Endocrine Therapies
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
Abiraterone was discovered through research in the early 1990s led by Mike Jarman and colleagues at the Institute of Cancer Research (London, UK) to discover and develop new drug treatments for prostate cancer. A patent protecting the molecule was filed in 1993, and commercialization rights were assigned to (the then) British Technology Group (BTG) plc, a UK-based drug discovery company. BTG licensed abiraterone to Cougar Biotechnology which started development work, and Cougar was then acquired by Johnson & Johnson, which carried out the late-stage development work, and Janssen-Cilag (now part of the Johnson & Johnson Group) now markets the approved agent.
Urological cancer
Peter Hoskin, Peter Ostler in Clinical Oncology, 2020
Radium 223 is a bone-seeking radioisotope which emits alpha particles. These have a short range in tissue and thus the radiation dose can be concentrated at sites of radium uptake, typically sites of osteoblastic response to metastases. It is given as an intravenous injection every 4 weeks for a course of six injections and has been shown to have similar effects on chemotherapy or second-line hormone therapy such as abiraterone or enzalutamide. Because of its short range there is limited toxicity which may include fatigue and mild reductions in blood indices.
Basic Science and Molecular Oncology
Manit Arya, Taimur T. Shah, Jas S. Kalsi, Herman S. Fernando, Iqbal S. Shergill, Asif Muneer, Hashim U. Ahmed in MCQs for the FRCS(Urol) and Postgraduate Urology Examinations, 2020
Abiraterone inhibits CYP17 enzymes that are expressed in testicular, prostatic and adrenal tissues. The 17-alpha-hydroxylase component catalyses the conversion of pregnenolone and progesterone to their 17-alpha-hydroxy derivatives. 17,20-lyase catalyses the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, which are androgens and precursors of testosterone. Abiraterone also acts as a partial AR antagonist.
An up-to-date evaluation of abiraterone for the treatment of prostate cancer
Published in Expert Opinion on Pharmacotherapy, 2021
Jason Shpilsky, Julia Stevens, Glenn Bubley
Research on the role of abiraterone for the various settings of prostate cancer is ongoing, especially around sequencing of treatments. One multicenter open-label crossover trial sought to identify the most effective sequence of abiraterone and enzalutamide for mCRPC [31]. Patients who had not received prior treatment for their mCRPC (n = 202) were randomized to either abiraterone followed by enzalutamide upon progression (A→E) or enzalutamide followed by abiraterone (E→A). The primary endpoint was time to second PSA progression. A→E was associated with a longer median time to second PSA progression compared to the reverse sequence (19.3 vs 15.2 mos, HR 0.66, P = 0.036). This was driven by a lower PSA response to second-line abiraterone than to second-line enzalutamide (4% vs 36%, P < 0.001). Abiraterone appears to have poor effectiveness in patients who have progressed on an androgen receptor inhibitor such as enzalutamide, suggesting abiraterone should be considered for initial therapy.
Advances in adrenocortical carcinoma pharmacotherapy: what is the current state of the art?
Published in Expert Opinion on Pharmacotherapy, 2022
Valentina Cremaschi, Andrea Abate, Deborah Cosentini, Salvatore Grisanti, Elisa Rossini, Marta Laganà, Mariangela Tamburello, Antonella Turla, Sandra Sigala, Alfredo Berruti
Our group demonstrated an antitumor activity of abiraterone acetate, a drug currently in use in metastatic prostate cancer. Our preclinical in vitro and in vivo studies on ACC models indicated that the mechanism of abiraterone cytotoxic effect was the increase in intracellular progesterone concentrations [29,30], which could have an antineoplastic activity in ACC. This hypothesis was then validated by further studies demonstrating a direct cytotoxic effect of progesterone (alone or combined with mitotane) in different ACC cell models, expanding the experimental tools available to study at preclinical levels a phenotypically heterogenous disease such as ACC [31,32]. Interestingly, we demonstrated that progesterone was able to reduce the β-catenin nuclear translocation [31] in NCI-H295R cells that carry a β-catenin pathogenic mutation [33]. Moreover, on the basis of the detectable, albeit scarce, the presence of estrogen receptor β in different cellular models of ACC, we studied the combination of progesterone with the selective estrogen receptor modulator tamoxifen, which did not show superior cytotoxicity compared to progesterone alone [32]. These encouraging preclinical results of progesterone prompted us to design a randomized phase II clinical study aimed to explore the antitumor effect of the progestin analog megestrol acetate in ACC patients.
Abiraterone acetate plus prednisone/prednisolone in hormone-sensitive and castration-resistant metastatic prostate cancer
Published in Expert Review of Precision Medicine and Drug Development, 2021
Jürgen E Gschwend, Kurt Miller
AA is a pro-drug of its active metabolite abiraterone formulated to increase oral bioavailability [5]. Abiraterone selectively and irreversibly inhibits CYP17, leading to inhibition of testicular, adrenal and intratumoral testosterone synthesis [5]. The tablets should be taken only on an empty stomach (either at least 1 h before or 2 hours after a meal), since systemic exposure to abiraterone increases up to 10-fold when taken with food [5]. In addition to blocking androgen synthesis, CYP17 inhibition may also result in increased mineralocorticoid levels via reduction in serum cortisol and a consequent increase in adrenocorticotrophic hormone (ACTH) that drives the mineralocorticoid production cascade [6]. Main adverse events (AEs) of abiraterone are those related to the mineralocorticoid excess, including hypertension, hypokalemia, and fluid retention/peripheral edema, which can be attenuated by inclusion of low-dose corticosteroids (prednisone or prednisolone) [5]. In mCRPC corticosteroids are often used to manage tumor-related symptoms, especially bone metastasis-related pain, or to prevent treatment-related toxicity [7]. In addition, available evidence suggests that corticosteroids may also offer direct antitumoral activity, resulting in PSA decline [7].
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