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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.
The dawn of targeted therapies for triple negative breast cancer (TNBC): a snapshot of investigational drugs in phase I and II trials
Published in Expert Opinion on Investigational Drugs, 2020
My-my Huynh, Mary Rose Pambid, Aarthi Jayanthan, Andrew Dorr, Gerrit Los, Sandra E. Dunn
AR+ TNBC represents a subgroup of cancers that have an even worse prognosis than AR- TNBC [63]. These AR+ cases fall into the luminal androgen receptor (LAR) molecular TNBC subtype, uniquely characterized by having high expression of genes in hormone regulated pathways [4]. Therefore, the AR inhibitor enzalutamide, which has been used successfully in castration resistant prostate cancer, is now being tested in an ongoing phase I trial (NCT02689427) in combination with paclitaxel as neoadjuvant therapy in AR+ TNBC. Another antiandrogen that has been successful in prostate cancer, bicalutamide, is in a phase II study in combination with ribociclib, a CDK4/6 inhibitor (NCT03090165). The modest response to treatment with antiandrogens alone has led to this combination, as it is hypothesized based on preclinical data in prostate cells, that CDK4/6 inhibition overcomes resistance mechanisms to antiandrogen therapy [64]. Other strategies for targeting the hormonal synthesis pathways in TNBC include several phase II trials testing orteronel, a nonsteroidal CYP17A1 inhibitor, that is important in androgen synthesis. These trials include orteronel, as a monotherapy in metastatic disease (NCT01990209) and in combination with enzalutamide in early stage TNBC (NCT02750358). This same combination is also being explored in advanced TNBC (NCT01889238).
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
Orteronel (TAK-700) is a nonsteroidal androgen synthesis inhibitor with greater specificity for 17,20-lyase activity and weak inhibition of 17α-hydroxylase, causing inhibition of CYP17A [35] and consequently inhibition of testosterone and dehydroepiandrosterone sulfate (DHEA-s) production [36]. This discrepant selectivity has a theoretical advantage of inhibiting testosterone biosynthesis while minimize the decrease of cortisol production, diminishing the risk of mineralocorticoid-related toxicities [37,38]. The phase I/II trial which evaluated orteronel in men with progressive, chemotherapy-naïve mCRPC and testosterone <50 ng/mL showed that at 12 weeks of treatment, 46% of patients (45 of 97) achieved testosterone <1 ng/mL [39]. Also, 54% of patients achieved DHEA-s levels <10 µg/dL. Clinical responses were also seen, and 54% (45/84) of evaluable patients had at least 50% of decline in PSA (PSA50) from baseline and 21% (18/84) had 90% decline in PSA. Radiographic responses were seen in 20% (10/51) of patients with measurable lesions [39]. Based on these promising results, larger trials were done in mCRPC.
The addition of apalutamide to ADT in the treatment of metastatic castration-sensitive prostate cancer: safety and efficacy
Published in Expert Review of Anticancer Therapy, 2020
Pedro Barata, Umang Swami, Neeraj Agarwal
Moving forward, we expect efficacy data of various other novel androgen axis inhibitors such as darolutamide (ARASENS), orteronel (SWOG-1216) and other non-hormonal therapies, such as immunotherapy (NCT02649855), radiopharmaceuticals (NCT03304418) and other chemotherapy agents (NCT03419234) which may potentially expand the treatment options further. Yet, unanswered questions such as comparative efficacy and safety profiles, the appropriate sequence of these agents, targeting pathways leading to resistance to androgen axis inhibitors and patient selection based on molecular biomarkers will require further evaluation.