Cushing's disease: adrenal steroidogenesis inhibitors.

Cushing's disease (CD), caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor, is the most common form of Cushing's syndrome (CS), accounting for approximately 70% of cases. CD requires a prompt diagnosis, an adequate treatment selection, and long-term management to limit hypercortisolism duration and long-term complications and improve patient outcomes. Pituitary surgery is the first-line option, which is non-curative in one third of patients, therefore requiring additional treatments. Medical therapy has recently acquired an emerging role, with the availability of several drugs with different therapeutic targets, efficacy and safety profiles. The current review focuses on efficacy and safety of steroidogenesis inhibitors, and particularly the historical drugs, ketoconazole and metyrapone, and the novel drugs levoketoconazole and osilodrostat, which seem to offer a rapid, sustained, and effective disease control. Ketoconazole should be preferred in females and in patients without severe liver disease; levoketoconazole may offer an alternative to classical ketoconazole, appearing characterized by a higher potency and potential lower hepatotoxicity compared to ketoconazole. Metyrapone should be preferred in males and in patients without severe or uncontrolled hypokalemia. Both ketoconazole and metyrapone may be preferred for short-term more than for long-term treatment. Osilodrostat may represent the best choice for long-term treatment, in patients with poor compliance to the multiple daily administration schedule, and in patients without severe or uncontrolled hypokalemia. Steroidogenesis inhibitors may be used alone or in combination, and associated with pituitary directed drugs, to improve the efficacy of the single drugs, allowing a potential use of lower doses for each drug, and hypothetically reducing the rate of adverse events associated with the single drugs. Clinicians may tailor medical therapy on the specific clinical scenario, considering disease history together with patients' characteristics and hypercortisolism's degree, addressing the needs of each patient in order to improve the therapeutic outcome and to reduce the burden of illness, particularly in patients with persistent or recurrent CD.

Cushing's disease: role of preoperative and primary medical therapy.

Transsphenoidal surgery is the first-line treatment for Cushing's disease. However, some situations may require the use of a primary medical treatment, such as in patients with severe life-threatening hypercortisolism, a situation which can be handled by fast-acting steroidogenesis inhibitors, instead of classical bilateral adrenalectomy. Primary medical treatment could also be considered in patients with non-severe hypercortisolism, but the evidence is far less convincing for its systematic use. The aim of this short review is to explain briefly the different circumstances in which primary medical therapy could be considered, the limits of this approach, and the way in which to initiate and monitor the treatment.

Apalutamide plus abiraterone acetate and prednisone versus placebo plus abiraterone and prednisone in metastatic, castration-resistant prostate cancer (ACIS): a randomised, placebo-controlled, double-blind, multinational, phase 3 study.

BACKGROUND: The majority of patients with metastatic castration-resistant prostate cancer (mCRPC) will have disease progression of a uniformly fatal disease. mCRPC is driven by both activated androgen receptors and elevated intratumoural androgens; however, the current standard of care is therapy that targets a single androgen signalling mechanism. We aimed to investigate the combination treatment using apalutamide plus abiraterone acetate, each of which suppresses the androgen signalling axis in a different way, versus standard care in mCRPC. METHODS: ACIS was a randomised, placebo-controlled, double-blind, phase 3 study done at 167 hospitals in 17 countries in the USA, Canada, Mexico, Europe, the Asia-Pacific region, Africa, and South America. We included chemotherapy-naive men (aged ≥18 years) with mCRPC who had not been previously treated with androgen biosynthesis signalling inhibitors and were receiving ongoing androgen deprivation therapy, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a Brief Pain Inventory-Short Form question 3 (ie, worst pain in the past 24 h) score of 3 or lower. Patients were randomly assigned (1:1) via a centralised interactive web response system with a permuted block randomisation scheme (block size 4) to oral apalutamide 240 mg once daily plus oral abiraterone acetate 1000 mg once daily and oral prednisone 5 mg twice daily (apalutamide plus abiraterone-prednisone group) or placebo plus abiraterone acetate and prednisone (abiraterone-prednisone group), in 28-day treatment cycles. Randomisation was stratified by presence or absence of visceral metastases, ECOG performance status, and geographical region. Patients, the investigators, study team, and the sponsor were masked to group assignments. An independent data-monitoring committee continually monitored data to ensure ongoing patient safety, and reviewed efficacy data. The primary endpoint was radiographic progression-free survival assessed in the intention-to-treat population. Safety was reported for all patients who received at least one dose of study drug. This study is completed and no longer recruiting and is registered with ClinicalTrials.gov, number NCT02257736. FINDINGS: 982 men were enrolled and randomly assigned from Dec 10, 2014 to Aug 30, 2016 (492 to apalutamide plus abiraterone-prednisone; 490 to abiraterone-prednisone). At the primary analysis (median follow-up 25·7 months [IQR 23·0-28·9]), median radiographic progression-free survival was 22·6 months (95% CI 19·4-27·4) in the apalutamide plus abiraterone-prednisone group versus 16·6 months (13·9-19·3) in the abiraterone-prednisone group (hazard ratio [HR] 0·69, 95% CI 0·58-0·83; p<0·0001). At the updated analysis (final analysis for overall survival; median follow-up 54·8 months [IQR 51·5-58·4]), median radiographic progression-free survival was 24·0 months (95% CI 19·7-27·5) versus 16·6 months (13·9-19·3; HR 0·70, 95% CI 0·60-0·83; p<0·0001). The most common grade 3-4 treatment-emergent adverse event was hypertension (82 [17%] of 490 patients receiving apalutamide plus abiraterone-prednisone and 49 [10%] of 489 receiving abiraterone-prednisone). Serious treatment-emergent adverse events occurred in 195 (40%) patients receiving apalutamide plus abiraterone-prednisone and 181 (37%) patients receiving abiraterone-prednisone. Drug-related treatment-emergent adverse events with fatal outcomes occurred in three (1%) patients in the apalutamide plus abiraterone-prednisone group (2 pulmonary embolism, 1 cardiac failure) and five (1%) patients in the abiraterone-prednisone group (1 cardiac failure and 1 cardiac arrest, 1 mesenteric arterial occlusion, 1 seizure, and 1 sudden death). INTERPRETATION: Despite the use of an active and established therapy as the comparator, apalutamide plus abiraterone-prednisone improved radiographic progression-free survival. Additional studies to identify subgroups of patients who might benefit the most from combination therapy are needed to further refine the treatment of mCRPC. FUNDING: Janssen Research & Development.

Impact of pretreatment anemia on upfront abiraterone acetate therapy for metastatic hormone-sensitive prostate cancer: a multicenter retrospective study.

BACKGROUND: Anemia has been a known prognostic factor in metastatic hormone-sensitive prostate cancer (mHSPC). We therefore examined the effect of anemia on the efficacy of upfront abiraterone acetate (ABI) in patients with mHSPC. METHODS: We retrospectively evaluated 66 mHSPC patients with high tumor burden who received upfront ABI between 2018 and 2020 (upfront ABI group). We divided these patients into two groups: the anemia-ABI group (hemoglobin < 13.0 g/dL, n = 20) and the non-anemia-ABI group (n = 46). The primary objective was to examine the impact of anemia on the progression-free survival (PFS; clinical progression or PC death before development of castration resistant PC) of patients in the upfront ABI group. Secondary objectives included an evaluation of the prognostic significance of upfront ABI and a comparison with a historical cohort (131 mHSPC patients with high tumor burden who received androgen deprivation therapy (ADT/complete androgen blockade [CAB] group) between 2014 and 2019). RESULTS: We found that the anemia-ABI group had a significantly shorter PFS than the non-anemia-ABI group. A multivariate Cox regression analysis showed that anemia was an independent prognostic factor of PFS in the upfront ABI group (hazard ratio, 4.66; P = 0.014). Patients in the non-anemia-ABI group were determined to have a significantly longer PFS than those in the non-anemia-ADT/CAB group (n = 68) (P < 0.001). However, no significant difference was observed in the PFS between patients in the anemia-ABI and the anemia-ADT/CAB groups (n = 63). Multivariate analyses showed that upfront ABI could significantly prolong the PFS of patients without anemia (hazard ratio, 0.17; P < 0.001), whereas ABI did not prolong the PFS of patients with anemia. CONCLUSION: Pretreatment anemia was a prognostic factor among mHSPC patients who received upfront ABI. Although the upfront ABI significantly improved the PFS of mHSPC patients without anemia, its efficacy in patients with anemia might be limited.

Syncope due to non-sustained episodes of Torsade de Pointes associated to androgen-deprivation therapy use: a case presentation.

BACKGROUND: Abiraterone is a medication frequently used for metastatic castrate-resistant prostate cancer. We report a case of non-sustained episodes of TdP associated with severe hypokalemia due to androgen-deprivation therapy. Few case presentations describe this association; the novelty lies in the potentially lethal cardiovascular events among cancer patients receiving hormonal therapy. CASE PRESENTATION: A 70-year-old male presented with recurrent syncope without prodrome. ECG revealed frequent ventricular ectopy, non-sustained episodes of TdP, and severe hypomagnesemia and hypokalemia. During potassium and magnesium infusion for repletion, the patient underwent temporary transvenous atrial pacing. As part of the work-up, coronary angiography revealed a mild coronary artery disease, and transthoracic echocardiogram showed a moderately depressed ejection fraction. After electrolyte disturbances were corrected, the QT interval normalized, and transvenous pacing was no longer necessary. Abiraterone was discontinued during the admission, and the patient returned to baseline. CONCLUSIONS: Cancer treatment is complex and requires a multidisciplinary approach. We presented a case of non-sustained TdP associated with androgen-deprivation therapy in an elderly patient with mild coronary artery disease and moderately reduced ejection fraction. Close follow-up and increased awareness are required in patients with hormonal treatment, especially in the setting of other cardiovascular risk factors.

Levoketoconazole, the 2S,4R Enantiomer of Ketoconazole, a New Steroidogenesis Inhibitor for Cushing's Syndrome Treatment.

INTRODUCTION: Racemic ketoconazole (RK) is a steroidogenesis inhibitor used for treatment of Cushing's syndrome. Levoketoconazole (COR-003), the pure 2S,4R enantiomer, is potentially more potent and safe compared to RK. We compared in vitro effects of levoketoconazole and RK on adrenocortical and pituitary adenoma cells. MATERIALS AND METHODS: HAC15 cells and 15 primary human neoplastic adrenocortical cultures (+/- ACTH), and murine (AtT20) and human corticotroph adenoma cultures were incubated with levoketoconazole or RK (0.01-10 µM). Cortisol and ACTH were measured using a chemiluminescence immunoassay system, and steroid profiles by liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: In HAC15, levoketoconazole inhibited cortisol at lower concentrations (IC50: 0.300 µM) compared to RK (0.611 µM; P < 0.0001). IC50 values of levoketoconazole for basal cortisol production in primary adrenocortical cultures varied over a 24-fold range (0.00578-0.140 µM), with 2 patients having a higher sensitivity for levoketoconazole vs RK (2.1- and 3.7-fold). LC-MS/MS analysis in selected cases revealed more potent inhibition of cortisol and other steroid profile components by levoketoconazole vs RK. In AtT20, levoketoconazole inhibited cell growth and ACTH secretion (10 µM: -54% and -38%, respectively), and levoketoconazole inhibited cell number in 1 of 2 primary human corticotroph pituitary adenoma cultures (-44%, P < 0.001). CONCLUSION: Levoketoconazole potently inhibits cortisol production in adrenocortical cells, with a variable degree of suppression between specimens. Levoketoconazole inhibits adrenal steroid production more potently compared to RK and might also inhibit ACTH secretion and growth of pituitary adenoma cells. Together with previously reported potential advantages, this indicates that levoketoconazole is a promising novel pharmacotherapy for Cushing's syndrome.

Risk of major adverse cardiovascular events among second-line hormonal therapy for metastatic castration-resistant prostate cancer: A real-world evidence study.

BACKGROUND: To evaluate the possible major adverse cardiovascular events (MACE) associated with second-line hormonal therapy in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: We performed a population-based real-world cohort study of 4962 prostate cancer patients between 2014 and 2017 utilizing the Chang Gung Research Database of Taiwan. The second-line hormonal therapies included enzalutamide and abiraterone acetate. The outcomes of interest were MACE, including acute coronary syndrome (ACS), ischemic stroke (IS), and heart failure (HF) events that resulted in hospitalization. Cox proportional-hazards models with inverse probability of treatment weighting (IPTW) with propensity scores were used. RESULTS: After IPTW, 288 patients were prescribed second-line hormonal therapy and 1575 received first-line androgen-deprivation therapy (ADT). Of all patients diagnosed with MACE, the event rates were 2.92% in the second-line hormonal group and 2.22% in the first-line ADT group. The mean follow-up period was 9.52 months for the second-line hormonal group. Patients who received second-line hormonal therapy exhibited a significantly increased risk for MACE (hazard ratio [HR]: 3.15; 95% confidence interval [CI]: 2.03-4.89), ACS (HR: 4.94; 95% CI: 2.36-10.33), and HF (HR: 2.83; 95% CI: 1.53-5.25), compared with the first-line ADT group, but a similar risk for IS was observed in both groups (HR: 1.70; 95% CI: 0.95-3.04). CONCLUSIONS: The real-world evidence study revealed increased risks for MACE in mCRPC patients receiving second-line hormonal therapy.

miRNA320a-3p/RUNX2 signal programming mediates the transgenerational inheritance of inhibited ovarian estrogen synthesis in female offspring rats induced by prenatal dexamethasone exposure.

Our previous studies found that prenatal dexamethasone exposure could cause abnormal follicular development in fetal rats. This study intends to observe the transgenerational inheritance effects of ovarian estrogen inhibition in offspring exposed to dexamethasone (0.2 mg/kg • d) from gestational day 9 (GD9) to GD20 in Wistar rats, and explore the intrauterine programming mechanisms. Prenatal dexamethasone exposure reduced the expression of ovarian cytochrome P450 aromatase (P450arom), the level of serum estradiol (E2) and the number of primordial follicles, while increased the number of atresia follicles before and after birth in F1 offspring rats. At the same time, the expression of miRNA320a-3p in F1 ovaries was down-regulated, and RUNX2 expression increased significantly. These changes were continued to F2 and F3 generations, accompanied by consistently down-regulated miRNA320a-3p expression in oocyte of F1 and F2 adult offspring. In vitro, fetal rat ovaries and KGN human ovarian granulosa cells were treated with dexamethasone. It showed that dexamethasone decreased miRNA320a-3p and P450arom expression, as well as E2 synthesis, and increased RUNX2 expression. All these effects could be reversed by the GR antagonist RU486. The overexpression of miRNA320a-3p in vitro could also reverse the effects of dexamethasone on RUNX2, P450arom, and E2 levels. The dual-luciferase reporter gene experiment further confirmed the direct targeted regulation of miRNA320a-3p on RUNX2. These results indicate that prenatal dexamethasone exposure induces ovarian E2 synthesis inhibition mediated by the GR/miRNA320a-3p/RUNX2/P450arom cascade signal in fetal rat ovary, which has transgenerational inheritance effects and may related to the inhibited miRNA320a-3p expression in oocyte.

Impact of mutations in homologous recombination repair genes on treatment outcomes for metastatic castration resistant prostate cancer.

INTRODUCTION: A significant proportion of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor mutations in homologous recombination (HR) repair genes, with some of these mutations associating with increased tumor susceptibility to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy. While mutations in some HR repair genes (e.g., BRCA1/2) have been associated with a more aggressive clinical course, prior studies correlating HR mutational status with treatment response to androgen receptor (AR) signaling inhibitors (ARSIs) or taxane-based chemotherapy have yielded conflicting results. METHODS: We conducted a single-center retrospective analysis to assess clinical outcomes to conventional, regulatory-approved therapies in mCRPC patients with somatic (monoallelic and biallelic) and/or germline HR repair mutations compared to patients without alterations as determined by clinical-grade next-generation sequencing assays. The primary endpoint was PSA30/PSA50 response, defined as ≥30%/≥50% prostate-specific antigen (PSA) reduction from baseline. Secondary endpoints of PSA progression-free survival (pPFS) and clinical/radiographic progression-free survival (crPFS) were estimated using Kaplan-Meier methods. RESULTS: A total of 90 consecutively selected patients were included in this analysis, of which 33 (37%) were identified to have HR repair gene mutations. Age, race, Gleason score, prior surgery, and receipt of prior radiation therapy were comparable between carriers and non-carriers. There was no evidence that PSA30/PSA50 differed by HR gene mutational status. Median pPFS and crPFS ranged 3-14 months across treatment modalities, but there was no evidence either differed by HR gene mutational status (all p>0.05). There was also no difference in outcomes between those with BRCA2 or PALB2 mutations (n = 17) compared to those without HR repair mutations. CONCLUSION: HR gene mutational status was associated with comparable clinical outcomes following treatment with ARSIs or taxane-based chemotherapy. Additional prospective studies are needed to confirm these findings.

Advances in prostate cancer.

BACKGROUND: Prostate cancer is a common tumour type in Australian men. OBJECTIVE: The aim of this article is to review important changes in prostate cancer diagnosis and management over the past five years, particularly as they pertain to general practice. DISCUSSION: The management of prostate cancer has changed significantly in recent years, particularly the use of imaging, with the introduction of prostate magnetic resonance imaging as routine in the diagnostic pathway, and the increasing use of prostate-specific membrane antigen positron emission tomography for early stratification in the salvage setting for failure of primary treatment in localised disease. In addition, upfront combinations of androgen deprivation therapy with other systemic treatments have yielded significant gains in overall survival for patients with metastatic disease. There has also been an increasing recognition of the association between germline DNA repair defects and progressive disease, and interest in the potential to identify patients for therapies that target these defects. There have been significant changes in how prostate cancer is diagnosed and managed in the past five years, with the introduction of new clinical pathways that were unprecedented just a decade previously.

Plasma cell-free DNA-based predictors of response to abiraterone acetate/prednisone and prognostic factors in metastatic castration-resistant prostate cancer.

BACKGROUND: The combination of abiraterone acetate and prednisone (AA/P) is used to treat metastatic prostate cancer, but molecular predictors of treatment response are not well elucidated. We evaluated plasma circulating tumor DNA- (ctDNA-) based copy number alterations (CNAs) to determine treatment-related predictive and prognostic biomarkers for metastatic castration-resistant prostate cancer (mCRPC). METHODS: Serial plasma specimens were prospectively collected from 88 chemotherapy-naive mCRPC patients before and after 12 weeks of AA/P treatment. Sequencing-based CNA analyses were performed on 174 specimens. We evaluated CNA-associated 12-week responses for primary resistance, time to treatment change (TTTC) for secondary resistance, and overall survival for prognosis (P < 0.05). Associations with primary resistance were analyzed using the Fisher exact test. Kaplan-Meier survival curves and Cox regression analyses were used to determine the associations of CNAs with acquired resistance and overall survival. RESULTS: ctDNA reduced by 3.89% in responders and increased by 0.94% in nonresponders (P = 0.0043). Thirty-one prostate cancer-related genes from whole genome CNAs were tested. AR and AR enhancer amplification were associated with primary resistance (P = 0.0039) and shorter TTTC (P = 0.0003). ZFHX3 deletion and PIK3CA amplification were associated with primary resistance (P = 0.026 and P = 0.017, respectively), shorter TTTC (P = 0.0008 and P = 0.0016, respectively), and poor survival (P = 0.0025 and P = 0.0022, respectively). CNA-based risk scores combining selected significant associations (AR, NKX3.1, and PIK3CA) at the univariate level with TTTC were predictive of secondary resistance (P = 0.0002). and established prognoses for survival based on CNAs in ZFHX3, RB1, PIK3CA, and OPHN1 (P = 0.002). Multigene risk scores were more predictive than individual genes or clinical risk factors (P < 0.05). CONCLUSION: Plasma ctDNA CNAs and risk scores can predict mCRPC-state treatment and survival outcomes.

Timing of androgen deprivation monotherapy and combined treatments in castration-sensitive and castration-resistant prostate cancer: a narrative review.

PURPOSE: Standard androgen deprivation therapy (ADT) can be initiated early at the time of diagnosis in asymptomatic castration-sensitive advanced prostate cancer. This definition has recently been expanded to also include an early combined treatment with standard ADT and new antihormonal drugs. We aimed to present the best available evidence for the timing of initiation of ADT monotherapy and combined treatments in castration-sensitive/-resistant prostate cancer. METHODS: For this narrative review, we searched Cochrane reviews in the Cochrane Library, systematic reviews and randomized controlled trials in MEDLINE, phase III and ongoing trials in ClinicalTrials.gov and screened the reference lists to extract articles of interest. One author screened the references which were finally included after assessing their relevance through discussion with other experts in the field. RESULTS: The identified references were grouped by medication (standard ADT, androgen biosynthesis inhibitor, androgen receptor antagonists or combined therapies) and tumor stage (castration sensitive or resistant). The evidence was narratively summarized and discussed in the context of the current therapeutic landscape. CONCLUSIONS: Early standard ADT can reduce symptoms of disease progression and may extend progression-free and overall survival. The patient should be well informed about the higher rates of treatment-related side effects. Deferring standard ADT might be indicated only for well-informed or unfit patients. Early standard ADT is increasingly combined with new antihormonal drugs in castration-sensitive metastatic prostate cancer to gain additional survival and quality of life benefits. Combined treatment at the time of development of castration-resistant disease is well established.

Behavioral and steroidogenic pharmacology of phenyl ring substituted etomidate analogs in rats.

BACKGROUND: Cushing's syndrome is an endocrine disorder characterized by the overproduction of adrenocortical steroids. Steroidogenesis enzyme inhibitors are the mainstays of pharmacological treatment. Unfortunately, they produce significant side effects. Among the most potent inhibitors is the general anesthetic etomidate whose GABAA receptor-mediated sedative-hypnotic actions restrict use. In this study, we defined the sedative-hypnotic and steroidogenesis inhibiting actions of etomidate and four phenyl-ring substituted etomidate analogs (dimethoxy-etomidate, isopropoxy-etomidate, naphthalene-etomidate, and naphthalene (2)-etomidate) that possess negligible GABAA receptor modulatory activities. METHODS: In the first set of experiments, male Sprague-Dawley rats were assessed for loss of righting reflexes (LoRR) after receiving intravenous boluses of either etomidate (1 mg/kg) or an etomidate analog (40 mg/kg). In the second set of experiments, rats were assessed for LoRR and their abilities to produce adrenocortical and androgenic steroids after receiving 2-h infusions (0.5 mg kg- 1 min- 1) of either etomidate or an etomidate analog. RESULTS: All rats that received etomidate boluses or infusions had LoRR that persisted for minutes or hours, respectively. In contrast, no rat that received an etomidate analog had LoRR. Compared to rats in the vehicle control group, rats that received etomidate analog infusions had plasma corticosterone and aldosterone concentrations that were reduced by 80-84% and 68-94%, respectively. Rats that received etomidate infusions had plasma corticosterone and aldosterone concentrations that were also significantly reduced (by 92 and 96%, respectively). Rats that received etomidate or isopropoxy-etomidate had significant reductions (90 and 57%, respectively) in plasma testosterone concentrations whereas those that received naphthalene-etomidate had significant increases (1400%) in plasma dehydroepiandrosterone concentrations. Neither etomidate nor any etomidate analog significantly affected plasma androstenedione and dihydrotestosterone concentrations. CONCLUSIONS: Our studies demonstrate that the four phenyl-ring substituted etomidate analogs form a novel class of compounds that are devoid of sedative-hypnotic activities and suppress plasma concentrations of adrenocortical steroids but vary in their effects on plasma concentrations of androgenic steroids.

Pituitary Adenomas: What Are the Key Features? What Are the Current Treatments? Where Is the Future Taking Us?

Pituitary tumors are a heterogeneous group of lesions (usually benign) and proper understanding of the anatomy, physiology, and pathology of the hypothalamic/pituitary region is essential to make an accurate diagnosis and define the essential treatment options (i.e., surgery, medical therapies, and radiotherapy, alone or in combination). Surgery is the primary treatment for acromegaly, Cushing disease, thyroid-stimulating hormone-secreting adenomas, resistant prolactinomas, and nonfunctioning pituitary adenomas causing mass effect. Medical and radiation therapy are reserved in cases in which surgery is not possible or does not provide a complete cure. In the last decades, tremendous innovations (i.e., targeted drugs and refined surgical tools and techniques) have expanded the treatment strategies for pituitary adenomas. We herein report the current indications for and depiction of the surgical techniques in pituitary surgery, review current medical treatments, and provide a glimpse of future possibilities.

Cabergoline in severe ectopic or occult Cushing's syndrome.

CONTEXT: Cabergoline has been shown to have some effect in the treatment of moderate Cushing's disease, but its effectiveness in Cushing's syndrome of ectopic or occult origin remains to be investigated. CASE SERIES: In this case series, cabergoline was used in combination with steroidogenesis inhibitors in nine patients with severe Cushing's syndrome of ectopic or occult origin. Cabergoline's effectiveness enabled rapid withdrawal of the steroidogenesis inhibitors and long-term control of the hypercortisolism in three of the cases. REVIEW OF THE LITERATURE: In the literature, we found only 11 cases of ectopic or occult Cushing's syndrome treated with dopamine receptor agonists, alone or in combination. Yet of these 11 cases, 10 responded. CONCLUSIONS: Although limited, the existing experience highlights the potential value of cabergoline in the treatment of ectopic or occult Cushing's syndrome.

Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial.

BACKGROUND: In the interim analyses of the LATITUDE study, the addition of abiraterone acetate plus prednisone to androgen deprivation therapy (ADT) led to a significant improvement in overall survival and radiographic progression-free survival compared with placebos plus ADT in men with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (mCSPC). Here, we present long-term survival outcomes and safety of abiraterone acetate plus prednisone and ADT from the final analysis of the LATITUDE study. METHODS: This is a multicentre, randomised, double-blind, phase 3 trial done at 235 sites in 34 countries. Eligible patients (men aged ≥18 years) had newly diagnosed, histologically or cytologically confirmed prostate cancer with metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and at least two of the three high-risk prognostic factors (Gleason score of ≥8, presence of three or more lesions on bone scan, or presence of measurable visceral metastasis except lymph node metastasis). Patients were randomly assigned (1:1) to receive abiraterone acetate (1000 mg) once daily orally plus prednisone (5 mg) once daily orally and ADT (abiraterone acetate plus prednisone group) or matching placebos plus ADT (placebo group); each treatment cycle was 28 days. Randomisation was done by a centralised interactive web response system in a country-by-country scheme using permuted block randomisation, stratified by presence of visceral disease and ECOG performance status. The coprimary endpoint of overall survival was assessed in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT01715285 and is complete. FINDINGS: Between Feb 12, 2013, and Dec 11, 2014, 1209 patients were screened, of whom ten were ineligible because of study site violations. 1199 patients were randomly assigned to either the abiraterone acetate plus prednisone group (n=597) or placebo group (n=602). After the results of the first interim analysis (cutoff date Oct 31, 2016), the study was unmasked to patients and investigators, and patients in the placebo group were allowed to cross over to receive abiraterone acetate and prednisone plus ADT treatment as per a protocol amendment (Feb 15, 2017) in an open-label extension phase of the study (up to 18 months from the protocol amendment). This final analysis (data cutoff Aug 15, 2018) was done after a median follow-up of 51·8 months (IQR 47·2-57·0) and 618 deaths (275 [46%] of 597 in the abiraterone acetate plus prednisone group and 343 [57%] of 602 in the placebo group). Overall survival was significantly longer in the abiraterone acetate plus prednisone group (median 53·3 months [95% CI 48·2-not reached]) than in the placebo group (36·5 months [33·5-40·0]), with a hazard ratio of 0·66 (95% CI 0·56-0·78; p<0·0001). The most common grade 3-4 adverse events were hypertension (125 [21%] in the abiraterone acetate plus prednisone group vs 60 [10%] in the placebo group vs three [4%] in the 72 patients who crossed over from placebo to abiraterone acetate plus prednisone) and hypokalaemia (70 [12%] vs ten [2%] vs two [3%]). Serious adverse events of any grade occurred in 192 (32%) of 597 patients in the abiraterone acetate plus prednisone group, 151 (25%) of 602 in the placebo group, and four (6%) of 72 in the crossover group. The most common treatment-related serious adverse event was hypokalaemia (four [1%] patients in the abiraterone acetate plus prednisone group and none in the other groups). Treatment-related deaths occurred in three (<1%) patients each in the abiraterone acetate plus prednisone group (gastric ulcer perforation, sudden death, and cerebrovascular accident) and the placebo group (sudden death, cerebrovascular accident, and pneumonia), with none in the crossover group. INTERPRETATION: The combination of abiraterone acetate plus prednisone with ADT was associated with significantly longer overall survival than placebos plus ADT in men with newly diagnosed high-risk mCSPC and had a manageable safety profile. These findings support the use of abiraterone acetate plus prednisone as a standard of care in patients with high-risk mCSPC. FUNDING: Janssen Research & Development.

Repurposing steroidogenesis inhibitors for the therapy of neuropsychiatric disorders: Promises and caveats.

Steroids exert a profound influence on behavioral reactivity, by modulating the functions of most neurotransmitters and shaping the impact of stress and sex-related variables on neural processes. This background - as well as the observation that most neuroactive steroids (including sex hormones, glucocorticoids and neurosteroids) are synthetized and metabolized by overlapping enzymatic machineries - points to steroidogenic pathways as a powerful source of targets for neuropsychiatric disorders. Inhibitors of steroidogenic enzymes have been developed and approved for a broad range of genitourinary and endocrine dysfunctions, opening to new opportunities to repurpose these drugs for the treatment of mental problems. In line with this idea, preliminary clinical and preclinical results from our group have shown that inhibitors of key steroidogenic enzymes, such as 5α-reductase and 17,20 desmolase-lyase, may have therapeutic efficacy in specific behavioral disorders associated with dopaminergic hyperfunction. While the lack of specificity of these effects raises potential concerns about endocrine adverse events, these initial findings suggest that steroidogenesis modulators with greater brain specificity may hold significant potential for the development of alternative therapies for psychiatric problems. This article is part of the Special Issue entitled 'Drug Repurposing: old molecules, new ways to fast track drug discovery and development for CNS disorders'.