Strategies for managing ACTH dependent mineralocorticoid excess induced by abiraterone.

BACKGROUND: Abiraterone strongly inhibits androgen synthesis but may lead to an increase in mineralocorticoid hormones that may impair its long term tolerability in patients with prostate cancer. How to implement available therapies in the management and prevention of these potential side effects is a matter of current clinical research. METHODS: The acute and long term consequences of mineralocorticoid excess and the effects of available treatments have been reviewed. Prospective studies in which abiraterone was employed were identified to assess the frequency and severity of the mineralocorticoid excess syndrome and the efficacy of ameliorating therapeutic approaches. RESULTS: Glucocorticoids to inhibit the ACTH increase that drives mineralocorticoid synthesis and mineralocorticoid receptor (MR) antagonists can be used in the management of the abiraterone-induced mineralocorticoid excess syndrome. Phase I and II trials of abiraterone without additional therapies revealed that mineralocorticoid excess symptoms occur in the majority of patients. Eplerenone, a specific MR antagonist, seems to be effective but it does not control the mineralocorticoid excess. Glucorticoid supplementation to control ACTH drive is therefore needed. In several randomized trials the addition of prednisone (10mg daily) to abiraterone was not able to prevent mineralocorticoid excess syndrome in many cases and thus cannot be considered the gold standard. CONCLUSION: At present, the best conceivable treatment for managing the abiraterone-induced mineralocorticoid excess consists of the administration of glucocorticoid replacement at the lowest effective dose ± MR antagonists and salt deprivation. The drug doses should be modulated by monitoring blood pressure, fluid retention and potassium levels during therapy.

Abiraterone for the treatment of metastatic castrate-resistant prostate cancer.

OBJECTIVE: To review the clinical pharmacology, efficacy, and safety of abiraterone acetate for metastatic castrate-resistant prostate cancer (mCRPC) and evaluate the drug for health-system formulary inclusion. DATA SOURCES: Literature was identified through a search of MEDLINE (1977-February 2012) and International Pharmaceutical Abstracts (1977-February 2012) using the search term abiraterone. References of identified articles were reviewed. STUDY SELECTION AND DATA EXTRACTION: All clinical trials published in English were evaluated. Studies conducted in the setting of mCRPC were included in the literature review. DATA SYNTHESIS: Despite benefits from androgen deprivation for the treatment of prostate cancer, most patients experience disease progression within 12-48 months, a phase described as castrate resistant. Abiraterone is the only Food and Drug Administration-approved hormonal treatment option for mCRPC in men who have received docetaxel and is recommended as a second-line agent for this indication in the National Comprehensive Cancer Network prostate cancer guidelines. One Phase 3 study, 2 Phase 2 studies, and 2 Phase 1 studies conducted in the setting of second-line treatment of mCRPC were identified. Treatment with abiraterone was associated with at least a 50% reduction in prostate-specific antigen (PSA) in 38-51% of patients; PSA progression ranged from 5.6-10.2 months. The only study assessing mortality outcomes found a 13% absolute reduction in mortality (ie, 42% vs 55%; HR 0.65; 95% CI 0.54 to 0.77), relative to placebo, over a median 12.8 months of follow-up. Abiraterone has been compared only to placebo, not to existing treatment options. CONCLUSIONS: Abiraterone provides a moderate improvement in disease progression and mortality in a patient population with limited treatment options. It is recommended to add this medication to outpatient formularies restricted to second-line treatment of mCRPC.

HE3286: a novel synthetic steroid as an oral treatment for autoimmune disease.

HE3286 (17alpha-ethynyl-5-androstene-3beta, 7beta, 17beta-triol) is a synthetic derivative of a natural anti-inflammatory steroid, beta-AET (5-androstene-3beta, 7beta, 17beta-triol). HE3286 is orally bioavailable and treats established disease in models of ulcerative colitis, collagen-induced arthritis, and collagen antibody-induced arthritis, reducing clinical signs of disease and proinflammatory signals, including IL-6 and matrix metallopeptidase 3. HE3286 modulates nuclear factor kappaB through an unknown mechanism but does not interact with any of the steroid-binding nuclear hormone receptors and is not immune suppressive. HE3286 was safe and well tolerated in phase I studies and is under evaluation in multicenter phase I/II clinical trials for ulcerative colitis and arthritis. HE3286 may provide a new treatment option for patients with inflammatory and autoimmune diseases.

Beta-androstenes and resistance to viral and bacterial infections.

This report illustrates that the beta-androstenes are indeed able to upregulate the host immune response to a level that enables the host to resist lethal infection by viruses or bacteria. These agents consist of a subgroup of steroids, which also mediates a rapid recovery of hematopoietic precursor cells after whole-body lethal radiation injury. In vivo, the androstenes increase the levels of the Th1 cytokines such as IL-2, IL-3, and IFN. Similar to hydrocortisone, they suppress inflammation, but without immune suppression, and have a role in the maintenance of the Th1/Th2 balance and immune homeostasis.