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National audience; OBJECTIVE: The aim of this study was to describe the profile of adverse drug reactions (ADRs) observed with abiraterone and enzalutamide, based on cases registered in the French regional pharmacovigilance centres to identify potential pharmacovigilance signals. METHODS: We extracted from the French pharmacovigilance database all cases of ADRs or drug interactions involving abiraterone or enzalutamide from the time they market authorization date until December 31st, 2017. Signal detection results have been transmitted by the French Agency for Health Products (ANSM). The data were compared with those of the risk management plans for each drug and the literature. RESULTS: Among the 233 observations analyzed, nearly 62% involved abiraterone as a suspect drug and 38% involved enzalutamide; only 1 case involved both drugs. The ADRs profile is different between the drugs. Abiraterone is mostly associated with expected cardiac diseases (heart failure, and QT prolongation), expected with the drug. Also described, several cases of hepatotoxicity have been reported, however some cases with fatal outcome suggest that despite a follow-up of the liver function tests, it is difficult to anticipate this risk. Signals concerning acute renal failure and ischemic stroke have arisen. Enzalutamide is more particularly associated with various neurological disorders (convulsions, hallucinations, fatigue, and memory impairment) expected with the drug. While ischemic heart disease is also expected, signals of heart failure and atrial fibrillation have arisen. A potential hepatotoxicity of the molecule is discussed because of cases of cholestatic hepatitis. CONCLUSION: The analysis of the French pharmacovigilance database cases allows to confirm an expected and monitored risk profile in the risk management plan for both drugs. Several signals have arisen, some of which will be investigated through a pharmacoepidemiology study.

Venous thromboembolism and arterial ischemic events are the main deleterious diseases associated with the use of combined hormonal contraceptives (CHC). Even though their composition has been substantially improved, the vascular risk persists with the most recent CHCs use. If the vascular risk associated with CHCs containing 50μg EE is significantly higher than with those containing less than 50μg, there is no evidence that the CHCs containing either 30 or 20μg of EE induce different venous risks. CHC containing gestodene, desogestrel, drospirenone or cyproterone acetate are associated with a higher risk of venous thrombosis compared with levonorgestrel-containing CHCs. CHC containing norgestimate are associated with similar venous thrombosis risk than CHC containing levonorgestrel. Venous thrombosis risk of non-oral routes of administration of CHC appears to be equivalent to the risk of CHC containing gestodene or desogestrel, but this result is based on a small number of epidemiological studies. Before prescribing a CHC, it is important to determine all vascular risk factors. Family history of ischemic arterial event or venous thromboembolism disease should be routinely sought before any CHC prescription. All CHCs are contraindicated in women with biological thrombophilia, in women with combined vascular risk factors, in women with first-degree family history of arterial or venous event (under age 50) as well as in women suffering of migraine with aura. Progestin-only contraceptives are not associated with vascular risk (arterial or venous) outside of medroxyprogesterone acetate. In women with higher vascular risk, progestin-only contraceptives (administered by oral, sous-cutaneous or intra-uterine routes) can be prescribed.

Genetic instability is one part of the oncogenic process. Gene mutations involved in DNA repair mechanisms can promote this genetic instability and participate in oncogenesis and metastatic progression. In prostate cancer, DNA repair abnormalities mainly correspond to somatic or constitutional mutations of the BRCA2 and ATM genes. Therapeutic management of metastatic castration-resistant prostate cancer (mCRPC) is currently based on new hormonal therapies (abiraterone, enzalutamide) and taxane-type chemotherapy (docetaxel or cabazitaxel). Preliminary data tend to indicate a specific activity of agents causing DNA breaks (platinum salts) and PARP inhibitors in patients with these DNA repair abnormalities. The frequency of DNA repair gene mutations in patients with prostate cancer (around 20%) and the antitumor response of PARP inhibitors make it a possible short-term therapeutic strategy with several registering clinical trials ongoing.

Despite castrate levels of androgens, the androgen receptor (AR) remains active and continues to drive prostate cancer progression. Since the approval of docetaxel, four additional agents that show a survival benefit have been registered on the basis of randomized phase 3 trials. These have included enzalutamide and abiraterone, two agents designed specifically to affect the androgen axis, sipuleucel-T, which stimulates the immune system and cabazitaxel, a chemotherapeutic agent. Denosumab was shown to significantly delay skeletal-related events. Clinicians are challenged with a multitude of treatment options and potential sequencing of these agents that, consequently, make clinical decision making more complex. The induction of constitutively-active AR splice variants (AR-Vs) driving clonal proliferation of AR-negative and AR-independent metastases may be one major potential mechanism of resistance to new hormone therapies.

Corticosteroids are commonly used in the treatment of prostate cancer resistant to castration (PCRC), partly due to the inhibitory effects on adrenal androgen production acting as a pituitary suppressant.A literature search was conducted in PubMed/MEDLINE database using the following key words: prostate cancer; castration resistance; metastasis; corticotherapy.Corticosteroids exert direct anti-tumoral activities mediated by the glucocorticoids receptor and involving cellular/tissue functions as growth, apoptosis, inflammation, metastasis, differentiation and angiogenesis. As a pain relieving agents, corticosteroids significantly relieve PCRC clinical symptoms, especially those due to bone metastasis. In the comparative arm of phase II-III trials, corticosteroids administered daily produce a PSA decline. Among the adverse effects due to corticosteroids, bone loss and cardiovascular risk should be carefully monitored. In association with abiraterone acetate, corticosteroids increase overall survival in PCRC patients, and reduce the mineralocorticoid side effects of abiraterone.Corticosteroids in monotherapy for PCRC have a limited efficacy. In association with abiraterone acetate it reduces the mineralocorticoid toxicity and enhances the androgenic suppression.

Docetaxel has been the cornerstone in the treatment of castration- resistant prostate cancer (CRPC) since 2004. The recent and almost simultaneous arrival of new and effective molecules - several of which are already available on the market - has added to the CRPC treatment arsenal. Several studies have explored the optimal order in which these new treatments should be administered. The aim of this review was to present their respective predictive and evaluative factors and suggest potential administration sequences.The PubMed medical literature citations database was searched using the following key words: prostate cancer, castration resistant, metastatic, targeted therapy, treatment sequence, immunotherapy and clinical trials. The reports of the most recent European and North American congresses were also included.While no predictive factors have been clearly identified for these new therapies to date, a Gleason score of not less than 8 and one or more chemotherapy sessions seemed to be predictive of lower efficacy for abiraterone. Promising elements for further investigation include the circulating tumour cell count and variation in this count per treatment, ERG mutation status or the intratumoural androgen status. Substitution criteria have not yet been reported but, as is the case with all hormone therapies, changes in PSA levels emerge as a valuable indicator of the efficacy of abiraterone. The best treatment sequence for patients who develop castration-resistance remains to be defined.Although new molecules have recently become available, the experience with their use is limited. Thus, no predictive markers of response rates and treatment outcomes or data concerning the best treatment sequence to use in patients with CRPC are as yet available.

Docetaxel chemotherapy is a standard treatment for fit men with symptomatic castration-resistant prostate cancer. Unfortunately docetaxel resistant disease will systematically develop and second-line treatment may be appropriate. Until recently no standard treatment was approved in this setting and mitoxantrone was commonly used. Three new drugs have shown benefit in randomised phase 3 multicenter clinical trials published since 2010. Cabazitaxel, abiraterone and enzalutamide were shown to prolong overall survival of men with metastatic castration-resistant prostate cancer previously treated with chemotherapy. Although still modest these results were deemed clinically significant and led to the reimbursement of Jevtana (cabazitaxel) and Zytiga (abiraterone) in Belgium in 2012.

Among the 35 new molecular entities approved by the FDA in 2011, 17 were particularly notable for their significant contributions to the health of patients, including abiraterone acetate, vandetanib, belatacept and fidaxomicin. Thus, abiraterone acetate, namely Zytiga®, was included as the first in a new class of drugs to treat late-stage prostate cancer. The ability of Zytiga® to prolong survival in these patients was considered as significant because they have few other treatments options and the benefits of Zytiga® outweighed the risks of reported side-effects. Vandetanib, namely Caprelsa®, was also considered as a relevant drug since it represents the first drug approved to treat particularly aggressive medullary thyroid cancer, an orphan disease. Despite huge progress in transplantation, renal transplantation remains a serious problem since patients treated with the calcineurin inhibitors cyclosporine and tacrolimus are at high risk of developing renal injury. With longer follow-up, the novel immunosuppressant belatacept continued to show better renal function compared with a cyclosporine-based regimen, as well as a consistent safety profile and comparable efficacy. It was approved by the Food and Drug Administration in June 2011 for the prophylaxis of organ rejection in adult recipients of a kidney transplant acting by a selective T-cell costimulation blocker given as an infusion. Clostridium difficile is currently the most important cause of infectious diarrhea in the United States. Fidaxomicin, a macrolide antibiotic, was recently approved for treatment of these infections (CDIs). It could be an alternative treatment for infection with C. difficile, with similar efficacy and safety to vancomycin. Fidaxomicin has minimal activity against Bacteroides species, which may be advantageous in maintaining colonization resistance and protecting the gastrointestinal tract from colonization by C. difficile.

Recently, new agents have been developed in the treatment of prostate cancer. Our aim was to review phase III studies that involved novel agents in the treatment of castration resistant prostate cancer.PubMed databases were searched for original articles published with the search terms: prostate cancer, castration resistant, metastatic, targeted therapy, biologic agents, immunotherapy and clinical trials. Proceedings from 2008 of conferences of the American Society of Clinical Oncology, American Urological Association, and the European Association of Urology were also searched. We included phase III studies that involved: abiraterone, MDV 3100, cabazitaxel, sipuleucel-T, radium-223, and denosumab.Abiraterone and MDV 3100 are two new hormotherapies that showed an increased overall survival of 15 and 18 months respectively before after docetaxel based chemotherapy in randomized trials. Cabazitaxel became the standard second line chemotherapy after docetaxel. Sipuleucel-T has emerged as the first approved vaccine in prostate cancer. It showed a 22 % reduction of mortality and a prolonged survival time of 4.1 months compared to placebo. A radium-223 based metabolic radiotherapy has showed a better overall survival, delayed and reduced skeletal-related events in placebo controlled randomized trials. Denosumab also delayed the first skeletal-related event in a zoledronic acid controlled trial (20.7 versus 17.1 months, P=0.0002). Moreover, Denosumab delays bone metastases by 4.1 months compared to placebo.The novel agents that emerged in the treatment of prostate cancer showed an efficacy in placebo controlled trials. They added new tools in the armamentarium of therapies of castration resistant prostate cancer.

To provide current and emerging evidence on oral contraceptives and the risk of venous thromboembolism.Articles published in English from 2005 were retrieved through searches of PubMed and Medline, using the following terms: venous thromboembolism, VTE, contraception, oral contraceptives, hormonal contraception. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Searches were updated on a regular basis and incorporated in the guideline to May 2010. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.The quality of evidence was rated using the criteria described by the Canadian Task Force on Preventive Health Care (Table). SUMMARY STATEMENTS: 1. Modern oral contraceptives offer highly effective contraception and a range of non-contraceptive benefits. (I) 2. Venous thromboembolism, although rare, remains one of the serious adverse consequences of hormonal contraception. Best evidence indicates that venous thromboembolism rates in non-users of reproductive age approximate 4-5/10 000 women per year; rates in oral contraceptive users are in the range of 9-10/10 000 women per year. For comparison, venous thromboembolism rates in pregnancy approach 29/10 000 overall and may reach 300-400/10 000 in the immediate postpartum period. (II-1) 3. Research demonstrates that oral contraceptives with ≤ 35 µg of ethinyl estradiol carry a lower risk of venous thromboembolism than oral contraceptives with 50 µg. (II-2) Although preliminary data suggest a possible further reduction in venous thromboembolism with oral contraceptives with35 µg ethinyl estradiol, robust data to support this conclusion are presently lacking. 4. Recent contradictory evidence and the ensuing media coverage of the venous thromboembolism risk attributed to the progestin component of certain newer oral contraceptive products have led to fear and confusion about the safety of oral contraceptives in general and drospirenone-containing oral contraceptives in particular. "Pill scares" of this nature have occurred in the past, with panic stopping of the pill, increased rates of unplanned pregnancy, and no subsequent decrease in venous thromboembolism rates. (II-3) 5. Two high quality research studies that addressed the venous thromboembolism risk associated with various oral contraceptives found comparable venous thromboembolism rates with drospirenone-containing oral contraceptives and other approved products. (II-1) 6. Two reports suggesting an increased risk of venous thromboembolism with drospirenone-containing oral contraceptives have significant methodological flaws that render their conclusions suspect. It seems likely that residual confounding could have distorted both the results and the conclusions of these reports. (II-3).

Objective We sought to verify if an oral contraceptive (OC) containing drospirenone affects the cardiovascular risk of patients with polycystic ovary syndrome (PCOS). Study Design A total of 28 women with PCOS (16 lean [group A] and 12 overweight [group B]) were assessed at baseline and after 6 months therapy with an OC. Leptin, homocysteine, endothelin-1, and flow-mediated dilatation of brachial artery were measured. Results The brachial artery diameter and the pulsatility index, after the reactive hyperemia, did not change in group A; it improved significantly in group B after 6 months of treatment. At baseline and after therapy the plasma levels of homocysteine and endothelin-1 did not differ among the groups. Leptin was significantly lower at baseline in group A compared to group B. Conclusion The OC containing drospirenone does not seem to affect the surrogate markers of cardiovascular risk in lean patients with PCOS.

Despite that greater knowledge of prostate cancer biology has led to the isolation of many new and promising targets, treatment of metastatic prostate cancer is still challenging. New agents targeting these molecules are currently under development in large randomized phase III trials, to improve overall survival and the quality of life of patients with metastatic castrate-resistant prostatic cancer (CRPC). Cytotoxic chemotherapy (docetaxel-based chemotherapy) demonstrated clinical benefit on overall survival, but could be improved. Drugs targeting directly or not the androgen receptor such as abiraterone or new specific peripheral anti-androgens (MDV3100) are very promising. Bone targeted therapies (endothelin1 receptor A inhibitor, RANK ligant, metabolic irradiation) are also very promising and are in development in large phase III trials. Antiangiogenic therapies could also be effective in CRPC. Autologous vaccin against prostatic acid phosphatase seems to prolong overall survival and other vaccin and immunotherapy strategies are in development (anti-CTLA4 antibody). A recent analogue of thalidomide, probably more efficient, lenalidomide is also in development.

Following American randomised controlled epidemiologic studies (HERS, WHI), regulatory authorities have advised that postmenopausal hormone therapy, using minimal effective dosages, is indicated for the first line treatment of climacteric symptoms during a limited, and problem-related period of time, and for second line prevention of osteoporosis when a non-hormonal treatment cannot be used. Observation of a discrete increase in cardiovascular and breast cancer risk in hormone users currently appears to partly justify this rather strict attitude. We report here results of studies concerning a new continuous combination regimen (Angeliq), associating a "half-dose" estrogen (estradiol 1 mg/d) with potentially less thrombogenic impact than a standard (2 mg) dose, and the new progestin drospirenone (2 mg/d). The latter demonstrates a high level of endometrial safety as well as unique antialdosterone properties (reduction of symptoms related to water retention; potential cardioprotective effects) and consistent antiandrogenic properties, useful for both metabolic and clinical issues. Accordingly, Angeliq constitutes a new therapeutic approach, in good agreement with updated guidelines related to hormone replacement therapy.

27 boars aged 100 days were allocated to 3 experimental groups. The control group was untreated. The 2 other groups were given injections of LHRH, bound to BSA, with either Freund complete adjuvant or alumina gel. 4 immunisations were achieved at weekly intervals and a fifth injection was performed after 4 weeks. In animals treated with alumina gel, no specific antibodies were obtained. In the other hand, all 9 boars treated with FCA exhibited significant titers of specific anti-LHRH antibodies. In these animals, the neutralisation of blood LHRH induced a significant decline in both LH and FSH concentrations. Consequently, fat androstenone levels dropped dramatically, down to low levels, similar to those observed in surgically castrated males.

The role of protein-binding in the physiology of steroids is of great complexity. The following are envisaged: the types of protein, methods of binding and the affinity of steroids for proteins, and the variations in free fraction according to plasma protein levels; the functions of binding proteins on the activity and clearance of steroids as well as on the peripheral conversion of androgens; the factors which influence variations in binding protein levels and in particular the influence of circulating levels of natural hormones and the influence of hormone treatment.

The aim of the present experiment was to determine whether age, live weight, or a combination of both, was the most important factor influencing fat 5 alpha-androstenone levels in male pigs. Three groups of 50 boars each were fed either on a liberal plane of nutrition (CTRL group) or were restricted (SW and SA groups). Fat 5 alpha-androstenone was measured three times in each pig (on biopsies at two different times and at slaughter) at either the same live weight (SW) or at the same age (SA) as CTRL boars. In addition, the genital tract was dissected at slaughter. SW boars (aged 169 days) exhibited higher fat 5 alpha-androstenone levels than CTRL boars (aged 139 days) when the first biopsy was taken at 80 kg of live weight (1.2 vs 0.8 microgram/g; P less than 0.05). By the time of the second biopsy (100 kg of live weight) and at slaughter (125 kg) there was no significant difference between the SW and CTRL groups, although the SW were 43-55 days older than the CTRL. At all three measurement times, fat 5 alpha-androstenone was lower in SA than in CTRL boars which were 21-36 kg heavier (0.5 vs 0.8 micrograms/g at 139 days; 0.9 vs 1.3 micrograms/g at 160 days; 1.2 vs 2.0 micrograms/g at 185 days; P less than 0.001). Partial correlations between fat 5 alpha-androstenone and age were significant at the first biopsy, whereas partial correlations with live weight were significant at all three times of measurement. In SA boars weighing 90 kg there was a significant correlation between fat 5 alpha-androstenone and all the developmental traits of the genital tract. In SW and CTRL pigs weighing 125 kg, fat 5 alpha-androstenone was significantly correlated with accessory sex gland development but not with testis or epididymis weight. From the present data it is concluded that both age and live weight had a significant effect on fat 5 alpha-androstenone levels in young, light boars. In older, heavier boars, age had no effect per se but live weight still had a significant influence on 5 alpha-androstenone concentrations. In boars weighing 90 kg, fat 5 alpha-androstenone level depended on sexual maturity. When the animals were sexually mature at 125 kg of live weight, 5 alpha-androstenone level depended on the individual's potentiality for steroid production, which is probably under genetic control.