seviteronel (INO-464)

P1b, N=65, Recruiting, St Vincent's Hospital, Sydney | Not yet recruiting --> Recruiting | Trial primary completion date: Jul 2023 --> Jul 2024

The first finding in line with expectations is that androgen receptor antagonists, represented by enzalutamide, have been studied and shown to have anti-glioblastoma effects. Expectantly, one of these small molecules, seviteronel, progressed to the Phase II clinical trial stage. These findings suggest that targeting the androgen receptor for glioblastoma may be a promising therapeutic option.

While radiosensitising in AR + TNBC, AR inhibition does not modulate radiation sensitivity in AR+/ER+ breast cancer. The efficacy of ER antagonists in combination with RT may also be dependent on AR expression.

Since there are only limited therapeutic agents available, such as abiraterone, galeterone, and seviteronel, which are being developed for prostate cancer, information on any potent natural anticancer compounds, such as vinca alkaloids, for prostate cancer treatment is limited. The results of this study show that CYP17A1 inhibition by Morusflavone could be an important therapeutic target for prostate cancer. Further preclinical and clinical evaluations of the lead compound Morusflavone are required to evaluate whether it can serve as a potential inhibitor of CYP17A1, which will be a new hope for prostate cancer treatment.

P1b, N=65, Not yet recruiting, St Vincent's Hospital, Sydney | Initiation date: Jul 2021 --> Nov 2021

Cytochrome P450 (P450) 17A1 catalyzes the 17α-hydroxylation of progesterone and pregnenolone as well as the subsequent lyase cleavage of both products to generate androgens...Here we considered the mechanisms of inhibition of drugs that have been developed to inhibit P450 17A1, including ketoconazole, seviteronel, orteronel, and abiraterone, the only approved inhibitor used for prostate cancer therapy, as well as clotrimazole, known to inhibit P450 17A1...These results are in contrast to inhibitors of P450 3A4, an enzyme with a larger active site in which complete inhibition is not observed with ketoconazole and clotrimazole until the changes are completed. Overall, our the results indicate that both P450 17A1 reactions-17α-hydroxylation and lyase activity-are inhibited by the initial binding of any of these inhibitors, even though subsequent conformational changes occur.

P1b, N=65, Not yet recruiting, St Vincent's Hospital, Sydney

The purpose of this study was to investigate the pre-clinical activity of the CDK4/6 inhibitor abemaciclib in combination with an agent that targets both androgen biosynthesis and AR activity, seviteronel, using TNBC cell lines expressing high AR, cell line xenografts and an AR positive, androgen-responsive TNBC patient-derived xenograft (PDX). Implications. While cell cycle inhibitors are FDA-approved for use in ER-positive breast cancer, our studies suggest that they may also be effective in AR+ TNBC, perhaps combined with AR targeted agents.

P2a, N=4, Terminated, St Vincent's Hospital, Sydney | N=16 --> 4 | Trial completion date: Aug 2021 --> Feb 2021 | Recruiting --> Terminated | Trial primary completion date: Aug 2020 --> Feb 2021; Sponsor

Seviteronel was not generally well tolerated nor associated with significant clinical responses in patients with mCRPC who had previously received enzalutamide. Further investigation of single-agent seviteronel in this patient population is not warranted; however, studies investigating seviteronel with low-dose dexamethasone are ongoing in patients with androgen receptor-positive tumors.

Enzalutamide and seviteronel treatment also had different effects on AR and AR target genes as measured by immunoblot and qPCR. These results implicate AR as a mediator of radioresistance in AR+ TNBC models and support the use of seviteronel as a radiosensitizing agent in AR+ TNBC.