antagonists.
Once-daily oral seviteronel is currently being evaluated in a Phase 2 clinical study in women and men who have TNBC or advanced ER+ breast cancer following progression with at least one prior endocrine therapy. The study is collecting biomarkers that may be used to better understand which patients may most benefit from this novel treatment. Seviteronel has received fast-track status from the FDA for accelerated development for the treatment of women with advanced AR+ TNBC and men and women with advanced ER+ breast cancer.
Castration-Resistant Prostate Cancer (CRPC)
Prostate cancer is the second most common form of cancer affecting men in the United States: an estimated one in six will be diagnosed with the disease in his lifetime. Annually, approximately 240,000 men will be diagnosed with prostate cancer and 36,000 men will die due to metastatic castration-resistant prostate cancer (CRPC).
AR-directed agents for CRPC using CYP17 inhibitor, abiraterone (Zytiga™) or the AR antagonist, enzalutamide (Xtandi™) have changed CRPC treatment landscape in the last several years. While the benefit provided by abiraterone and enzalutamide has confirmed that CRPC remains predominantly hormonally-dependent and that drugs that disrupt AR signaling are effective, men taking abiraterone or enzalutamide ultimately have disease progression.
Many of the resistance mechanisms that make sequential administration of abiraterone and enzalutamide difficult involve changes in AR sequence and/or expression levels. These AR aberrations induced by abiraterone or enzalutamide are thought to be ‘addressable’ – that is they can be corrected by treating the cancer with an AR-directed agent that blocks the specific AR aberration. Results from preclinical models and early clinical studies support the concept that seviteronel ‘addresses’ these genetic aberrations and that it can effectively treat prostate cancers that have become resistant to abiraterone and/or enzalutamide. The molecular biomarkers of resistance to abiraterone and enzalutamide may act as ‘guideposts’ that can alert physicians to initiate a new therapy, such as seviteronel. Early clinical results have shown that some men who never did or who have stopped responding to enzalutamide or abiraterone – or even to both drugs – can benefit from seviteronel.
Once-daily oral seviteronel is currently being evaluated in multiple Phase 2 clinical studies in men whose prostate cancer has become resistant to abiraterone, enzalutamide, or both. The results of these studies will identify patients who respond to seviteronel as well as provide biomarker ‘guideposts’ that signal the need to change therapy from abiraterone or enzalutamide to seviteronel. Seviteronel has received fast-track status from the FDA for accelerated development for the treatment of men with CRPC for whom abiraterone and enzalutamide are ineffective. Innocrin plans to use the results from its ongoing studies in future discussions with the FDA to further accelerate the development of seviteronel for these men.