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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
These six NSAAs are described in the sections below in more detail. Other nonsteroidal inhibitors such as orteronel which was developed but not progressed, and molecules such as proxalutamide and seviteronel which are still in development at the time of writing, are described in the Experimental Anti-Androgen Agents section below.
Little support for a protective effect of ADT against COVID-19
Published in Scandinavian Journal of Urology, 2022
Thus, the accumulating evidence points to that androgen signaling inhibition is neither a friend or foe in COVID-19. However, there is one study by a group of researchers testing the anti-androgen proxalutamide in a randomized trial in Brazil, which showed a clear support of the initial hypothesis. The results are remarkable with 70–90% reduction of hospitalization in COVID-19 patients [9]. Proxalutamide, an antiandrogen, is a not yet approved drug but is currently used in trials on prostate and breast cancer (NCT03899467 and NCT04103853). The difference in results from the studies using the anti-androgens enzalutamide and proxalutamide is intriguing. However, soon a trial evaluating degarelix (GnRH antagonist) by Rettig et al. [10] will be presented. That study investigates medical castration by degarelix in hospitalized COVID-19 patients with a similar protocol as the COVIDENZA trial. Hopefully, the results will help in interpreting the conflicting trial results regarding the potential of targeting androgen signaling to decrease COVID-19 symptoms.
Androgen receptor modulators: a review of recent patents and reports (2012-2018)
Published in Expert Opinion on Therapeutic Patents, 2019
Shinya Fujii, Hiroyuki Kagechika
Further clinical trials of these two second-generation NSAAs for treatment of several types of CRPC are ongoing, together with trials of other novel NSAAs, such as darolutamide (15) [41,42]. Darolutamide (ODM-201, 15) is structurally distinct from enzalutamide (13) and apalutamide (14), binds to both wild-type and mutated ARs with high affinity, and exhibits full antagonistic activity toward these receptors, including the recently reported F876L-mutated AR that has been detected in CRPC patients treated with apalutamide (14) and enzalutamide (13) [43,44]. Darolutamide (15) completed phase III clinical trial and a NDA has been filed. The diarylthiohydantoin derivative proxalutamide (GT-0918, 16) is also a second-generation NSAA exhibiting increased affinity toward AR compared to enzalutamide (13) and apalutamide (14) [45]. Proxalutamide (16) not only acts as an antagonist toward AR, but also downregulates AR. Proxalutamide (16) entered phase III trial for prostate cancer. ODM-204 (17) [46] is a p-cyano-m-trifluoromethylaniline derivative with an imidazole moiety; it exhibits dual inhibitory activity toward AR transcription and Cyp17A1, which is involved in the formation of DHT (2) and testosterone (1) [47]. ODM-204 (17) is in phase I clinical trial for CRPC. Another new agent is TRC253, a novel, high-affinity competitive inhibitor of AR TRC253 and a pan-inhibitor of multiple AR mutants, including F876L [48]. TR253 is in phase I/II clinical trials.
Perspectives on the current and emerging chemical androgen receptor antagonists for the treatment of prostate cancer
Published in Expert Opinion on Pharmacotherapy, 2019
Athanasios E. Dellis, Athanasios G. Papatsoris
Proxalutamide (GT-0918) is a NSAA – specifically, a selective high-affinity silent antagonist of the AR, that inhibits AR-mediated gene transcription more potently than bicalutamide (by 5- to 10- fold) and ENZ (by 2- to 5- fold) and maintains silent antagonism in CRPC cells [65]. It has also been found to down-regulate the AR, which could further confer it greater efficacy against CRPC compared to existing NSAAs. Unlike ENZ, the drug showed low central nervous system distribution and no induction of seizures in animals [65]. A Phase 1/2 (phase 1: dose escalation stage/phase 2: dose expansion stage), multi-center, open-label, two-stage study is currently recruiting mCRPC patients who progressed after both hormonal therapy (AA or ENZ) and chemotherapy (docetaxel), or cannot tolerate either or both therapies, in order to evaluate the safety, tolerability, and pharmacokinetics of proxalutamide [66].