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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Other NSAAs are being developed at the time of writing. For example, proxalutamide is a close analog of enzalutamide (GT-0918), and is being developed by Suzhou Kintor Pharmaceuticals for the treatment of prostate cancer. It is reported to be more potent than bicalutamide and enzalutamide in inhibiting AR-mediated gene transcription, and to have low central nervous system penetration. Proxalutamide entered Phase II clinical trials for prostate cancer in 2017. Another NSAA, seviteronel (VT-464), has a novel structure unrelated to other NSAAs, and is being developed by Viamet Pharmaceuticals and Innocrin Pharmaceuticals for the treatment of prostate and breast cancer. It is a CYP17A1 inhibitor and works by inhibiting the biosynthesis of androgens and estrogens. Seviteronel entered Phase II clinical trials for both prostate cancer and breast cancer in 2017.
Androgen receptor: A promising therapeutic target in breast cancer
Published in Critical Reviews in Clinical Laboratory Sciences, 2019
Stella K. Vasiliou, Eleftherios P. Diamandis
Additionally, some CYP17A inhibitors (abiraterone, orteronel, seviteronel) have been recently used in on-going clinical trials (Table 2). Currently, a phase I study is in-progress, to assess the activity, pharmacokinetics, and safety of seviteronel as an anti-AR treatment of 19 women with ER+ BCa and TNBC [239]. Up-to-date results show toxicity side effects at certain drug concentrations/doses, but the administration of 450 mg once a day, is considered a tolerant dose to be used in a phase II study. In addition, a clinical trial that integrates anti-AR treatment with immunotherapy is openly recruiting (NCT02971761), which will deliver combined pembrolizumab (Anti-PD-1) and GTx-024 (SARM) to AR+TNBC patients [143,240]. Several current clinical studies that are investigating AR inhibition as a monotherapy or in a multi-therapy are listed in Table 2.
Investigational luteinizing hormone releasing hormone (LHRH) agonists and other hormonal agents in early stage clinical trials for prostate cancer
Published in Expert Opinion on Investigational Drugs, 2019
Nirmish Singla, Rashed A. Ghandour, Ganesh V. Raj
Seviteronel (VT-464) is an investigational nonsteroidal inhibitor of the CYP17A1 enzyme, thereby targeting the synthesis of androgen. Due to its selectivity for CYP17A1, seviteronel may not require concomitant administration of a glucocorticoid, unlike abiraterone, which interferes with steroid production [53–55]. The efficacy of seviteronel is supported by preclinical studies in CRPC cell lines and xenograft models that are responsive (C4-2) or resistant (MR49C, MR49F) to enzalutamide [55]. Recruitment recently completed for an open label phase II trial of seviteronel in patients with progressive, metastatic CRPC previously treated with enzalutamide (NCT02130700), which is also studying its role in patients with breast cancer. The single-arm phase IIa START trial, investigating seviteronel combined with dexamethasone in patients with AR-positive solid tumors including prostate and breast cancer, is also actively recruiting (NCT03600467).
Investigational therapies targeting the androgen signaling axis and the androgen receptor and in prostate cancer – recent developments and future directions
Published in Expert Opinion on Investigational Drugs, 2018
Pedro Isaacsson Velho, Michael A. Carducci
Seviteronel (VT-464) is a selective nonsteroidal, orally available CYP17 inhibitor; which act inhibiting selectively the 17,20-lyase enzyme [42]. Seviteronel has diminished activity against CYP17 hydroxylase and therefore does not inhibit cortisol synthesis. Preclinical studies showed that seviteronel demonstrated superior activity than abiraterone in numerous CRPC models [43]. Animal studies showed that seviteronel, such as abiraterone, suppressed plasma testosterone concentrations by 90% after subcutaneous administration [44]. Because of the specificity for 17,20-lyase, VT-464 has different actions among different hormones. Differently than abiraterone, which increases corticosterone levels, VT-464 results in reduction of this hormone [42]. On the other hand, abiraterone suppresses cortisol levels, whereas VT-464 has only a minor influence [44]. Also, progesterone and pregnenolone are reduced with VT-464; in contrast, these are increased with abiraterone [45]. VT-464 demonstrated anticancer activity in xenograft models, showing significant reduction in tumor volumes [46]. This drug is now currently being tested in several phase I/II trials, in mCRPC treatment-naïve patients (NCT02012920), post-enzalutamide (NCT02130700); and after progression with enzalutamide and abiraterone (NCT02445976).