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The Journal of Urology Jul 2021This multicenter randomized phase 2 trial investigates the impact of intense androgen deprivation on radical prostatectomy pathologic response and radiographic and... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
This multicenter randomized phase 2 trial investigates the impact of intense androgen deprivation on radical prostatectomy pathologic response and radiographic and tissue biomarkers in localized prostate cancer (NCT02903368).
MATERIALS AND METHODS
Eligible patients had a Gleason score ≥4+3=7, prostate specific antigen >20 ng/mL or T3 disease and lymph nodes <20 mm. In Part 1, patients were randomized 1:1 to apalutamide, abiraterone acetate, prednisone and leuprolide (AAPL) or abiraterone, prednisone, leuprolide (APL) for 6 cycles (1 cycle=28 days) followed by radical prostatectomy. Surgical specimens underwent central review. The primary end point was the rate of pathologic complete response or minimum residual disease (minimum residual disease, tumor ≤5 mm). Secondary end points included prostate specific antigen response, positive margin rate and safety. Magnetic resonance imaging and tissue biomarkers of pathologic outcomes were explored.
RESULTS
The study enrolled 118 patients at 4 sites. Median age was 61 years and 94% of patients had high-risk disease. The combined pathologic complete response or minimum residual disease rate was 22% in the AAPL arm and 20% in the APL arm (difference: 1.5%; 1-sided 95% CI -11%, 14%; 1-sided p=0.4). No new safety signals were observed. There was low concordance and correlation between posttherapy magnetic resonance imaging assessed and pathologically assessed tumor volume. PTEN-loss, ERG positivity and presence of intraductal carcinoma were associated with extensive residual tumor.
CONCLUSIONS
Intense neoadjuvant hormone therapy in high-risk prostate cancer resulted in favorable pathologic responses (tumor 5 mm) in 21% of patients. Pathologic responses were similar between treatment arms. Part 2 of this study will investigate the impact of adjuvant hormone therapy on biochemical recurrence.
Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Drug Therapy, Combination; Humans; Leuprolide; Male; Middle Aged; Prednisone; Preoperative Period; Prostatectomy; Prostatic Neoplasms; Risk Assessment; Thiohydantoins; Treatment Outcome
PubMed: 33683939
DOI: 10.1097/JU.0000000000001702 -
Asian Journal of Andrology 2017This study was designed to evaluate the efficacy, tolerability, and sequential administration of abiraterone acetate (AA) and enzalutamide (Enz) for metastatic... (Comparative Study)
Comparative Study Review
This study was designed to evaluate the efficacy, tolerability, and sequential administration of abiraterone acetate (AA) and enzalutamide (Enz) for metastatic castration-resistant prostate cancer (mCRPC). A literature search was performed with PubMed, Embase, and Web of Science databases to identify relevant studies. Reviewed literature included published phase III trials of AA or Enz in mCRPC and studies regarding their sequential administration. Given the difference in control arms in AA (active comparator) and Enz (true placebo) randomized phase III studies, indirect comparisons between AA and Enz in mCRPC showed no statistically significant difference in overall survival in prechemotherapy and postchemotherapy settings (HR: 0.90, 95% CI, 0.73-1.11; HR: 0.85, 95% CI, 0.68-1.07). Compared with AA, Enz may better outperform control arms in treating mCRPC both before and after chemotherapy regarding secondary endpoints based on indirect comparisons: time to prostate-specific antigen (PSA) progression (HR: 0.34, 95% CI, 0.28-0.42; HR: 0.40, 95% CI, 0.30-0.53), radiographic progression-free survival (HR: 0.37, 95% CI, 0.28-0.48; HR: 0.61, 95% CI, 0.50-0.74), and PSA response rate (OR: 18.29, 95% CI, 11.20-29.88; OR: 10.69, 95% CI, 3.92-29.20). With regard to the effectiveness of Enz following AA or AA following Enz, recent retrospective case series reported overall survival and secondary endpoints for patients with mCRPC progression after chemotherapy. However, confirmatory head-to-head trials are necessary to determine the optimal sequencing of these agents.
Topics: Abiraterone Acetate; Antineoplastic Agents; Benzamides; Disease-Free Survival; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome
PubMed: 27212123
DOI: 10.4103/1008-682X.178483 -
Pharmaceutics May 2022Abiraterone acetate is a prodrug of abiraterone used in combination with prednisone as a standard therapeutic strategy for hormone-resistant prostate cancer (mCRPC). Due...
Development of Abiraterone Acetate Nanocrystal Tablets to Enhance Oral Bioavailability: Formulation Optimization, Characterization, In Vitro Dissolution and Pharmacokinetic Evaluation.
Abiraterone acetate is a prodrug of abiraterone used in combination with prednisone as a standard therapeutic strategy for hormone-resistant prostate cancer (mCRPC). Due to the poor solubility and permeability, the release and absorption of abiraterone acetate are low and reduce its bioavailability. In this project, abiraterone acetate tablets prepared using nanocrystal technology were developed to overcome the drawbacks of normal tablets by enhancing in vitro dissolution rate and oral bioavailability. The abiraterone acetate nanocrystal suspensions were prepared by top-down wet milling method using a planetary ball mill with the mixture of Poloxamer 407 and Poloxamer 188 as the optimized stabilizer at a ratio of 7:1. The optimized nanocrystals were freeze-dried and characterized using DLS, TEM, DSC, and XRD. The abiraterone acetate nanocrystal tablets significantly improve the in vitro dissolution rate of abiraterone acetate compared to raw materials. Although exhibiting a similar dissolution rate compared to the Zytiga tablets, the nanocrystal tablets significantly improve the oral bioavailability with C and AUC being 3.51-fold and 2.80-fold higher, respectively, in the pharmacokinetic study. The present data indicate that nanocrystal is a promising strategy for improving the dissolution and bioavailability of abiraterone acetate.
PubMed: 35745707
DOI: 10.3390/pharmaceutics14061134 -
Cancer Management and Research 2017Abiraterone acetate has established a major role in the treatment paradigm of metastatic castration-resistant prostate cancer ever since pivotal trials, COU-AA-301 and... (Review)
Review
Abiraterone acetate has established a major role in the treatment paradigm of metastatic castration-resistant prostate cancer ever since pivotal trials, COU-AA-301 and COU-AA-302, have shown benefit in both the second-line and first-line (post- and pre-chemotherapy) setting, respectively, with improvement in overall survival as well as secondary end points such as prostate-specific antigen (PSA) and radiographic response rates, time to PSA progression, and progression-free survival. There has been a lot of interest and emphasis in the evaluation of patient-related outcomes (PROs) as it relates to quality of life, pain, adverse events, fatigue, and among others, in the use of different agents that have been shown to improve survival. This review examines the companion PROs in conjunction with abiraterone acetate use. This is particularly relevant since PROs are increasingly viewed as a key metric for drug label claims in granting approval across regulatory agencies, including the US Food and Drug Administration and the European Medicines Agency.
PubMed: 28744160
DOI: 10.2147/CMAR.S139305 -
Pharmaceutics Aug 2023Abiraterone acetate (AbirAc) is the most used steroidal therapeutic agent for treatment of prostate cancer. The mainly hydrophobic molecular surface of AbirAc results in...
Abiraterone acetate (AbirAc) is the most used steroidal therapeutic agent for treatment of prostate cancer. The mainly hydrophobic molecular surface of AbirAc results in its poor solubility and plays an important role for retention of abiraterone in the cavity of the receptor formed by peptide chains and heme fragments. In order to evaluate the hydrolytic stability of AbirAc, to modify its solubility by formation of new solid forms and to model bonding of this medication with the heme, a series of d-metal complexes with AbirAc was obtained. AbirAc remains stable in water, acetonitrile, tetrahydrofuran, and ethanol, and readily interacts with dications as a terminal ligand to create discrete complexes, including [FePC(AbirAc)] and [ZnTPP(AbirAc)] (HPC = phthalocyanine and HTPP = 5,10,15,20-tetraphenylporphyrine) models for ligand-receptor bonding. In reactions with silver(I) nitrate, AbirAc acts as a bridge ligand. Energies of chemical bonding between AbirAc and these cations vary from 97 to 235 kJ mol and exceed those between metal atoms and water molecules. This can be indicative of the ability of abiraterone to replace solvent molecules in the coordination sphere of biometals in living cells, although the model [ZnTPP] complex remains stable in CDCl, CDCl, and 1,1,2,2-tetrachloroethane- solvents and decomposes in polar dimethylsulfoxide- and methanol- solvents, as follows from the H DOSY spectra. Dynamics of its behavior in 1,1,2,2-tetrachloroethane- were studied by ROESY and NMR spectra.
PubMed: 37765151
DOI: 10.3390/pharmaceutics15092180 -
Frontiers in Oncology 2023Abiraterone acetate (ABI) and Enzalutamide (ENZA) are second-generation hormone drugs that show breakthrough activity in post-chemotherapy, metastatic...
BACKGROUND
Abiraterone acetate (ABI) and Enzalutamide (ENZA) are second-generation hormone drugs that show breakthrough activity in post-chemotherapy, metastatic castration-resistant prostate cancer (mCRPC). The leading oncological and urological guidelines indicate both drugs with the same strong recommendation. There is a lack of randomized trials which compare the efficacy of ABI and ENZA. The current study aimed to compare the effectiveness of the drugs with an analysis of prognostic factors related to those drugs.
PATIENTS AND METHODS
The study included 420 patients with docetaxel (DXL) pretreated mCRPC from seven Polish cancer centers. Patients were treated according to inclusion and exclusion criteria in the Polish national drug program (1000 mg ABI and 10 mg prednisone, =76.2%; ENZA, 160 mg; =23.8%). The study retrospectively analyzed the overall survival (OS), time to treatment failure (TTF), PSA 50% decline rate (PSA 50%) and selected clinic-pathological data.
RESULTS
In the study group, the median OS was 17 months (95% CI: 15.6-18.3). The median OS (26.1 vs. 15.7 mo.; <0.001), TTF (14.2 vs. 7.6 mo.; <0.001) and PSA 50% (87.5 vs. 56%; <0.001) were higher in ENZA than in ABI treatment. Multivariate analysis shows that ENZA treatment and PSA nadir <17.35 ng/mL during or after DXL treatment were related to longer TTF. ENZA treatment, DXL dose ≥750 mg, PSA nadir <17.35 ng/mL during or after DXL treatment was related to longer OS.
CONCLUSIONS
ENZA treatment may be related to more favorable oncological outcomes than ABI treatment in the studied Polish population of patients. A 50% decline in PSA is an indicator of longer TTF and OS. Due to the non-randomized and retrospective nature of the analysis, the current results require prospective validation.
PubMed: 37077831
DOI: 10.3389/fonc.2023.1108937 -
Drugs in R&D Jun 2023Abiraterone acetate tablet is an inhibitor of androgen synthesis, primarily for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This study... (Randomized Controlled Trial)
Randomized Controlled Trial
Pharmacokinetics and Bioequivalence of Abiraterone Acetate Tablets in Healthy Chinese Volunteers: An Open, Randomized, Single-Dose, Three-Period, Three-Sequence Crossover Study.
BACKGROUND AND OBJECTIVE
Abiraterone acetate tablet is an inhibitor of androgen synthesis, primarily for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This study evaluated the bioequivalence and pharmacokinetics of the reference and test formulations of abiraterone acetate tablets in healthy Chinese volunteers.
METHODS
A single-center, open, single-dose, randomized, three-period, three-sequence, semi-repeat (only repeated reference formulations), and reference formulation-corrected fasting reference-scaled average bioequivalence test was conducted in 36 healthy volunteers included in this study. Volunteers were randomly assigned to one of three groups in a 1:1:1 ratio. There was a minimum 7-day washout period between each dose. Blood samples were collected at prescribed time intervals, the plasma concentration of abiraterone acetate tablets was determined by liquid chromatography-tandem mass spectrometry, and adverse events were recorded.
RESULTS
Under fasting conditions, the maximum plasma concentration (C) was 27.02 ± 14.21 ng/mL, area under the concentration-time curve from time zero to time t (AUC) was 125.30 ± 82.41 h·ng/mL, and AUC from time zero to infinity (AUC) was 133.70 ± 83.99 h·ng/mL. The 90% confidence intervals (CIs) of the geometric mean ratio (GMR) of AUC and AUC were in the range of 0.8000-1.2500, and the coefficient of variation (CV) of C was more than 30%. The Critbound result was - 0.0522, and the GMR was between 0.8000 and 1.2500.
CONCLUSION
Both test and reference formulations of abiraterone acetate tablets were bioequivalent in healthy Chinese subjects under fasting conditions.
TRIAL REGISTRATION
ClinicalTrials.gov identifier NCT04863105, registered 26 April 2021-retrospectively registered ( https://register.
CLINICALTRIALS
gov/prs/app/action/SelectProtocol?sid=S000ARAA&selectaction=Edit&uid=U00050YQ&ts=2&cx=-vbtjri.
Topics: Male; Humans; Therapeutic Equivalency; Abiraterone Acetate; Cross-Over Studies; East Asian People; Area Under Curve; Fasting; Tablets; Healthy Volunteers
PubMed: 37012461
DOI: 10.1007/s40268-023-00418-6 -
Frontiers in Oncology 2021The androgen receptor-targeting drugs abiraterone acetate and enzalutamide have shown positive results as treatments for metastatic castration-resistant prostate cancer...
OBJECTIVE
The androgen receptor-targeting drugs abiraterone acetate and enzalutamide have shown positive results as treatments for metastatic castration-resistant prostate cancer (mCRPC). Therefore, a meta-analysis was conducted to compare the efficacy and safety of abiraterone acetate and enzalutamide in patients with mCRPC.
METHODS
We retrieved relevant articles from PubMed, Cochrane, and EMBASE published before December 31, 2020. Eleven articles were initially selected, and four phase III, double-blind, randomized controlled trials of abiraterone acetate and enzalutamide that involved 5199 patients with mCRPC were included. The end points were time to prostate-specific antigen progression (TTPP), according to the prostate-specific antigen working group criteria; overall survival (OS); and radiographic progression-free survival (rPFS).
RESULTS
Four randomized, controlled clinical trials involving 5199 patients were included in this study. The results of the meta-analysis showed that compared with placebo alone, abiraterone significantly improved OS (HR=0.69, 95% CI: 0.60-0.8, P<0.00001), rPFS (HR=0.64, 95% CI: 0.57-0.71, P < 0.00001), and TTPP (HR=0.52, 95% CI: 0.45-0.59, P < 0.00001) in patients with mCRPC. Compared with placebo, enzalutamide significantly improved OS (HR=0.67, 95% CI: 0.59-0.75, P<0.00001), rPFS (HR=0.33, 95% CI: 0.29-0.37, P< 0.00001), and TTPP (HR=0.19, 95% CI: 0.17-0.22, P < 0.00001). An indirect comparison was performed to compare the efficacy of abiraterone and enzalutamide. The results showed that there was no significant difference between abiraterone and enzalutamide with regard to improving the OS of patients with mCRPC (HR=1.03, 95% CI: 0.854-1.242). Enzalutamide was superior to abiraterone with regard to improving rPFS in patients with mCRPC (HR=0.516, 95% CI: 0.438-0.608). With regard to improving TTPP, the efficacy of enzalutamide was better than that of abiraterone (HR=0.365, 95% CI: 0.303-0.441). In sAE, there was no difference between abiraterone and enzalutamide (P=0.21, I 38%).
CONCLUSIONS
Compared with placebo, both abiraterone and enzalutamide significantly prolonged OS, rPFS, and TTPP in patients with mCRPC. There was no difference in safety between abiraterone and enzalutamide. In addition, enzalutamide had better efficacy than abiraterone with regard to improving rPFS and TTPP but not OS, but the level of evidence was low. Therefore, a large direct comparison trial is needed to compare the efficacy of the two drugs.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO, identifier (CRD42021226808).
PubMed: 34513709
DOI: 10.3389/fonc.2021.732599 -
The Journal of Steroid Biochemistry and... Jan 2017Steroid 17-hydroxylase 17,20-lyase (cytochrome P450c17, P450 17A1, CYP17A1) catalyzes two major reactions: steroid 17-hydroxylation followed by the 17,20-lyase... (Review)
Review
Steroid 17-hydroxylase 17,20-lyase (cytochrome P450c17, P450 17A1, CYP17A1) catalyzes two major reactions: steroid 17-hydroxylation followed by the 17,20-lyase reactions. The most severe mutations in the cognate CYP17A1 gene abrogate all activities and cause combined 17-hydroxylase/17,20-lyase deficiency (17OHD), a biochemical phenotype that is replicated by treatment with the potent CYP17A1 inhibitor abiraterone acetate. The adrenals of patients with 17OHD synthesize 11-deoxycorticosterone (DOC) and corticosterone but no 19-carbon steroids, similar to the rodent adrenal, and DOC causes hypertension and hypokalemia. Loss of 17,20-lyase activity precludes sex steroid synthesis and leads to sexual infantilism. Rare missense CYP17A1 mutations minimally disrupt 17-hydroxylase activity but cause isolated 17,20-lyase deficiency (ILD), Mutations in the POR gene encoding the required cofactor protein cytochrome P450-oxidoreductase causes a spectrum of disease from ILD to 17OHD combined with 21-hydroxylase and aromatase deficiencies, sometimes including skeletal malformations. Mutations in the CYB5A gene encoding a second cofactor protein cytochrome b also selectively disrupt 17,20-lyase activity and cause the purest form of ILD. The clinical manifestations of these conditions are best understood in the context of the biochemistry of CYP17A1.
Topics: Abiraterone Acetate; Adrenal Hyperplasia, Congenital; Animals; Antihypertensive Agents; Corticosterone; Cytochromes b5; Desoxycorticosterone; Female; Genotype; Glucocorticoids; Gonadotropins; Humans; Hypertension; Hypospadias; Infertility; Male; Mineralocorticoids; Mutation; Mutation, Missense; Oxidation-Reduction; Steroid 17-alpha-Hydroxylase; Steroid 21-Hydroxylase
PubMed: 26862015
DOI: 10.1016/j.jsbmb.2016.02.002 -
Current Oncology (Toronto, Ont.) Oct 2019Prostate cancer (pca) is the most common non-dermatologic cancer and the 3rd leading cause of male cancer mortality in Canada. In patients with high-risk localized or... (Review)
Review
BACKGROUND
Prostate cancer (pca) is the most common non-dermatologic cancer and the 3rd leading cause of male cancer mortality in Canada. In patients with high-risk localized or recurrent pca, management typically includes the combination of long-term androgen deprivation therapy (adt) and radiotherapy (rt). New androgen-receptor-axis targeted therapies (arats), which await validation, offer an option to intensify therapy.
METHODS
In this narrative review, we report the relevant history that has supported combining adt with rt. The literature in PubMed was searched for studies involving pca and novel arats (abiraterone acetate, enzalutamide, apalutamide, darolutamide) published between 1995 and 2019. Literature discussing clinical trials in which those modalities were combined was extracted and synthesized into a combined molecular and clinical discussion. Potential treatment intensification mechanisms and rationales are explored.
RESULTS
Early results from three phase i/ii trials demonstrated that concurrent abiraterone acetate, adt, and rt is safe, improves the extent of chemical castration, and is associated with limited treatment failures. A single study implies synergy for radiosensitization beyond that facilitated by conventional adt. Studies investigating the combination of other arats with rt are under way, including multiple phase iii trials, but short-term results are not yet available.
Topics: Abiraterone Acetate; Androgen Antagonists; Benzamides; Combined Modality Therapy; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Pyrazoles; Randomized Controlled Trials as Topic; Thiohydantoins
PubMed: 31708657
DOI: 10.3747/co.26.5005