Effect Of Abiraterone Acetate Research Articles

Exploration of Abiraterone acetate loaded Nanostructured lipid carriers for bioavailability improvement and circumvention of fast-fed variability.

Abiraterone acetate (ABA), a biopharmaceutical class IV drug suffers from solubility and permeability pitfalls resulting in limited oral bioavailability and positive food effect, i.e. multi-fold enhancement in drug absorption in the presence of food. This poses difficulties to physicians towards the estimation of dose and dosage regimen required for efficacious therapy of prostate cancer (PCa). Nanostructured lipid carriers (NLC) have demonstrated tremendous outcomes in enhancing the oral bioavailability of various entities along with food effect attenuation. In this study, Quality by design and multivariate analysis was employed for optimization of ABA loaded NLC (ABA NLC). The optimal size, PDI and zeta potential obtained using QbD were 134.6nm, 0.163 and -15.7mV respectively. Ex vivo qualitative and quantitative intestinal permeability studies demonstrated improved traversion of NLC through the intestinal segments. In vitro dissolution profile in biorelevant fast and fed gastric and intestinal media revealed minimal differences for ABA NLC compared to ABA. In vivo pharmacokinetics was performed to decipher the efficacy of ABA NLC in mitigating the food effect of ABA. The studies demonstrated 14.51-fold and 1.94-fold improvement in oral bioavailability during fasted and fed state respectively as compared to free ABA. The absorption mechanism of ABA NLC using chylomicron flow blocking approach conveyed lymphatic uptake as the major mechanism. Cmax fast/fed ratio was 0.9758 whereas, AUC fast/fed ratio was 0.9386, which being nearly equivalent, confirmed the food effect attenuation. Therefore, the results of the study demonstrate optimal pharmacokinetics of ABA NLC and its utility in circumventing the fast fed variability.

Interaction of the Anticancer Drug Abiraterone with dsDNA

The electroanalytical characteristics of double-stranded DNA (dsDNA) and the complex of dsDNA and the antitumor drug abiraterone acetate (AA) were studied by differential pulse voltammetry. The effect of abiraterone acetate on dsDNA was shown, which was registered by alteration the intensity of electrochemical oxidation of purine heterocyclic bases guanine and adenine using screen printed electrodes modified with functionalized carbon nanotubes. The binding constants (Kb) of the [dsDNA-AA] complex for guanine and adenine were 1.63×104 M-1 and 1.93×104 M-1, respectively. The electrochemical coefficients of the toxic effect were calculated as the ratio of the intensity of the electrochemical oxidation signals of guanine and adenine, in the presence of abiraterone acetate to the intensity of the electrooxidation signals of these nucleobases without drug (%). At concentrations of abiraterone acetate exceeding 60 μM, a decrease in the currents of electrochemical oxidation of guanine and adenine by 50% or more is recorded. Based on the analysis of electrochemical parameters and values ​​of binding constants, an assumption was made about the mechanism of interaction of abiraterone acetate with DNA, mainly due to the formation of hydrogen bonds with the minor groove. An electrochemical DNA biosensor was first used to study the mechanism of interaction of the anticancer drug abiraterone acetate with dsDNA.

The effects of selected inhibitors on human fetal adrenal steroidogenesis differs under basal and ACTH-stimulated conditions

BackgroundDisordered fetal adrenal steroidogenesis can cause marked clinical effects including virilization of female fetuses. In postnatal life, adrenal disorders can be life-threatening due to the risk of adrenal crisis and must be carefully managed. However, testing explicit adrenal steroidogenic inhibitory effects of therapeutic drugs is challenging due to species-specific characteristics, and particularly the impact of adrenocorticotropic hormone (ACTH) stimulation on drugs targeting steroidogenesis has not previously been examined in human adrenal tissue. Therefore, this study aimed to examine the effects of selected steroidogenic inhibitors on human fetal adrenal (HFA) steroid hormone production under basal and ACTH-stimulated conditions.MethodsThis study used an established HFA ex vivo culture model to examine treatment effects in 78 adrenals from 50 human fetuses (gestational weeks 8–12). Inhibitors were selected to affect enzymes critical for different steps in classic adrenal steroidogenic pathways, including CYP17A1 (Abiraterone acetate), CYP11B1/2 (Osilodrostat), and a suggested CYP21A2 inhibitor (Efavirenz). Treatment effects were examined under basal and ACTH-stimulated conditions in tissue from the same fetus and determined by quantifying the secretion of adrenal steroids in the culture media using liquid chromatography-tandem mass spectrometry. Statistical analysis was performed on ln-transformed data using one-way ANOVA for repeated measures followed by Tukey’s multiple comparisons test.ResultsTreatment with Abiraterone acetate and Osilodrostat resulted in potent inhibition of CYP17A1 and CYP11B1/2, respectively, while treatment with Efavirenz reduced testosterone secretion under basal conditions. ACTH-stimulation affected the inhibitory effects of all investigated drugs. Thus, treatment effects of Abiraterone acetate were more pronounced under stimulated conditions, while Efavirenz treatment caused a non-specific inhibition on steroidogenesis. ACTH-stimulation prevented the Osilodrostat-mediated CYP11B1 inhibition observed under basal conditions.ConclusionsOur results show that the effects of steroidogenic inhibitors differ under basal and ACTH-stimulated conditions in the HFA ex vivo culture model. This could suggest that in vivo effects of therapeutic drugs targeting steroidogenesis may vary in conditions where patients have suppressed or high ACTH levels, respectively. This study further demonstrates that ex vivo cultured HFAs can be used to evaluate steroidogenic inhibitors and thereby provide novel information about the local effects of existing and emerging drugs that targets steroidogenesis.

What are the effects of abiraterone acetate as adjunct to androgen deprivation therapy (ADT) for men with metastatic hormone-sensitive prostate cancer?

What are the effects of abiraterone acetate as adjunct to androgen deprivation therapy (ADT) for men with metastatic hormone-sensitive prostate cancer?

Effects of abiraterone acetate plus prednisone on bone turnover markers in chemotherapy-naïve mCRPC patients after ADT failure: A prospective analysis of the italian real-world study ABITUDE

BackgroundBone remodeling is disrupted in metastatic disease, which affects > 70% of metastatic castration-resistant prostate cancer (mCRPC) patients. As a result, abnormal levels of specific bone turnover biomarkers (BTMs) are released. In this prospective ancillary analysis of the Italian real-world study ABITUDE, four markers were measured during abiraterone acetate plus prednisone (AAP) treatment in chemotherapy-naïve mCRPC men failing androgen-deprivation therapy. MethodsPatients were enrolled if a blood sample was obtained before the first administration of abiraterone (baseline); ad-hoc blood samples were withdrawn during routine tests after 3, 6, and 12 months. A centralized lab measured bone alkaline phosphatase (BALP, osteoblast activity marker), type-I collagen-C-telopeptide (CTX-1, bone resorption marker), parathyroid hormone (PTH) and vitamin D (vitD). At each time point, intra-patient variations vs baseline were compared by the signed-rank test (statistical significance: P-value < 0.05). ResultsOf 481 patients enrolled in ABITUDE, 186 (median age: 76 [range: 53–93] years) met the substudy criteria: 74.7% had bone metastases, 11.8% were on bone-targeted therapies (BTT) and 14.0% on vitD supplementation. BALP decreased significantly at month 6 (P = 0.0010) and 12 (P < 0.0001) and CTX-1 at month 6 (P = 0.0028); PTH increased at month 3 (P < 0.0001); no significant difference in vitD levels was observed. Similar findings were observed in BTT-untreated patients. The reduction in BALP and CTX-1 levels was more pronounced in patients with than without bone metastases; in the latter group, no significant variation in BALP and CTX-1 levels was observed. ConclusionsAAP seems to exert an effect on the microenvironment of metastatic but not of normal bone, which likely contributes to its antitumoral activity.

Survival outcome in patients with metastatic castration-resistant prostate cancer according to first-line treatment.

5570 Background: Therapeutic strategy in metastatic castration-resistant prostate cancer (mCRPC) has evolved significantly with the introduction of abiraterone acetate in association with prednisone/prednisolone in first-line treatment in December 2012. This work aimed to compare the effectiveness of abiraterone acetate and docetaxel as first-line treatments for mCRPC, in real-life setting. Methods: Patients with mCRPC were identified in the main scheme of the National Healthcare System database (SNDS), which covers about 86% of the French population, and capturing all reimbursed healthcare expenditures and hospital discharge summaries. Those initiating docetaxel or abiraterone acetate in 1st line in 2014 were included and 1:1 matched on the previous prostate cancer stage before mCRPC status, the delay from the date of initial diagnosis and a high-dimensional propensity score. The 36-month overall survival and the 36-month discontinuation-free survival (i.e. survival time until treatment switch or death) were compared using Cox proportional hazards risk model. Results: In 2014, out of the 12,951 patients with prevalent mCRPC, 1,214 initiated docetaxel in 1st line and 2 444 initiated abiraterone. A total of 716 patients per group were matched with good comparability (C-statistic = 0.6). The median duration of docetaxel–defined as the time between the first and the last infusion–was 7.3 months with a median of 6 infusions. The median duration of abiraterone acetate–corresponding to the period covered by the dispensed drug–was 9.1 months. Near 70% of the docetaxel and 62% of the abiraterone acetate patients received a 2nd line of treatment. Results related to the main survival outcomes are presented in the table below. Conclusions: First-line treatment with abiraterone acetate in mCRPC patients results in a better 36-month overall survival and discontinuation-free survival compared to docetaxel in real-life setting. [Table: see text]

Effectiveness of abiraterone acetate plus prednisone in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer in a large prospective real-world cohort: the ABItude study.

Background:Real-world data on chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone plus prednisone are limited, largely deriving from small retrospective studies.Methods:ABitude is an Italian, observational, prospective, multicenter study of mCRPC patients receiving abiraterone plus prednisone in clinical practice. Chemotherapy-naïve mCRPC patients were consecutively enrolled at abiraterone start (February 2016 to June 2017) and are being followed for 3 years, with evaluation approximately every 6 months. Several clinical and patients reported outcomes were examined.Results:In this second interim analysis, among 481 enrolled patients, 453 were evaluable for analyses. At baseline, the median age was 77 years and ~69% of patients had comorbidities (mainly cardiovascular diseases). Metastases were located mainly at bones and lymph nodes; 8.4% of patients had visceral metastases. During a median follow-up of 18 months, 1- and 2-year probability of radiographic progression-free survival were 73.9% and 56.2%, respectively; the corresponding rates for overall survival were 87.3% and 70.4%. In multivariable analyses, the number of bone metastases significantly affected radiographic progression-free survival and overall survival. During abiraterone plus prednisone treatment, 65% of patients had a ⩾50% prostate-specific antigen decline, and quality of life remained appreciably high. Among symptomatic patients according to the Brief Pain Inventory) (32%), scores significantly declined after 6 months of treatment. Overall, eight patients (1.7%) had serious adverse reactions to abiraterone.Conclusions:Abiraterone plus prednisone is effective and safe for chemotherapy-naïve mCRPC patients in clinical practice.

P050 - Effectiveness of abiraterone acetate in elderly chemotherapy-naïve patients with metastatic castration-resistant prostate cancer

P050 - Effectiveness of abiraterone acetate in elderly chemotherapy-naïve patients with metastatic castration-resistant prostate cancer

P049 - Effectiveness of abiraterone acetate in elderly patients with metastatic castration-resistant prostate cancer after docetaxel-based chemotherapy

P049 - Effectiveness of abiraterone acetate in elderly patients with metastatic castration-resistant prostate cancer after docetaxel-based chemotherapy

The IMAAGEN Study: Effect of Abiraterone Acetate and Prednisone on Prostate Specific Antigen and Radiographic Disease Progression in Patients with Nonmetastatic Castration Resistant Prostate Cancer

We evaluated the use of abiraterone acetate (1,000 mg) plus prednisone (5 mg) in patients with high risk, nonmetastatic, castration resistant prostate cancer. Patients considered at high risk for progression to metastatic disease (prostate specific antigen 10 ng/ml or greater, or prostate specific antigen doubling time 10 months or less) received abiraterone acetate plus prednisone daily in 28-day cycles. The primary study end point was the proportion of patients in whom a 50% or greater prostate specific antigen reduction was achieved during cycles 1 to 6. Secondary end points included time to prostate specific antigen progression, time to radiographic evidence of disease progression and safety. Of the 131 enrolled patients 44 (34%) remained on treatment with a median followup of 40.0 months. Median age was 72 years (range 48 to 90). Of the patients 82.4% were white and 14.5% were black. Median screening prostate specific antigen was 11.9 ng/dl and median prostate specific antigen doubling time was 3.4 months. Prostate specific antigen was significantly reduced (p <0.0001) with a 50% or greater prostate specific antigen reduction in 86.9% of cases and a 90% or greater reduction in 59.8%. Median time to prostate specific antigen progression was 28.7 months (95% CI 21.2-38.2). Median time to radiographic evidence of disease progression was not reached but on sensitivity analysis in 15 patients it was estimated to be 41.4 months (95% CI 27.6-not estimable). Baseline testosterone 12.5 ng/dl or greater and a 90% or greater prostate specific antigen reduction at cycle 3 were associated with longer time to prostate specific antigen progression and radiographic evidence of disease progression. Outcomes in black patients were similar to those in other patients. Adverse events, grade 3 or greater adverse events and serious adverse events were reported in 96.2%, 61.1% and 43.5% of patients, respectively. In patients with high risk, nonmetastatic, castration resistant prostate cancer treatment with abiraterone acetate plus prednisone demonstrated a significant 50% or greater prostate specific antigen reduction with encouraging results for the secondary end points, including the safety of 5 mg prednisone.

Review on quality of life in CRPC patients

Health-related quality of life (HRQoL) deteriorates rapidly in patients with advanced-stage cancer, with patients seriously disturbed by fatigue, sleep disorders, bone pain, constipation and other disease related symptoms. As treatment and prognosis continues to improve, reducing symptoms and improving quality of life with minimum of toxicities have become important therapeutic goals. The effectiveness of abiraterone acetate and enzalutamide in both prolonging life and improving quality of life in asymptomatic or mildly symptomatic patients with metastatic castrations-resistant prostate cancer (mCRPC) has been clinically proven.

IMAAGEN trial safety and efficacy update: Effect of abiraterone acetate and low-dose prednisone on prostate-specific antigen and radiographic disease progression in patients with nonmetastatic castration-resistant prostate cancer.

5061Background: IMAAGEN is a phase 2, multicenter study evaluating abiraterone acetate (AA) 1000 mg plus prednisone 5 mg (AA+P5) for the treatment of patients (pts) with nonmetastatic castration-re...

MP50-20 IMPACT OF ABIRATERONE ACETATE IN PROSTATE SPECIFIC ANTIGEN TRIAL UPDATE: EFFECT OF ABIRATERONE ACETATE AND LOW DOSE PREDNISONE ON PROSTATE-SPECIFIC ANTIGEN AND RADIOGRAPHIC DISEASE PROGRESSION IN PATIENTS WITH NON-METASTATIC CASTRATION-RESISTANT PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) II1 Apr 2016MP50-20 IMPACT OF ABIRATERONE ACETATE IN PROSTATE SPECIFIC ANTIGEN TRIAL UPDATE: EFFECT OF ABIRATERONE ACETATE AND LOW DOSE PREDNISONE ON PROSTATE-SPECIFIC ANTIGEN AND RADIOGRAPHIC DISEASE PROGRESSION IN PATIENTS WITH NON-METASTATIC CASTRATION-RESISTANT PROSTATE CANCER Charles Ryan, E. David Crawford, Neal D Shore, Willie Underwood, Anil Londhe, Shawn Black, Tracy McGowan, and Philip W. Kantoff Charles RyanCharles Ryan More articles by this author , E. David CrawfordE. David Crawford More articles by this author , Neal D ShoreNeal D Shore More articles by this author , Willie UnderwoodWillie Underwood More articles by this author , Anil LondheAnil Londhe More articles by this author , Shawn BlackShawn Black More articles by this author , Tracy McGowanTracy McGowan More articles by this author , and Philip W. KantoffPhilip W. Kantoff More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.454AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Abiraterone acetate (AA) 1000mg, in combination with prednisone (P), 10mg daily is indicated for the treatment of patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). IMAAGEN is a phase II, multi-center study with a primary endpoint that evaluated the ability of AA plus 5 mg of prednisone (AA+5) to decrease PSA levels in pts with nmCRPC and a rising PSA; primary results have been reported earlier1. Herein we report updated results on secondary endpoints and safety from the IMAAGEN study (Nov 3, 2014 database cut-off date). METHODS All enrolled pts had high risk non-metastatic castration resistant prostate cancer (nmCRPC): PSA value ≥10ng/mL or PSA doubling time ≤10 months at screening. Pts received AA+5 daily; each treatment cycle=28 days. Reported endpoints include time to PSA progression, time to radiographic progressive disease, and safety. RESULTS At the time of the data cutoff, 62 (47.3%) of the 131 patients enrolled in IMAAGEN remained on treatment in the study. The median duration of exposure was 17.9 months (range 0.1 to 40.7 months). Median time to PSA progression was 28.7 months (95% CI 21.2, NE). There were 21 confirmed radiographic progression events. The median time to radiographic progressive disease was not reached. 95.4% of pts had an adverse event (AE) (54.9% had a Grade 3 or higher) and 38.2% had a serious AE (SAE) with 35.9% having an SAE of Grade 3 or higher. 13.0% of pts had AEs resulting in discontinuation of study treatment. Four pts had AEs resulting in death (coronary artery disease, myocardial infarction, acute respiratory failure, and pneumonia). CONCLUSIONS Treatment of high risk nmCRPC patients with AA+5 resulted in a median time to PSA progression of 28.7 months. The median time to radiographic disease progression was not reached. The safety profile of AA+5 reported in this IMAAGEN trial update is consistent with the safety profile from previously reported studies of abiraterone acetate 1000mg in combination with either 5mg or 10mg prednisone. 1ASCO 2014 IMAAGEN primary endpoint poster presentation © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e680 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Charles Ryan More articles by this author E. David Crawford More articles by this author Neal D Shore More articles by this author Willie Underwood More articles by this author Anil Londhe More articles by this author Shawn Black More articles by this author Tracy McGowan More articles by this author Philip W. Kantoff More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

A Study on the Clinical Outcome of Abiraterone Acetate in Castration Resistant Prostate Cancer Patients

INTRODUCTION : Abiraterone acetate is a selective inhibitor of androgen biosynthesis that potently and irreversibly blocks CYP17, a crucial enzyme in testosterone and oestrogen synthesis, resulting in virtually undetectable serum and intratumoral androgens. AIM : To study the clinical outcome of Abiraerone Acetate in castration resistant prostate cancer patients, by measuring their PSA (Prostate specific antigen) value. To find out the effect of Abiraterone acetate on lab parameters(Serum Creatinine. Potassium, CBC) by administering this drug. METHODS : This is a retrospective analysis to evaluate the efficacy and safety of abiraterone acetate in castration resistant prostate cancer patients. 14 men with CRPC who experienced treatment failure with one or more lines of treatment (hormonal manipulation or chemotherapy) were given abiraterone acetate (1,000 mg daily) with prednisone (5 mg twice daily). RESULTS AND DISCUSSION : 42% patients shows good response in reduction in PSA value and 16% had progression and 42% had stable disease. Haemoglobin, Potassium and Serum Creatinine levels were not affected by Abiraterone. One patient had severe GI intolerance and the drug had to be stopped. In this study the final analysis shows that abiraterone acetate significantly lowered the PSA value and prolonged progression free survival in patients with metastatic castration-resistant prostate cancer who have progressed after first line or second line treatment. The median duration of drug exposure and overall average median survival of CRPC who received AA was found to be 11.1 months [range 3-18]. Abiraterone plus prednisone therapy can be given orally in an outpatient setting, providing an additional benefit for both patients and clinicians.

IMAAGEN trial update: Effect of abiraterone acetate and low dose prednisone on PSA and radiographic disease progression in patients with non-metastatic castration-resistant prostate cancer.

5053 Background: Abiraterone acetate (AA) 1000mg, in combination with prednisone (P), 10mg daily is indicated for the treatment of patients (pts) with metastatic castration-resistant prostate cance...

Cancer treatment: at what cost?

Nursing and Residential CareVol. 17, No. 3 EditorialCancer treatment: at what cost?Beverley AndersonBeverley AndersonSearch for more papers by this authorBeverley AndersonPublished Online:18 Feb 2015https://doi.org/10.12968/nrec.2015.17.3.173AboutSectionsView articleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareShare onFacebookTwitterLinked InEmail View article References Aapro MS (2012) Management of advanced prostate cancer in senior adults: the new landscape. Oncologist 17(Suppl 1): 16–22 Crossref, Google ScholarAttard G, Reid AHM, Yap TA et al. (2008) Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol 26(28): 4563–71. doi: https://doi.org/10.1200/JCO.2007.15.9749 Crossref, Google ScholarCancer Research UK (2011) Where did abiraterone come from? http://tinyurl.com/mg39ml9 (accessed 27 January 2015) Google ScholarCancer Research UK (2014) Prostate cancer. http://tinyurl.com/l7aru6y (accessed 27 January 2015) Google Scholarde Bono JS, Logothetis CJ, Molina A, Fizazi K et al. (2011) Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364(21): 1995–2005. doi: https://doi.org/10.1056/NEJMoa1014618 Crossref, Google ScholarFizazi K, Scher HI, Molina A, Logothetis CJ et al. (2012) Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 13(10): 983–92. doi: https://doi.org/10.1016/S1470-2045(12)70379-0 Crossref, Google ScholarGravanis I, Lopez AS, Hemmings RJ, Jiménez JC et al. (2013) The European medicines agency review of abiraterone for the treatment of metastatic castration-resistant prostate cancer in adult men after docetaxel chemotherapy and in chemotherapy-naive disease: summary of the scientific assessment of the committee for medicinal products for human use. Oncologist 18(9): 1032–42. doi: https://doi.org/10.1634/theoncologist.2013-0092 Crossref, Google ScholarLogothetis CJ, Basch E, Molina A, Fizazi K et al. (2012) Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol 13(12): 1210–7. doi: https://doi.org/10.1016/S1470-2045(12)70473-4 Crossref, Google ScholarMacmillan Cancer Support (2014) Abiraterone acetate (Zytiga). http://tinyurl.com/p6b5apk (accessed 27 January 2015) Google ScholarMulders PFA, Molina A, Marberger M, Saad F et al. (2014) Efficacy and safety of abiraterone acetate in an elderly patient subgroup (aged 75 and older) with metastatic castration-resistant prostate cancer after docetaxel-based chemotherapy. Eur Urol 65(1): 875–83. doi: https://doi.org/10.1016/j.eururo.2013.09.005 Crossref, Google ScholarNational Cancer Institute (2012) Abiraterone Improves Survival in Metastatic Prostate Cancer. http://tinyurl.com/3m4orwt (accessed 27 January 2015) Google ScholarNational Institute of Health and Care Excellence (2011) Prostate cancer (metastatic, hormone relapsed, not treated with chemotherapy) – abiraterone acetate (with prednisolone) [ID503]: appraisal consultation document. http://tinyurl.com/nvx4tgv (accessed 27 January 2015) Google ScholarNational Institute of Health and Care Excellence (2014a) Prostate Cancer: diagnosis and treatment, NICE Clinical Guideline 175. http://tinyurl.com/pu6ccrm (accessed 27 January 2015) Google ScholarNational Institute of Health and Clinical Excellence (2014b) NICE appraisal of earlier treatment with abiraterone for prostate cancer. http://tinyurl.com/kmhrnz7 (accessed 27 January 2015) Google ScholarParker C, Sartor O (2011) Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 365(8): 767. doi: https://doi.org/10.1056/NEJMc1107198#SA3 Google ScholarPezaro CJ, Mukherji D, De Bono JS (2012) Abiraterone acetate: redefining hormone treatment for advanced prostate cancer. Drug Discov Today 17(5–6): 221–6. doi: https://doi.org/10.1016/j.drudis.2011.12.012 Crossref, Google ScholarProstate Cancer UK (2014) Abiraterone should definitely be an option for men who haven't had chemotherapy. http://tinyurl.com/k7b9dy9 (accessed 27 January 2015) Google ScholarRathkopf DE, Smith MR, De Bono JS et al. (2013) Updated interim analysis of COU-AA-302, a randomized phase III study of abiraterone acetate in patients with metastatic castration-resistant prostate cancer (mCRPC) without prior chemotherapy. http://tinyurl.com/pr5ocav (accessed 27 January 2015) Google ScholarScher, HI., Logothetis, C., Molina, A., Goodman, OB., Sternberg, CN., Chi, KN., Kheoh, TS., Itagg, CM., Fizazi, de Bono, JS. et al. (2010) Improved Survival outcomes in clinically relevant patient subgroups from COU-AA-301, a phase III study of abiraterone acetate plus prednisone in patients with metastatic castration-resistant prostate cancer after docetaxel-based chemotherapy, http://tinyurl.com/oph44n5 (accessed 27 January 2015) Google ScholarSmith R (2014) Prostate cancer patients ‘unjustly’ denied drug, The Telegraph. http://tinyurl.com/pvchebo (accessed 27 January 2015) Google ScholarThe Institute of Cancer Research (2014a) Abiraterone: a story of scientific innovation and commercial partnership. http://tinyurl.com/m2ehlpy (accessed 27 January 2015) Google ScholarThe Institute of Cancer Research (2014b) NICE pauses abiraterone decision for further price discussions. http://tinyurl.com/oeg3s5c (accessed 27 January 2015) Google Scholar FiguresReferencesRelatedDetailsCited byA Perspective on Uro-Oncology Management and the Macmillan Uro-Oncology CNS (MUCNS) Role in this Management23 March 2022 2 March 2015Volume 17Issue 3ISSN (print): 1465-9301ISSN (online): 2052-2932 Metrics History Published online 18 February 2015 Published in print 2 March 2015 Information© MA Healthcare LimitedPDF download

Abstract IA11: The role of bone microenvironment in the lethal progression of prostate cancer

Abstract Lethal prostate cancer (PCa) is clinically characterized by bone-homing and bone- forming metastases, and bone is frequently the initial organ involved in castrate-resistant progression. These clinical observations led investigators to develop bone-tropic radiopharmaceuticals to treat men with advanced PCa. The ability of the bone-homing alpha emitter (RAD-223) to prolong progression free and overall survival establishes the therapeutic relevance of targeting bone 1. The long accepted paradigm of PCa progression has been dominated by the model of evolution from androgen dependence to androgen independence under the selective pressure of castration. Thus, Src family kinases (SFKs) were investigated experimentally and clinically for the treatment of putative “androgen independent” PCa, as SFKs play a role in both tumor growth and bone turnover. The roles of SFKs in migration, invasion, survival of tumor cells, and osteoclast and osteoblast function in tumor microenvironment were supported by numerous clinical and laboratory observations 2, 3. Despite promising phase I /II reports of dasatinib, a multikinase and potent SFK inhibitor, in men with advanced PCa 4, 5, a phase III trial failed to yield the expected survival advantage 6. The result of this trial highlights the difficulties in translating data from cell line models to biologically heterogeneous clinical PCa and in transitioning from phase I/II to phase III clinical trials. The efficacy of dasatinib was not observed likely due to persistent AR signaling, which remains the primary driver of progression in bone by the transition from paracrine to intracrine androgen signaling 7. Based on these considerations, we are testing the efficacy of an androgen biosynthesis inhibitor in combination with dasatinib to better understand the relevance of mechanism(s). A co–clinical investigational strategy is being applied to better define biomarkers to predict clinical efficacy. These studies also highlight the importance of preclinical work that utilizes models that better reflect the heterogeneity of PCa. This problem is partly overcome by patient- derived xenografts (PDX) 8, 9 10. These models reflect many aspects of PCa in bone and can be used to identify therapy targets and better identify both mechanisms of drug efficacy and development of resistance. Studies in PDX have led to identification of FGF signaling as a therapy target 11. Additional studies in PDX implicated the tumor microenvironment in the striking bone responses observed with cabozantinib 13. These observations led us to propose a model of prostate cancer progression founded on the hypothesis that cancer progresses from being an endocrine-driven cancer (Dihydrotestosterone-dependent) to paracrine/intracrine driven (microenvironment-dependent), and then finally to a cell autochthonous phase 12. Continued studies should lead to decisions on therapy treatment that are based on an understanding of markers that predict disease progression. This new paradigm will also result in more effective therapy combinations.

Effect of abiraterone acetate and low-dose prednisone on PSA in patients with nonmetastatic castration-resistant prostate cancer: The results from IMAAGEN core study.

5086 Background: Abiraterone acetate (AA) is a prodrug of abiraterone, which is a selective, irreversible CYP17 inhibitor of androgen biosynthesis and significantly reduces testosterone production ...

Effects of abiraterone acetate and enzalutamide on muscle and adipose mass in men with metastatic castration-resistant prostate cancer (mCRPC).

5088 Background: Abiraterone acetate (AA) and enzalutamide (MDV3100), two androgen receptor-directed compounds, have been shown to improve survival for patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after Docetaxel.. Since these drugs might be used at an early-stage in the future, and skeletal muscle (SM) and adipose tissue (AT) are known to be prognosis parameters, the aim of this study was to evaluate the body composition changes in patients with mCRPC treated with AA and MDV3100. Methods: Patients included in AFFIRM (n=62 treated with MDV3100 and placebo n=28) and COU-AA-301 (n=24 treated with AA+Prednisone (P)10mg/day and placebo+P n= 13) trials at the Institute Gustave Roussy were included in the analysis. Cross-sectional areas (cm2) of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and SM were assessed by computed tomography imaging at 3rd lumbar vertebra and were indexed for height (cm2/m2) with Slice-O-Matic software V4.3 at baseline, 3, 6 and 12 months of treatment. The data from patients treated with AA or MDV3100 were compared to placebo-patients and tissues changes were compared to baseline. We used the validated sarcopenic definitions as SM index less than 52.4 (cm2/m2). Results: For all cohort, median age was 69 years (range: 48-83), median weight was 79 kg (range: 47-150) and median BMI was 25.9 kg/m2(range: 18-46). At inclusion, 74 patients (58%) were overweight or obese (BMI&gt;24.9 kg/m2), and only 2 patients were underweight (BMI&lt;18.5kg/m2). 97 patients (81%) were sarcopenic, and 56 (75%) of overweight or obese patients were sarcopenic. Over 3 months, the patients from the entire cohort lost muscle mass (mean change: 4.5±7.5% (» 0.7 kg of muscle)) (P=0.01) . A non significant loss of SAT -4.6±19.2% and a non significant increase of VAT (+10.7±50.3% ) were observed. A similar pattern was observed at 6 months. There was no significant difference between body composition changes in treated groups and placebo. Conclusions: Sarcopenia is highly prevalent in patients with advanced CRPC. Unexpectedly, no difference in body composition changes was observed between patients treated with MDV3100 or AA and placebo.

Effect of abiraterone acetate (AA) on patient-reported pain in metastatic castration-resistant prostate cancer (mCRPC) post-docetaxel: Results of longitudinal sensitivity analyses.

9618 Background: The COU-AA-301 phase 3 trial showed that AA + prednisone (P) improved overall survival in mCRPC patients (pts) post-docetaxel. Compared with P alone, AA + P also had significant benefits on patient-reported pain. Here we describe post hoc sensitivity analyses of pain data from that trial, using different methods to compensate for the potential impact of missing data. Methods: Pts with mCRPC progressing after docetaxel-based chemotherapy were randomized 2:1 to AA + P or placebo + P. Pain intensity and interference of pain with daily activities were assessed with the Brief Pain Inventory-Short Form (BPI-SF) questionnaire at baseline, Day 15 of Cycle 1, and Day 1 of each 28-day treatment cycle thereafter until treatment discontinuation. The effect of treatment on BPI-SF scores was analyzed using repeated measure mixed-effects (RMM) models, piecewise linear mixed-effects (PWLME) models, and joint mixed-effects and log time-to-dropout (JMEL) models. RMM and PWMLE models assumed missing data (due to death, study dropout, or administrative issues) to be missing at random, the JMEL model to be missing not at random. Model results were compared between treatment arms. Results: 797 pts were randomized to AA + P, and 398 to P only. RMM model estimates suggested statistically significant (p &lt; 0.05) differences in change from baseline for pain intensity and pain interference scores in favor of AA + P at the majority of study visits through cycle 11. PWLME models yielded significantly smaller areas under the curve (AUCs) for AA + P vs P for pain intensity (p = 0.0031) and pain interference (p = 0.0006); smaller AUCs reflect better pain outcomes. Results using JMEL models were nearly identical to those with PWLME models, with AUCs for AA + P significantly smaller than for P alone for pain intensity (p = 0.0031) and pain interference (p = 0.0007). Conclusions: Using various modeling methods that assess the impact of missing data, AA + P showed superior patterns of pain outcomes over time compared with P only in mCRPC pts refractory to docetaxel. These results support the previously reported pain benefits of AA + P over P alone from the same trial. Clinical trial information: NCT00638690.