abiraterone-acetate and abiraterone

The phase 3 trial ERA223 demonstrated an increased fracture rate and no survival advantage for metastatic castration resistant prostate cancer (mCRPC) patients on Radium-223 (Ra-223) with abiraterone, leading to regulatory restrictions on combination therapy. However, less than half of trial patients received bone health agents (BHA). We reviewed electronic health record (EHR) data evaluating fracture rates for patients on BHA receiving Ra-223, androgen deprivation therapy and either abiraterone or enzalutamide.. We conducted a retrospective, cohort analysis of EHR data of mCRPC patients on Ra-223 treated at a single community center by a single provider between 2010 and 2018. The primary objective was evaluating fracture rates for patients on BHA receiving Ra-223 and abiraterone. We conducted a secondary analysis for enzalutamide.. One hundred seventy-seven patients received Ra-223 concurrently with abiraterone or enzalutamide between November 2010 and August 2018. The median age was 73 at first Ra-223 dose (range 40-93). The median follow-up time from last Ra-223 dose was 30 months (range 2-106). One hundred sixty-four patients (93%) received BHAs. One hundred fifty-nine patients (89%) were on a BHA before and/or during Ra-223. Sixty-seven patients received denosumab (38%), 63 received zoledronic acid (36%), and 29 received both nonconcurrently (16%). Eleven patients (6.2%) experienced a fracture after starting Ra-223, 9 of which occurred while on prior and/or concurrent BHA. We observed a 5.7% fracture rate for mCRPC patients who received combination therapy and denosumab or zoledronic acid.. This real-world analysis demonstrating a low fracture rate in patients with mCRPC receiving a BHA while on Ra-223 and abiraterone or enzalutamide may inform current clinical practice.

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Androgens; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bone Density; Denosumab; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Radium; Retrospective Studies; Zoledronic Acid

Current guidelines suggest radiotherapy as a first-line treatment for prostate cancer, along with prostatectomy, and androgen deprivation therapy. Abiraterone is a first-in-class medicinal product recommended in the treatment of metastatic castration resistant prostate cancer (mCRPC) that targets androgen receptors and inhibits systemic synthesis. However, successful therapy with this drug may pose some challenges. It has to be administered as an inactive prodrug - abiraterone acetate. It is also dissolved and absorbed poorly with large interindividual variability and exhibits considerable food effects. Additionally, the recommended daily dose of the drug is high (1000 mg abiraterone acetate), and the cost of the therapy is burdensome. The following review focuses on the strategies to optimize therapy with abiraterone acetate. First, it summarizes current findings on abiraterone pharmacokinetics and accentuates the need for utilizing therapeutic monitoring in clinical practice. Next, it extensively describes the options for improving the low bioavailability of the drug. The two major approaches are the utilization of the positive food effect to increase the exposure and development of supergenerics. The review emphasizes how different formulation approaches lead to increased solubility and impact the outcomes of pre-clinical and clinical trials. The review concludes with a discussion on possible future directions that may lead to the increase of the therapeutic efficacy of abiraterone.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Drug Monitoring; Humans; Male; Pharmaceutical Preparations; Prostatic Neoplasms, Castration-Resistant

Optimal treatment sequencing of abiraterone and enzalutamide in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) is challenging. Real-world data (RWD) allow a better understanding of health economic implications in the real world.. To determine survival and cost outcomes for two real-world treatment sequences, comparing abiraterone to enzalutamide (AA → ENZ) with enzalutamide to abiraterone (ENZ → AA).. A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Searches were performed in Medline, Embase, and Web of Science.. Seventeen studies met our inclusion criteria. Of studies with survival outcomes, 10 featured AA → ENZ treatment sequences (n = 575), four ENZ → AA sequences (n = 205), and three both sequences. Better survival outcomes were demonstrated in the AA → ENZ cohorts in several studies reporting prostate-specific antigen (PSA) progression-free survival (PSA-PFS), combined PSA-PFS, and PSA decline ≥50%. Three studies showed shorter treatment duration in cohorts receiving second-line enzalutamide compared with abiraterone. Collectively, six RWD costing studies described patients with mCRPC who experienced treatment with enzalutamide (n = 4195), abiraterone (n = 10 372), AA → ENZ (n = 443), and ENZ → AA (n = 91). No study estimated the cost of treatment sequencing of AA → ENZ or ENZ → AA.. No head-to-head studies were found, but we hypothesise that the AA → ENZ sequence may be less costly than ENZ → AA, because time on treatment tends to be longer for a first-line treatment and abiraterone is less costly than enzalutamide. There are indications that PFS of AA → ENZ is superior to that of ENZ → AA, which supports the former sequence as more cost-effective.. Better survival outcomes were reported in several studies where patients with advanced prostate cancer received the abiraterone to enzalutamide sequence compared with the enzalutamide to abiraterone sequence. No study estimated the cost of sequencing either treatment approach.

Topics: Abiraterone Acetate; Androstenes; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Abiraterone acetate plus prednisone is approved in metastatic castration-resistant prostate cancer. There is some evidence in favour of the steroid switch from prednisone to dexamethasone in patients who progressed whilst on abiraterone acetate plus prednisone or prednisolone.. The aim of this review is to discuss the results from the clinical studies available, examining potential mechanisms of action and patient selection criteria for this treatment option.. A total of four studies were evaluated. Among possible eligibility criteria for steroid switch, we found: PSA progression without any radiological or clinical progression during abiraterone acetate + prednisone; no high-grade adverse events related to CYP-17 inhibition; and unfitness for chemotherapy or radium-223.. Although large randomized prospective trials are warranted, steroid switch seems to offer a good option for certain patients treated with abiraterone acetate plus prednisone or prednisolone.

Topics: Abiraterone Acetate; Adrenal Cortex Hormones; Aged; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Humans; Male; Middle Aged; Patient Selection; Prednisolone; Prednisone; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Metastatic castration-resistant prostate cancer (CRPC) is a potentially symptomatic disease with an eventual lethal outcome. Novel pharmaceutical agents are continuously studied with encouraging results in CRPC.. In this perspective, the authors present established and promising pharmacotherapeutic strategies for the management of CRPC; both with and without metastases. Apart from the different treatment strategies, the authors present the relevant sequence of treatment through disease progression.. Usually, docetaxel should be considered the first line treatment in mCRPC. Abiraterone acetate (AA) plus prednisone or enzalutamide (ENZ) could be alternative treatments in chemotherapy naïve patients. Sipuleucel-T has been approved for the treatment of asymptomatic or minimally symptomatic mCRPC. Ra-223 has been approved for patients with mCRPC with symptomatic bone metastases (not visceral metastases). Cabazitaxel has been approved as the second line treatment to docetaxel in mCRPC. No differences in the overall survival has been observed between sequences starting with docetaxel versus AA/ENZ. Between AA-to-ENZ and ENZ-to-AA sequence, the AA-to-ENZ sequence appeared to be more favorable than the ENZ-to-AA regarding progression-free survival but not overall survival. Carbazitaxel seemed to retain its activity regardless of the treatment sequence. Of note, ENZ and apalutamide have been approved in non-metastatic CRPC.

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Clinical Trials as Topic; Disease-Free Survival; Docetaxel; Drug Resistance, Neoplasm; Humans; Immunotherapy; Male; Nitriles; Phenylthiohydantoin; Prednisone; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Radium; Taxoids; Tissue Extracts

The development of a novel therapy to overcome primary and acquired resistance to abiraterone is an unmet need. This study aimed to evaluate the efficacy and safety of adding 5α-reductase inhibitor dutasteride to abiraterone, explore proof of concept, and identify candidates suitable for combination therapy. This phase II, single-arm, and open-label study enrolled second-generation antiandrogen- and chemotherapy-naïve patients with castration-resistant prostate cancer. Patients received abiraterone and prednisolone for 4 weeks, followed by adding dutasteride. The primary end point was a 50% prostate-specific antigen response rate. Serum concentrations of abiraterone and its metabolites as well as HSD3B1 and SRD5A2 genotypes were measured. The association between drug metabolism and genotypes and their impact on the efficacy of combination therapy were assessed. Among 21 patients, 18 (85.7%) achieved ≥50% PSA reduction. Median time to treatment failure was not reached during the median follow-up of 15.4 months. No patients experienced grade ≥3 adverse events. Although dutasteride reduced serum 3-keto-5α-abiraterone concentrations, higher serum 3-keto-5α-abiraterone concentrations on combination therapy were associated with a shorter time to treatment failure. HSD3B1 and SRD5A2 genotypes were associated with serum Δ4-abiraterone and 3-keto-5α-abiraterone concentrations before adding dutasteride, respectively. Time to treatment failure was longer in patients with homozygous wild-type HSD3B1, but comparable between those with the SRD5A2 genotype. The promising outcomes of this study warrant further investigation of combination therapy in a randomized trial. Stratification by HSD3B1 and SRD5A2 genetic profiles might identify patients suitable for combination therapy.

Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Abiraterone Acetate; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Dutasteride; Humans; Male; Membrane Proteins; Multienzyme Complexes; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Adding ipatasertib to abiraterone and prednisone/prednisolone significantly improved radiographic progression-free survival for patients with metastatic castration-resistant prostate cancer (mCRPC) with PTEN-loss tumours by immunohistochemistry in the IPATential150 trial (NCT03072238). Here we characterise the safety of these agents in subpopulations and assess manageability of key adverse events (AEs).. In this randomised, double-blind, phase 3 trial, patients with previously untreated asymptomatic or mildly symptomatic mCRPC were randomised 1:1 to receive ipatasertib-abiraterone or placebo-abiraterone (all with prednisone/prednisolone). AEs were analysed, focusing on key AEs of diarrhoea, hyperglycaemia, rash and transaminase increased.. 1097 patients received study medication and were assessed for safety (47% with PTEN-loss tumours by immunohistochemistry and 20% were Asian). Ipatasertib was associated with increased Grade 3/4 AEs and AEs leading to treatment discontinuation vs placebo. The rate of discontinuation of ipatasertib was 18% in patients with PTEN-loss and 21% overall. The frequencies of all-grade, Grade 3/4 and serious AEs were similar between the PTEN-loss and overall populations. Diarrhoea, hyperglycaemia, rash and transaminase elevation were more frequent in ipatasertib-treated patients, appearing rapidly after treatment initiation (median onset: 8-43 days for ipatasertib arm and 56-104 days for placebo). The ipatasertib discontinuation rate was 32% and 18% in Asian and non-Asian patients, respectively, despite similar baseline characteristics and Grade 3/4 AE frequencies between groups.. Ipatasertib plus abiraterone had an overall tolerable safety profile consistent with known toxicities. More AEs leading to drug discontinuation were observed with ipatasertib than placebo, but incidence would likely be lessened with prophylactic measures.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Exanthema; Humans; Hyperglycemia; Male; Prednisolone; Prednisone; Prostatic Neoplasms, Castration-Resistant

Enzalutamide and abiraterone both target androgen receptor signaling but via different mechanisms. The mechanism of action of one drug may counteract the resistance pathways of the other. We sought to determine whether the addition of abiraterone acetate and prednisone (AAP) to enzalutamide prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the first-line setting.. Men with untreated mCRPC were randomly assigned (1:1) to receive first-line enzalutamide with or without AAP. The primary end point was OS. Toxicity, prostate-specific antigen declines, pharmacokinetics, and radiographic progression-free survival (rPFS) were also examined. Data were analyzed using an intent-to-treat approach. The Kaplan-Meier estimate and the stratified log-rank statistic were used to compare OS between treatments.. In total, 1,311 patients were randomly assigned: 657 to enzalutamide and 654 to enzalutamide plus AAP. OS was not statistically different between the two arms (median, 32.7 [95% CI, 30.5 to 35.4] months for enzalutamide. The addition of AAP to enzalutamide for first-line treatment of mCRPC was not associated with a statistically significant benefit in OS. Drug-drug interactions between the two agents resulting in increased abiraterone clearance may partly account for this result, although these interactions did not prevent the combination regimen from having more nonhematologic toxicity.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Nitriles; Prednisone; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Early treatment intensification with neoadjuvant therapy may improve outcomes in patients with high-risk, localized prostate cancer treated with radical prostatectomy. Our objective was to compare pathologic, oncologic, and safety outcomes of neoadjuvant abiraterone acetate plus leuprolide acetate with or without cabazitaxel prior to radical prostatectomy in patients with localized, high-risk prostate cancer.. This open-label, multicenter, phase II trial randomized men with clinically localized, D'Amico high-risk prostate cancer to neoadjuvant abiraterone acetate (1,000 mg/day) and leuprolide acetate (22.5 mg every 3 months) with or without cabazitaxel (25 mg/m2) prior to radical prostatectomy. The primary outcome was pathologic complete response (pCR) or minimal residual disease (MRD). Secondary outcomes included surgical margins, lymph node involvement, pathologic stage, 12-month biochemical relapse-free survival (BRFS) rates, and safety profile.. The per-protocol population consisted of 70 patients [cabazitaxel arm (Arm A): 37, no cabazitaxel arm (Arm B): 33]. Median patient age and prostate-specific antigen levels were 63.5 years [interquartile range (IQR), 58.0-68.0] and 21.9 ng/mL (IQR, 14.6-42.8), respectively. pCR/MRD occurred in 16 (43.2%) versus 15 patients (45.5%) in arms A and B, respectively (P = 0.85). pCR occurred in two (5.4%) versus three patients (9.1%) in arms A and B, respectively (P = 0.66). Patients with ≤ 25% total biopsy cores positive had increased odds of pCR/MRD (P = 0.04). Patients with pCR/MRD had superior 12-month BRFS rates (96.0% vs. 62.0%, P = 0.03). Grade 3+ adverse events occurred in 42.5% and 23.7% of patients in arms A and B, respectively (P = 0.078).. Neoadjuvant cabazitaxel addition to abiraterone acetate/leuprolide acetate prior to radical prostatectomy did not improve pCR/MRD in clinically localized, high-risk prostate cancer.

Topics: Abiraterone Acetate; Humans; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms

Docetaxel and abiraterone acetate plus prednisone or prednisolone (AAP) both improve survival when commenced alongside standard of care (SOC) androgen deprivation therapy in locally advanced or metastatic hormone-sensitive prostate cancer. Thus, patient-reported quality of life (QOL) data may guide treatment choices.. A group of patients within the STAMPEDE trial were contemporaneously enrolled with the possibility of being randomly allocated to receive either docetaxel + SOC or AAP + SOC. A mixed-model assessed QOL in those who had completed at least one QLQ-C30 + PR25 questionnaire. The primary outcome measure was difference in global-QOL (QLQ-C30 Q29&30) between patients allocated to docetaxel + SOC or AAP + SOC over the 2 years after random assignment, with a predefined criterion for clinically meaningful difference of > 4.0 points. Secondary outcome measures included longitudinal comparison of functional domains, pain, and fatigue, plus global-QOL at defined timepoints.. Five hundred fifteen patients (173 docetaxel + SOC and 342 AAP + SOC) were included. Baseline characteristics, proportion of missing data, and mean baseline global-QOL scores (docetaxel + SOC 77.8 and AAP + SOC 78.0) were similar. Over the 2 years following random assignment, the mean modeled global-QOL score was +3.9 points (95% CI, +0.5 to +7.2;. Patient-reported QOL was superior for patients allocated to receive AAP + SOC, compared with docetaxel + SOC over a 2-year period, narrowly missing the predefined value for clinical significance. Patients receiving AAP + SOC reported clinically meaningful higher global-QOL scores throughout the first year following random assignment.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Prostatic Neoplasms; Quality of Life

ARTO trial was designed to evaluate the difference in terms of outcomes between patients affected by oligo metastatic castrate resistant prostate cancer (mCRPC) treated with Abiraterone acetate and randomized to receive or not SBRT on all sites of disease. Here, we present a preliminary analysis conducted on patients enrolled at promoting institution.. To present a preliminary overview about population features, clinical outcomes, adverse events, quality of life and explorative translational research.. ARTO (NCT03449719) is a phase II trial including patients affected by oligo mCRPC, randomized to receive standard of care (GnRH agonist or antagonist plus abiraterone acetate 1000 mg and oral prednisone 10 mg daily) with or without SBRT on all metastatic sites of disease. All subjects have < 3 bone or nodal metastases. All patients are treated in I line mCRPC setting, no previous lines of treatment for mCRPC are allowed.. Data about a mono-centric cohort of 42 patients enrolled are presented in the current analysis, with focus on baseline population features, PSA drop at 3 months, biochemical response, and quality of life outcomes. Descriptive statistics regarding translational research are also presented.. Significant difference in terms of PSA drop at three months was not detected (p = 0.68). Biochemical response (PSA reduction > 50%) was reported in 73.7 versus 76.5% of patients in control vs SBRT arm, respectively (p = 0.84). All patients are alive. Progression occurred in 1 versus 0 patients in the control versus SBRT arm, respectively. After 3 months, an average decrease of 13 points in terms of Global Health Score was reported for the overall population. However, complete recovery was noticed at 6 months. Circulating tumor cells detection rate was 40%.. SBRT + Abiraterone treatment was safe and well tolerated, non-significant trend in terms of PSA drop and biochemical response at 3 months was detected in SBRT arm. Interestingly, CTCs detection in this selected cohort of oligo-mCRPC was lower if compared to historical data of unselected mCRPC patients.

Topics: Abiraterone Acetate; Androstenes; Chemoradiotherapy; Clinical Trial Protocols as Topic; Cohort Studies; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Radiosurgery; Treatment Outcome

Resistance to novel androgen signaling inhibition and metastatic castration-resistant prostate cancer (mCRPC) progression is likely dependent on tumor microenvironment interactions. The Src pathway and neoangiogenesis have been implicated in prostate cancer progression. We studied the effect of adding the targeted agents dasatinib and sunitinib to abiraterone acetate (AA) in men with mCRPC.. In this open-label randomized phase 2 study, mCRPC patients received AA. At resistance to AA, they were randomized 1:1 to combination with dasatinib or sunitinib. At second progression, patients crossed over. The primary end point was time to treatment failure (TTF), defined as time to progression or death. Secondary end points included overall survival and safety.. From March 2011 to February 2015, a total of 179 patients were enrolled and 132 subsequently randomized. Median TTF was 5.7 months in the dasatinib group and 5.5 months in the sunitinib group. There was no difference between the two groups in terms of TTF (hazard ratio, 0.85; 95% confidence interval, 0.59-1.22). Median overall survival from study entry was 26.3 months in the dasatinib group and 27.7 months in the sunitinib group (hazard ratio, 1.02; 95% confidence interval, 0.71-1.47). Grade 3 or higher adverse events related to study medication were more frequent with sunitinib (n = 44, 46%) compared to dasatinib (n = 26, 24%). At data cutoff, 7 patients were experiencing a continuous response to AA, with a median duration of treatment of 5.7 years.. There is no difference in overall survival and TTF between dasatinib and sunitinib combined with abiraterone in the treatment of patients with bone mCRPC.

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Dasatinib; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant; Random Allocation; Sunitinib; Treatment Outcome; Tumor Microenvironment

In the CARD study (NCT02485691), cabazitaxel significantly improved median radiographic progression-free survival (rPFS) and overall survival (OS) versus abiraterone/enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who had previously received docetaxel and progressed ≤12 mo on the alternative agent (abiraterone/enzalutamide).. To assess cabazitaxel versus abiraterone/enzalutamide in older (≥70 yr) and younger (<70 yr) patients in CARD.. Patients with mCRPC were randomized 1:1 to cabazitaxel (25 mg/m. Analyses of rPFS (primary endpoint) and safety by age were prespecified; others were post hoc. Treatment groups were compared using stratified log-rank or Cochran-Mantel-Haenszel tests.. Of the 255 patients randomized, 135 were aged ≥70 yr (median 76 yr). Cabazitaxel, compared with abiraterone/enzalutamide, significantly improved median rPFS in older (8.2 vs 4.5 mo; hazard ratio [HR] = 0.58; 95% confidence interval [CI] = 0.38-0.89; p = 0.012) and younger (7.4 vs 3.2 mo; HR = 0.47; 95% CI = 0.30-0.74; p < 0.001) patients. The median OS of cabazitaxel versus abiraterone/enzalutamide was 13.9 versus 9.4 mo in older patients (HR = 0.66; 95% CI = 0.41-1.06; p = 0.084), and it was 13.6 versus 11.8 mo in younger patients (HR = 0.66; 95% CI = 0.41-1.08; p = 0.093). Progression-free survival, prostate-specific antigen, and tumor and pain responses favored cabazitaxel, regardless of age. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 58% versus 49% of older patients receiving cabazitaxel versus abiraterone/enzalutamide and 48% versus 42% of younger patients. In older patients, cardiac adverse events were more frequent with abiraterone/enzalutamide; asthenia and diarrhea were more frequent with cabazitaxel.. Cabazitaxel improved efficacy outcomes versus abiraterone/enzalutamide in patients with mCRPC after prior docetaxel and abiraterone/enzalutamide, regardless of age. TEAEs were more frequent among older patients. The cabazitaxel safety profile was manageable across age groups.. Clinical trial data showed that cabazitaxel improved survival versus abiraterone/enzalutamide with manageable side effects in patients with metastatic castration-resistant prostate cancer who had previously received docetaxel and the alternative agent (abiraterone/enzalutamide), irrespective of age.

Topics: Abiraterone Acetate; Aged; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Disease-Free Survival; Docetaxel; Humans; Male; Nitriles; Phenylthiohydantoin; Prednisone; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

A common polymorphism (1245A>C) in the HSD3B1 gene is associated with increased de novo synthesis of androgens and worse outcomes in men treated with androgen-deprivation therapy for metastatic castration-sensitive prostate cancer. The objective of the study was to determine whether this polymorphism is associated with outcomes for metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone or enzalutamide.. A total of 547 patients treated with abiraterone or enzalutamide from two prospective cohorts were evaluated. The HSD3B1 genotype was determined by targeted sequencing and/or TaqMan single-nucleotide polymorphism genotyping. In cohort 1, patients were randomized to receive abiraterone + prednisone or enzalutamide. In cohort 2, patients received either agent according to investigator's choice. Prostate-specific antigen (PSA) response rate, time to PSA progression (TTPP), time to progression (TTP) and overall survival were determined. Associations between HSD3B1 genotypes and outcomes were evaluated via univariate Cox regression. Multivariable Cox model was used to determine the independent association of each covariate.. The HSD3B1 variant genotype (CC) was present in 15% of patients and was associated with worse TTP [hazard ratio (HR) 1.31, 95% confidence interval (CI) 1.02-1.67, P = 0.032] and PSA response rates (48% for CC versus 62% and 65% for AA and AC, respectively [P = 0.019]), with no significant difference in TTPP (HR 1.28, 95% CI 0.99-1.66, P = 0.064). The effect of genotype was similar for treatment with abiraterone or enzalutamide with a negative test for interaction for TTPP (P = 0.997) and TTP (P = 0.749). Multivariable analysis did not show a significant association between genotype and TTP or TTPP.. The HSD3B1 (CC) genotype was associated with shorter TTP and lower PSA response rate in patients with mCRPC treated with abiraterone or enzalutamide. However, the CC genotype did not provide prognostic information beyond that conferred by standard clinical variables, suggesting that it may not be a suitable stand-alone biomarker in mCRPC.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstenes; Benzamides; Germ Cells; Humans; Male; Multienzyme Complexes; Nitriles; Phenylthiohydantoin; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

We analyzed the potential of abiraterone acetate (henceforth abiraterone) to reduce androgen levels below lower limits of quantification (LLOQ) and explored the association with changes in PSA decline in metastatic castration-resistant prostate cancer (mCRPC) patients.. COU-AA-301 is a 2:1 randomized, double-blind, placebo-controlled study comparing abiraterone (1000 mg q.d.) plus low-dose prednisone (5 mg b.i.d.) with placebo plus prednisone in mCRPC patients post docetaxel. Serum testosterone, androstenedione and dehydroepiandrosterone sulfate from baseline to week 12 were measured by novel ultrasensitive two-dimensional liquid chromatography coupled to tandem mass spectrometry assays in a subset of subjects in each arm (abiraterone plus prednisone, n=80; prednisone, n=38). The association between PSA response (< or =50% baseline) and undetectable androgens (week 12 androgen level below LLOQ) was analyzed using logistic regression.. A significantly greater reduction in serum androgens was observed with abiraterone plus prednisone versus prednisone (all P < or = 0.0003), reaching undetectable levels for testosterone (47.2% versus 0%, respectively). A positive association was observed between achieving undetectable serum androgens and PSA decline (testosterone: odds ratio=1.54; 95% confidence interval: 0.546-4.347). Reduction of androgens to undetectable levels did not occur in all patients achieving a PSA response, and a PSA response did not occur in all patients achieving undetectable androgen levels.. Abiraterone plus prednisone significantly reduced serum androgens, as measured by ultrasensitive assays and was generally associated with PSA response. However, androgen decline did not uniformly predict PSA decline suggesting ligand-independent or other mechanisms for mCRPC progression.

Topics: Abiraterone Acetate; Androgens; Androstenes; Double-Blind Method; Humans; Kallikreins; Male; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Testosterone; Treatment Outcome

Persistent androgen synthesis under castration status in adrenal gland, testes and tumor cells is thought to be one of the major causes of development and progression of castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA), the prodrug of abiraterone, which is an inhibitor of androgen synthesis enzymes, was evaluated for pharmacokinetics, pharmacodynamics, preliminary efficacy and safety in Japanese patients with CRPC in a phase-1, open-label and dose-escalation study. Chemotherapy-naïve Japanese CRPC patients (N = 27) received one of four AA daily doses (250 mg [n = 9], 500 mg [n = 6], 1000 [1 h premeal] mg [n = 6] and 1000 [2 h postmeal] mg [n = 6]) continuously through 28-day treatment cycles. In the first cycle, AA monotherapy was given on days 1-7 for pharmacokinetics, and AA plus prednisone (5 mg twice daily) from days 8 to 28. Of 27 patients, 9 continued treatment with AA until the data cut-off date (18 July 2013). Over the evaluated dose range, plasma abiraterone concentrations increased with dose, with median tmax 2-3 h. At each dose level, mean serum corticosterone concentrations increased, while testosterone and dehydroepiandrosterone sulfate concentrations rapidly decreased following a single AA dose and were further reduced to near the quantification limit on day 8 regardless of the dose. At least 3 patients from each dose-group experienced ≥50% prostate-specific antigen reduction, suggesting clinical benefit from AA in Japanese CRPC patients. AA was generally well-tolerated, and, therefore, the recommended AA dosage regimen in Japanese CRPC patients is 1000 mg oral dose under modified fasting conditions (at least 1 h premeal or 2 h postmeal). This study is registered at ClinicalTrials.gov: NCT01186484.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androstadienes; Androstenes; Androstenols; Humans; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Steroid 17-alpha-Hydroxylase

Prostate cancer (PC) is the most common type of neoplasm in men and the fourth leading cause of mortality in Brazil. The prostate cancer refractory metastatic castration can be treated with abiraterone acetate (AA).. Its use has been associated with increased survival. However, there are also side effects associated with the use of this drug, such as severe electrolyte disturbances.. The objective is to report the clinical case of a patient with castration-resistant metastatic prostate cancer who developed ascending flaccid paralysis secondary to severe hypokalemia, probably due to hyperaldosteronism secondary to the use of Abiraterone Acetate, despite the use of Prednisone.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Humans; Hypokalemia; Male; Paralysis; Prednisone; Prostatic Neoplasms, Castration-Resistant

Comorbid diseases influence patient outcomes, yet little is known about how comorbidities interact with treatments for metastatic castrate-resistant prostate cancer (mCRPC). No head-to-head trials have compared the efficacy of abiraterone and enzalutamide - oral androgen-receptor targeted agents (ARTAs) for mCRPC. In patients with comorbid disease, outcomes with ARTAs may differ due to disparate mechanisms of action, adverse events, and drug interactions.. Retrospective observational study of US veterans initiating treatment for mCRPC with abiraterone or enzalutamide between September 2014 and June 2017. Treatment duration and overall survival (OS) was compared based on age and comorbid diseases. The association between ARTA and OS was assessed using Cox proportional hazards and propensity-score matched modeling while adjusting for potential confounders. Sensitivity analyses were performed based on patient age, comorbidities, and subsequent treatments for mCRPC.. Of 5822 veterans treated for mCRPC, 43.0% initially received enzalutamide and 57.0% abiraterone. Veterans initially treated with enzalutamide versus abiraterone were older (mean 75.8 vs. 75.0 years) with higher mean Charlson comorbidity index (4.4 vs. 4.1), and higher rates of cardiovascular disease or diabetes (74.2% vs. 70.6%). In the entire population, veterans initially treated with enzalutamide had longer median OS compared to those initially treated with abiraterone (24.2 vs. 22.1 months, p = 0.001). In veterans with cardiovascular disease or diabetes, median treatment duration with enzalutamide was longer (11.4 vs. 8.6 months, p < 0.001) with longer median OS compared to abiraterone (23.2 vs. 20.5 months, p < 0.001). In a propensity score matched cohort, enzalutamide was associated with decreased mortality compared to abiraterone (HR 0.90, 95% CI 0.84-0.96).. Veterans with cardiovascular disease or diabetes had longer treatment duration and OS with enzalutamide compared to abiraterone. Further study of ARTA selection may benefit men with metastatic castrate resistant prostate cancer and likely hormone sensitive prostate cancer, especially among patients with comorbid diseases.

Topics: Abiraterone Acetate; Cardiovascular Diseases; Diabetes Mellitus; Humans; Male; Nitriles; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome; Veterans

We assessed the impact of plasma trough concentrations of abiraterone (ABI) and its metabolite Δ4-abiraterone (D4A) and related polymorphisms on adverse events (AEs) in patients with metastatic prostate cancer who received abiraterone acetate (AA).. This prospective study enrolled patients with advanced prostate cancer treated with AA between 2016 and 2021. Plasma trough concentrations of ABI and D4A were measured using high-performance liquid chromatography. The impact of HSD3B1 rs1047303, SRD5A2 rs523349, and cytochrome P450 family 3A member 4 rs2242480 polymorphisms on plasma concentrations of ABI and D4A and the incidence of AEs were also assessed.. In 68 patients treated with AA, the median ABI and D4A concentrations were 18.1 and 0.94 ng/mL, respectively. The high plasma trough concentration of ABI (≥ 20.6 ng/mL) was significantly associated with the presence of any AE and its independent risk factor based on multivariable analysis (odds ratio, 7.20; 95% confidence interval (CI): 2.20-23.49). Additionally, a high plasma trough concentration of ABI was an independent risk factor of time to withdraw AA (hazard ratio, 4.89; 95% CI: 1.66-14.38). The risk alleles of three polymorphisms were not statistically associated with the ABI and D4A concentrations and the incidence of AEs.. The plasma trough concentration of ABI is associated with the presence of AEs and treatment failure after AA administration. ABI concentration monitoring may be useful in patients with prostate cancer who received AA.

Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Membrane Proteins; Prospective Studies; Prostatic Neoplasms, Castration-Resistant

We aimed to develop and validate a plasma extracellular vesicle circular RNA (circRNA)-based signature that can predict overall survival (OS) in first-line abiraterone therapy for metastatic castration-resistant prostate cancer (mCRPC) patients.. In total, 582 mCRPC patients undergoing first-line abiraterone therapy from four institutions were sorted by three phases. In the discovery phase, 30 plasma samples from 30 case-matched patients with or without early progression were obtained to generate circRNA expression profiles using RNA sequencing. In the training phase, differentially expressed circRNAs were examined using digital droplet PCR in a training cohort (n = 203). The circRNA signature was constructed using a least absolute shrinkage and selection operator Cox regression to predict OS. In the validation phase, the prognostic ability of this signature was prospectively validated in two external cohorts (Cohort I, n = 183; Cohort II, n = 166).. We developed a five-circRNA signature, based on circCEP112, circFAM13A, circBRWD1, circVPS13C and circMACROD2, which successfully stratified patients into high-risk and low-risk groups. The prognostic ability of this signature was prospectively validated in two external cohorts (P < 0.0001, P < 0.0001). Patients with high-risk scores had shorter OS than patients with low-risk scores.. This five-circRNA signature is a reliable predictor of OS for mCRPC patients undergoing abiraterone.

Topics: Abiraterone Acetate; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; RNA, Circular; Treatment Outcome

Patients with metastatic castration-resistant prostate cancer (mCRPC) are divided into three groups based on their response to Abiraterone treatment: best responder, responder, and non-responder. In the latter two groups, successful outcomes may not be achieved due to the development of drug-resistant cells in the tumor environment during treatment. To overcome this challenge, a secondary drug can be used to control the population of drug-resistant cells, potentially leading to a longer period of disease inhibition. This paper proposes using a combination of Docetaxel and Abiraterone in some polytherapy methods to control both the overall cancer cell population and the drug-resistant subpopulation. To investigate the competition and evolution of mCRPC cancer phenotypes, as in previous studies, the Evolutionary Game Theory (EGT) has been used as a mathematical modeling of evolutionary biology concepts.

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome

Topics: Abiraterone Acetate; Antineoplastic Agents; Drug Approval; Humans; Male; Prostatic Neoplasms, Castration-Resistant

Abiraterone Acetate (AA) is an important agent in the treatment of advanced prostate cancer. It was primarily approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) after failure of androgen deprivation therapy. There is still no available strong data regarding the impact of early decline of prostate-specific antigen (PSA) in the overall survival. The aim of this study was to evaluate the clinical efficacy of an early prostate-specific antigen response as a predictor of overall survival (OS) in metastatic castration-resistant prostate cancer when treated with Abiraterone Acetate.. A dual center, retrospective, cohort study on patients diagnosed with mCRPC treated with abiraterone between 2013 and 2020 was performed. Primary end-point was to demonstrate the efficacy of AA, with the analysis of PSA decline, and the correlation with overall survival.. The cohort analysis consisted of 84 patients with a median age of 71 ± 9 years. A PSA response of > 30% and > 50% at 60 and 90 days was associated with improved OS. Multivariate analysis revealed that a 60 day PSA decline of > 30% was predictive of overall survival. Median OS of diag-nosed mCRPC patients was 28 months. Docetaxel pre-treatment was not associated with longer OS. The median duration of drug exposure for patients submitted to AA was found to be 14 months.. Early PSA response rate can offer clinically meaningful information and can be considered a surrogate of longer OS. A > 30% or > 50% prostate-specific antigen decline at 60 and 90 days provided an important low-cost clinical tool to predict subsequent events in mCRPC patients treated with abiraterone.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androgen Antagonists; Cohort Studies; Disease-Free Survival; Humans; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Using large French retrospective study cohort of chemotherapy-naïve metastatic castration-resistant prostate cancer patients (mCRPC; n = 10,308) comparing survival between patients who initiated abiraterone (ABI; 64%) and those initiating enzalutamide (ENZ; 36%), the present objective was to describe treatment patterns in the 2 years following initiation.. Using the national health data system (SNDS) from 2014 to 2018, we first explored the number of treatment lines, and secondly, patterns of patient management using state sequence analysis; cluster analyses were performed on the 0 to 12 month and 13 to 24 month periods. Age, Charlson score, and duration of androgen deprivation therapy (ADT) were obtained for each cluster in the first year of follow-up.. Patients with only 1 treatment line accounted for 52%. In the 0 to 12 month sequence analysis, the main clusters among ABI/ENZ new users involved patients who continued the initial treatment (54% of 65% respectively) and discontinued active treatment (14.5% for both). Less than 2 years exposure to ADT prior to ABI/ENZ initiation was frequently observed for noncontrolled mCRPC, as shown in the death and switch from ABI/ENZ to docetaxel clusters. The clusters for a switch ABI/ENZ to ENZ/ABI involved 6% to 11% of the patients.. Our study suggested fairly similar patterns between ABI and ENZ initiation. The cluster of patients with active treatment discontinuation needs to be further investigated, as well as factors influencing therapeutic choice. Better understanding for the use of second-generation hormone therapy in mCRPC in real life, could improve its implementation by clinicians in the early stages of prostate cancer.

Topics: Abiraterone Acetate; Androgen Antagonists; Humans; Male; Nitriles; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Abiraterone is a first-in-class inhibitor of cytochrome P450 17A1 (CYP17A1), and its pharmacokinetic (PK) profile is susceptible to intrinsic and extrinsic variabilities. Potential associations between abiraterone concentrations and pharmacodynamic consequences in prostate cancer may demand further dosage optimization to balance therapeutic outcomes. Consequently, we aim to develop a physiologically based pharmacokinetic (PBPK) model for abiraterone via a middle-out approach to prospectively interrogate the untested, albeit clinically relevant, scenarios.. To characterize in vivo hydrolysis of prodrug abiraterone acetate (AA) and supersaturation of abiraterone, in vitro aqueous solubility data, biorelevant measurements, and supersaturation and precipitation parameters were utilized for mechanistic absorption simulation. CYP3A4-mediated N-oxidation and sulfotransferase 2A1-catalyzed sulfation of abiraterone were subsequently quantified in human liver subcellular systems. Iterative PBPK model refinement involved evaluation of potential organic anion transporting polypeptide (OATP)-mediated abiraterone uptake in transfected cells in the absence and presence of albumin.. The developed PBPK model recapitulated the duodenal concentration-time profile of both AA and abiraterone after simulated AA administration. Our findings established abiraterone as a substrate of hepatic OATP1B3 to recapitulate its unbound metabolic intrinsic clearance. Further consideration of a transporter-induced protein-binding shift established accurate translational scaling factors and extrapolated the sinusoidal uptake process. Subsequent simulations effectively predicted the PK of abiraterone upon single and multiple dosing.. Our systematic development of the abiraterone PBPK model has demonstrated its application for the prospective interrogation of the individual or combined influences of potential interindividual variabilities influencing the systemic exposure of abiraterone.

Topics: Abiraterone Acetate; Androstenes; Humans; Kinetics; Liver; Male; Models, Biological; Prospective Studies

Combining abiraterone (Abi) with androgen deprivation therapy (ADT) improves overall survival, compared to ADT only, in patients with metastatic castration-sensitive prostate cancer (mCSPC). In Japan, bicalutamide (Bica) and ADT (combined androgen blockade: CAB) is frequently provided for mCSPC. Because these two treatments have not been compared, mCSPC patients who received either treatment were retrospectively analyzed.. Of 178 patients with LATITUDE high-risk mCSPC, 103 had received ADT plus upfront Abi (Abi group) and 75 had received ADT plus Bica (Bica group) in multiple institutions of the Tokai Urologic Oncology Research Seminar. Kaplan-Meir curves were used to retrospectively analyze survival and cancer recurrence. Univariate and multivariate Cox regression analyses identified potential prognostic factors for progression-free survival (PFS).. Significant differences in major clinicopathological characteristics between the two groups were not observed. The rate of castration-resistant development was higher in the Bica compared to Abi group (50.6 vs. 25.2%, p < 0.001). The median PFS in the Bica group was 13.6 months {95% confidence interval [CI] 9.2-22.2}; however, in the Abi group, PFS did not reach the median {95% CI 18.5-not assessed [NA]; p < 0.001}. Time to second progression for the Abi group was superior (p = 0.07). Univariate and multivariate analyses revealed Gleason pattern 5, high alkaline phosphatase levels, and conventional CAB using Bica as significant prognostic factors for short PFS.. In patients with LATITUDE high-risk mCSPC, upfront use of Abi combined with ADT resulted in favorable prognostic outcomes compared with conventional ADT with Bica.

Topics: Abiraterone Acetate; Androgen Antagonists; Androgens; Androstenes; Anilides; Antineoplastic Combined Chemotherapy Protocols; Humans; Japan; Male; Neoplasm Recurrence, Local; Nitriles; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Tosyl Compounds

Spironolactone when combined with abiraterone in metastatic castration-resistant prostate cancer (mCRPC) may theoretically exert androgenic properties, thereby compromising the therapeutic effectiveness of abiraterone.. Two patients with a medical history of cardiovascular disease and mCRPC combined spironolactone within the course of abiraterone regimen. The abiraterone-spironolactone interaction was identified using the Lexicomp® interaction tool (classified as risk C).. Spironolactone treatment was maintained as it was considered beneficial due to the cardiac condition. The prostate-specific antigen (PSA) levels started to rise when these two drugs were used together. Eventually, tumour progression was observed.. There is increasing evidence that spironolactone behaves as a selective androgen receptor modulator. Strategies to overcome abiraterone-spironolactone interaction could involve the use of eplerenone, although this drug is also controversial. The best strategy should imply a multidisciplinary evaluation by cardiologists and oncologists.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Spironolactone; Treatment Outcome

The overall survival (OS) of metastatic castration-resistant prostate cancer (mCRPC) patients has improved since 2011 with the use of novel hormonal agents (NHAs). The incidence of brain metastases (mets) has been reported to increase since 2004 with the use of docetaxel, but not the incidence of visceral mets. Our objective was to study whether the use of NHAs increases the risk of developing visceral or brain mets (VBMs).. mCRPC patients with mets limited to bone (bmCRPC), treated at Tours University Hospital between 2007 and 2015, were included retrospectively. The primary endpoint was to determine whether treatment with NHAs was associated with an increased incidence of VBMs. Secondary endpoints included the search for putative predictive factors to develop VBMs.. On 187 bmCRPC patients included, 65 developed VBMs. VBM incidence increased in bmCRPC patients alive after 2011, compared to patients who died before (39.7 vs. 24.6%, P = .04). Meanwhile, their median OS increased from 16.3 months to 28.5 months (P = .01). The longer was the treatment with NHAs, the lower was the risk of VBMs (HR = 0.96, 95% CI [0.94; 0.99]), whereas age < 70 years (HR = 3.33, 95% CI [1.50; 7.40]) and low PSA level at diagnosis (HR = 1.58, 95% CI [1.16; 2.15]) increased this risk.. Though retrospective, our results showed an increased incidence of VBMs in bmCRPC patients after 2011. However, this was not associated with NHA exposure duration. The role of NHA exposure remains unclear and needs further investigation.

Topics: Abiraterone Acetate; Aged; Androstenes; Benzamides; Brain Neoplasms; Docetaxel; Humans; Male; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

To investigate the prognostic value and potential therapeutic target of the baseline serum hormones in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone.. This retrospective study was performed in patients with mCRPC receiving abiraterone acetate (AA) from July 2016 to September 2020. Patients who had serum hormone tests within 2 weeks before AA treatment were included. Univariate analysis and Cox regression were performed to evaluate the correlation of sex hormones with progression-free survival (PFS) and overall survival (OS). Prolactin (PRL) expression in the clinical specimens was evaluated by immunohistochemistry. Bone metastases were quantified by automated Bone Scan Index (aBSI).. The study included 61 patients with a median follow-up of 19.0 months. Patients with lower baseline PRL levels (median) responded better to AA than those with higher baseline PRL levels as indicated by prostate-specific antigen (PSA) reduction (PSA90, 66.7% vs. 25.8%, p = 0.001), PFS (19.6 vs. 7.9 months), and OS (52.8 vs. 19.2 months). Cox regression adjusted for clinical factors also confirmed that baseline PRL level was an independent predictive factor for PFS (hazard ratio = 1.096, p = 0.007). Prostatic PRL expression increased as the disease progressed. PRL expression was also detected in biopsy samples from bone metastasis but not in normal bone tissue, and the serum PRL levels were positively correlated with aBSIs (r = 0.28, p = 0.037).. Serum PRL levels are predictive of response to AA in patients with mCRPC. Serum PRL levels are positively correlated with the volume of metastatic bone disease.

Topics: Abiraterone Acetate; Androstenes; Humans; Male; Prolactin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Skeletal-related events (SREs) from bone metastases disease carry significant morbidity in men with metastatic castration resistant prostate cancer (mCRPC). The differential risk of SREs among patients receiving abiraterone acetate (AA) or enzalutamide (ENZ) is unknown.. To compare the risk of SREs among men with mCRPC receiving AA or ENZ, a retrospective cohort study using the SEER-Medicare Linked Database was conducted. Men with prostate cancer aged ≥65 years at first AA or ENZ prescription (index date) from 2011 to 2015 were identified. Patients were followed until the earliest occurrence of SRE, death, Medicare disenrollment, or December 31, 2016. The primary outcome was a composite endpoint of SRE (pathologic fracture, spinal cord compression, or surgery or radiation to bone) after the index date. Multivariable logistic regressions including key demographic and clinical covariates with death as a competing risk were conducted.. Overall, 5,856 patients were identified (4,207 received AA and 1,649 received ENZ). Median age was 76.5 years (IQR 71.4-82.3), 4,557 (77.8%) were White, 1,112 (19.2%) had recent chemotherapy, and 2,730 (46.6%) had recent zoledronic acid or denosumab. Eight-hundred and thirty-seven (14.3%) patients had ≥1 SRE after index date. In multivariable analyses, there was no difference in SRE risk based on AA and ENZ (HR=0.99 for ENZ, 95%CI 0.84-1.16, P=0.890). Denosumab was associated with lower SRE risk (HR=0.75, 95%CI 0.64-0.88, P=0.001).. In this large cohort of men with mCRPC, there was no difference in risk of SRE between AA and ENZ. Decision-making should be informed by prior therapies, comorbidities, toxicity profiles, and patient preferences. Denosumab has evidence of benefit in preventing SREs in this real-world population.

Topics: Abiraterone Acetate; Aged; Androstenes; Benzamides; Denosumab; Humans; Male; Medicare; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome; United States

Abiraterone acetate and enzalutamide are commonly employed in prostate cancer therapy in an interchangeable manner. These drugs are highly efficacious in androgen antagonism to improve patient outcomes, but they also carry noteworthy risk of adverse effects. Common toxicities vary amongst the two drugs and may have differential interactions with patient co-morbidities, but these patterns are unclear as co-morbidities typically serve as exclusion criteria in clinical trials. Hence, there is no existing guidance on how clinicians may tailor treatment based on patient-specific factors. Analysis of differential patient outcomes between these two drugs can inform future systematic reviews, new clinical studies, and clinical decision making.. The framework for this methodology was informed by the Joanna Briggs Institute methodology for scoping reviews. Title and abstract screening will be performed by two independent researchers to create an initial study inventory. This will be followed by full-text screening for study inclusion. Population-based studies describing patient outcomes, common toxicities, and associations with patient co-morbidities following abiraterone or enzalutamide therapy will be included. After data is extracted, it will be summarized for presentation.. The findings of this scoping review will be published in a peer-reviewed journal. The results will be used to inform future studies on patient-specific factors informing treatment choice between abiraterone and enzalutamide for castration-resistant prostate cancer. All data are from published openly accessible sources, and therefore, no ethical clearance is necessary. The protocol is also registered at https://doi.org/10.6084/m9.figshare.19149227.

Topics: Abiraterone Acetate; Androstenes; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Review Literature as Topic; Treatment Outcome

Metastatic castration-resistant prostate cancer (mCRPC) has a poor prognosis. Abiraterone acetate (AA), enzalutamide, and chemotherapy are first-line treatments for patients with mCRPC. This study examined prognostic factors for AA response in the form of prostate-specific antigen (PSA) kinetics throughout androgen-deprivation therapy (ADT) in chemonaïve patients with mCRPC.. We retrospectively included data from 34 chemonaïve patients with mCRPC who had received AA at some point between January 2017 and December 2018. We separated patients into two study arms according to the decrease in PSA percentages after use of AA for 3 months. We correlated PSA kinetics parameters with response and compared the two study groups with respect to PSA kinetics.. The patients' median age was 77 years. In the total group of patients, 64% had a response to AA, whereas 35% did not. The ratio of the PSA level at nadir to the level during ADT was significantly higher in the AA-sensitive group (19.78 vs. 1.03, p=0.019).. Patients who experienced a dramatic change in PSA level during ADT were more likely to be resistant to AA after progression to mCRPC. Chemotherapy rather than AA might be more suitable as a first-line treatment for these patients.

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Androgens; Androstenes; Humans; Kinetics; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

We identified resistance mechanisms to abiraterone acetate/prednisone (AA/P) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the Prostate Cancer Medically Optimized Genome-Enhanced Therapy (PROMOTE) study.. We analyzed whole-exome sequencing (WES) and RNA-sequencing data from 83 patients with metastatic biopsies before (V1) and after 12 weeks of AA/P treatment (V2). Resistance was determined by time to treatment change (TTTC).. At V2, 18 and 11 of 58 patients had either short-term (median 3.6 months; range 1.4-4.5) or long-term (median 29 months; range 23.5-41.7) responses, respectively. Nonresponders had low expression of TGFBR3 and increased activation of the Wnt pathway, cell cycle, upregulation of AR variants, both pre- and posttreatment, with further deletion of AR inhibitor CDK11B posttreatment. Deletion of androgen processing genes, HSD17B11, CYP19A1 were observed in nonresponders posttreatment. Genes involved in cell cycle, DNA repair, Wnt-signaling, and Aurora kinase pathways were differentially expressed between the responder and non-responder at V2. Activation of Wnt signaling in nonresponder and deactivation of MYC or its target genes in responders was detected via SCN loss, somatic mutations, and transcriptomics. Upregulation of genes in the AURKA pathway are consistent with the activation of MYC regulated genes in nonresponders. Several genes in the AKT1 axis had increased mutation rate in nonresponders. We also found evidence of resistance via PDCD1 overexpression in responders.. Finally, we identified candidates drugs to reverse AA/P resistance: topoisomerase inhibitors and drugs targeting the cell cycle via the MYC/AURKA/AURKB/TOP2A and/or PI3K_AKT_MTOR pathways.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Aurora Kinase A; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant

Despite advances and introduction of new therapies in the last decade, metastatic castration-resistant prostate cancer (mCRPC) has a poor prognosis. The development of androgen axis-targeted therapies such as abiraterone acetate, enzalutamide and darolutamide can prolong survival in mCPRC; however, resistance remains a barrier to prolonged response, necessitating exploration into resistance mechanisms and locoregional therapies. Here, we describe a patient with mCRPC that was progressing on abiraterone acetate. He was also found to have primary hyperaldosteronism from a functional adrenal adenoma, and thus he had a partial adrenalectomy to remove this tumour. Pathology confirmed an aldosterone-producing adrenal adenoma. After his adrenalectomy, he had a sharp decline in both his PSA (prostate specific antigen) and testosterone levels, and he enjoyed a year-long period of remission after his adrenalectomy. We propose several explanations for his response, the most likely being that his adenoma was producing both aldosterone and androgens. This is a unique case of mCRPC responding to partial adrenalectomy from a functional adrenal adenoma, and it raises insights that warrant further investigation into underlying mechanisms of resistance to androgen-targeted therapies.

Topics: Abiraterone Acetate; Adrenalectomy; Aldosterone; Androgens; Androstenes; Humans; Male; Nitriles; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Testosterone; Treatment Outcome

BACKGROUND Prostate cancer growth is primarily driven by testosterone and 5a-dihydrotestosterone. Abiraterone is an irreversible inhibitor of CYP17, and CYP17 inhibition is a required step in testosterone biosynthesis. Previous studies have shown that abiraterone trough levels are predictive of prostate-specific antigen (PSA) response in metastatic castrate-resistant prostate cancer (mCRPC). It has not been demonstrated if this association exists for patients with metastatic hormone-sensitive prostate cancer (mHSPC). In this study, we aimed to explore the correlation and association between abiraterone trough levels and PSA levels in patients with mHSPC. MATERIAL AND METHODS This was a single-center, prospective, observational study of patients with mHSPC being treated with abiraterone acetate (AA) 1000 mg once daily. Abiraterone trough levels (22-26 h after drug administration) were drawn at 1, 3, and 7 months after treatment initiation. RESULTS Thirteen patients with mHSPC were enrolled, and complete pharmacokinetic data were available for 8 patients. The mean trough levels at 1 month, 3 months, and 7 months were 34.49 ng/mL (3.36-240.46), 13.82 ng/mL (2.91-29.96), and 15.7 ng/mL (3.58-26.86), respectively. The correlation between the 1-month abiraterone trough level and 1-month PSA level was 0.29 (P=0.38), between 3-month abiraterone trough and 3-month PSA was -0.61 (P=0.08), and between 7-month abiraterone trough and 7-month PSA was -0.31 (P=0.54). CONCLUSIONS This study demonstrated a trend toward a negative correlation between 3-month abiraterone trough levels and PSA levels, but the correlation was not statistically significant. A study with a larger prospective sample size is needed to validate these findings.

Topics: Abiraterone Acetate; Androstenes; Dihydrotestosterone; Humans; Male; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Steroid 17-alpha-Hydroxylase; Testosterone; Treatment Outcome

Two pivotal randomized controlled trials (RCTs) demonstrate that abiraterone acetate + prednisone (AAP) combined with androgen deprivation therapy (ADT) significantly extends the survival of men with metastatic hormone-sensitive prostate cancer (mHSPC) compared with ADT alone. Their subgroup analyses indicate that the survival benefit is significant for younger men but not older men. We aimed to assess whether publication of the RCTs was associated with differential real-world AAP utilization by age groups.. Using TriNetX electronic medical records data collected from 43 healthcare organizations across the United States, we performed a difference-in-differences event study among men with newly diagnosed mHSPC observed from June 2014 to June 2019. Eligible subjects were identified based on a comprehensive published algorithm. We analyzed the change in utilization rate of AAP before versus after publication of the RCTs among men aged <70 years versus ≥70 years, adjusting for demographic factors and clinical conditions.. Our study included 6,888 men with newly diagnosed mHSPC with 12,738 observations, of whom 46% were aged <70 years. The prepublication trends of AAP utilization were similar between the age groups, whereas publication of the RCTs was associated with a 3.5% higher adjusted uptake rate of AAP among younger men (95% CI, 1.2%-5.8%) relative to older men. This estimate reflects an uptake rate nearly 3 times higher than would have been expected had younger men followed the same utilization trends as older men. The estimates remained consistent throughout the postpublication period.. Our study suggests that publication of the RCTs was associated with faster uptake of AAP among younger versus older men with newly diagnosed mHSPC, despite the absence of clinical guidance for differential treatment selection. This finding highlights the importance of confirmatory studies among older men, considering the uncertainties of subgroup analyses in RCTs.

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Androgens; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Prednisone; Prostatic Neoplasms

To assess whether the exposure-response relation for abiraterone is different in pre-chemotherapy patients compared to post-chemotherapy patients with metastatic castration-resistant prostate cancer (mCRPC).. Data were collected from three clinical studies in mCRPC patients treated with abiraterone acetate. Cox regression analysis was used to determine the relation between abiraterone exposure and survival (progression-free survival [PFS] and overall survival [OS]). An interaction term was used to test whether chemotherapy pretreatment was an effect modifier. To investigate the effect of the previously defined exposure threshold of 8.4 ng/mL on survival, Kaplan-Meier analysis was used.. In total, 98 mCRPC patients were included, of which 78 were pre-chemotherapy and 20 were post-chemotherapy patients. Chemotherapy pretreatment in mCRPC setting appears to be an effect modifier. In pre-chemotherapy patients, no significant association between abiraterone exposure and survival was observed (HR 0.68 [95% CI 0.42-1.10], P = .12 and HR 0.85 [95% CI 0.46-1.60], P = .61, PFS and OS, respectively) and no longer survival was seen for patients with an abiraterone exposure above the predefined threshold. In contrast, a significant association was seen in post-chemotherapy patients (HR 0.30 [95% CI 0.12-0.74], P = .01 and HR 0.38 [95% CI 0.18-0.82] P = .01, PFS and OS, respectively), with an increased survival when exposed above this threshold.. Chemotherapy pretreatment in mCRPC setting modifies the abiraterone exposure-response relation. No relation between abiraterone exposure and survival was seen for pre-chemotherapy patients. Therefore, potentially lower doses can be used in this setting to prevent overtreatment and reduce financial toxicity.

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Abiraterone and enzalutamide, androgen receptor pathway inhibitors (ARPI) for the treatment of metastatic castration-resistant prostate cancer (mCRPC), are at high risk of potential drug interactions (PDIs). We aimed to describe PDIs and their management, and triggered adverse events (AEs) in clinical practice.. We conducted a cross-sectional study in mCRPC patients who started treatment with abiraterone or enzalutamide in a university hospital between August 1st, 2016 and July 31st, 2020. Lexicomp® was used to identify and analyze PDIs, and the clinical records to assess their management and the occurrence of AEs.. We included 173 patients: 36.8% and 93.0% treated with abiraterone and enzalutamide, respectively, had at least 1 PDI. Globally, 6.3% of PDIs had X-risk (contraindication due to high probability of AE). Treatment was modified in 9.2% of patients and 9.8% suffered AEs due to PDIs. Factors associated with a higher risk of PDIs were polypharmacy (OR= 41.0, p  0.003) and treatment with enzalutamide (OR= 128.26, p < 0.001).. At least two-thirds of patients treated with ARPI suffered a PDI. Overall, abiraterone would have a more favorable PDI profile. Knowing these interaction profiles may be helpful to develop a more efficient therapeutic follow-up and to select the safest treatment.

Topics: Abiraterone Acetate; Androstenes; Benzamides; Cross-Sectional Studies; Drug Interactions; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Real-world evidence suggest that next generation hormonal agents (NHAs) abiraterone and enzalutamide were preferred as first-line (1L) therapies for metastatic castration-resistant prostate cancer (mCRPC) in the United States (US) pre-2020, with chemotherapies, particularly docetaxel, being preferred in subsequent lines (2L+). This real-world study described patient characteristics, treatment patterns, time on treatment (ToT) and overall survival (OS) among patients with mCRPC treated with 2L and 3L docetaxel post-NHAs in the mCRPC setting.. Adults with confirmed adenocarcinoma mCRPC diagnosis and ≥1 month of follow-up post-diagnosis were selected from a US electronic health record-derived oncology de-identified database (01/2013-03/2019). Based on the observed line of therapy sequences post-mCRPC diagnosis, patients who received NHA therapy in 1L and docetaxel therapy in 2L were included in the 2L docetaxel cohort, and patients who received NHA therapy in both 1L and 2L and docetaxel therapy in 3L were included in the 3L docetaxel cohort. ToT and OS were evaluated using Kaplan-Meier analysis.. Among 5,213 patients with mCRPC, 278 and 166 were included in the 2L and the 3L docetaxel cohorts, respectively (median age: 73 years for both cohorts). ADT was the most used class of medication pre-mCRPC (>75%). For the 2L cohort, the most common sequence post-mCRPC was 1L abiraterone → 2L docetaxel (52.5%), while the median ToT and OS post-2L start were 4.1 and 10.5 months, respectively; for the 3L cohort, the most common sequence post-mCRPC was 1L abiraterone → 2L enzalutamide → 3L docetaxel (67.5%), while the median ToT and OS post-3L start were 3.8 and 8.7 months, respectively.. This real-world study provides novel data on patients treated with docetaxel post-NHAs in a mCRPC setting and highlights the critical unmet need for developing more effective treatment options in this population.

Topics: Abiraterone Acetate; Adult; Aged; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Abiraterone acetate for metastatic castration-resistant prostate cancer is an acetylated prodrug to be hydrolyzed to abiraterone. Abiraterone acetate is known to be hydrolyzed by pancreatic cholesterol esterase secreted into the intestinal lumen. This study aimed to investigate the possibility that arylacetamide deacetylase (AADAC) expressed in enterocytes contributes to the hydrolysis of abiraterone acetate based on its substrate preference.. Abiraterone acetate hydrolase activity was measured using human intestinal (HIM) and liver microsomes (HLM) as well as recombinant AADAC. Correlation analysis between activity and AADAC expression was performed in 14 individual HIMs. The in vivo pharmacokinetics of abiraterone acetate was examined using wild-type and Aadac knockout mice administered abiraterone acetate with or without orlistat, a pancreatic cholesterol esterase inhibitor.. Recombinant AADAC showed abiraterone acetate hydrolase activity with similar K. AADAC is responsible for the hydrolysis of abiraterone acetate in the intestine and liver, suggesting that concomitant use of abiraterone acetate and drugs potently inhibiting AADAC should be avoided.

Topics: Abiraterone Acetate; Adolescent; Adult; Aged; Androstenes; Animals; Carboxylesterase; Carboxylic Ester Hydrolases; Female; Humans; Hydrolysis; Inhibitory Concentration 50; Intestines; Kinetics; Male; Mice, Knockout; Microsomes, Liver; Middle Aged; Orlistat; Recombinant Proteins

The human adrenal is the dominant source of androgens in castration-resistant prostate cancer (CRPC) and classic 21-hydroxylase deficiency (21OHD). Abiraterone, derived from the prodrug abiraterone acetate (AA), inhibits the activity of cytochrome P450 17-hydroxylase/17,20-lyase (CYP17A1), the enzyme required for all androgen biosynthesis. AA treatment effectively lowers testosterone and androstenedione in 21OHD and CRPC patients. The 11-oxygenated androgens are major adrenal-derived androgens, yet little is known regarding the effects of AA administration on 11-oxygenated androgens.. To test the hypothesis that AA therapy decreases 11-oxygenated androgens.. Samples were obtained from 21OHD or CRPC participants in AA or AA plus prednisone (AAP)-treatment studies, respectively.. We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure the 11-oxygenated androgens, 11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone, and 11-ketotestosterone, in plasma or serum samples from six 21OHD and six CRPC patients before and after treatment with AA or AAP, respectively.. In CRPC patients, administration of AAP (1000 mg/day AA with prednisone and medical castration) lowered all four 11-oxygenated androgens to below the lower limits of quantitation (<0.1-0.3 nmol/L), equivalent to 64-94% reductions from baseline. In 21OHD patients, administration of AA (100-250 mg/day for 6 days) reduced all 11-oxygenated androgens by on average 56-77% from baseline.. We conclude that AA and AAP therapies markedly reduce the production of the adrenal-derived 11-oxygenated androgens, both in patients with high (21OHD) or normal (CRPC) 11-oxygenated androgens at baseline, respectively. Reduction of 11-oxygenated androgens is an important aspect of AA and AAP pharmacology.

Topics: Abiraterone Acetate; Adrenal Hyperplasia, Congenital; Adult; Androgens; Androstenes; Chromatography, Liquid; Cytochrome P-450 Enzyme Inhibitors; Drug Therapy, Combination; Humans; Male; Prednisone; Prostatic Neoplasms; Tandem Mass Spectrometry; Testosterone

Prostate cancer (PC) is the second leading cause of cancer death among US men and accounts for considerable healthcare expenditures. We evaluated economic outcomes in men with chemotherapy-naïve metastatic castration-resistant PC (mCRPC) treated with enzalutamide or abiraterone acetate plus prednisone (abiraterone).. We performed a retrospective analysis on 3174 men (18 years or older) utilizing the Veterans Health Administration (VHA) database from 1 April 2014 to 31 March 2018. Men with mCRPC were included if they had at least one pharmacy claim for enzalutamide or abiraterone (first claim date = index date) following surgical or medical castration, had no chemotherapy treatment within 12 months prior to the index date, and had continuous VHA enrollment for at least 12 months pre- and post-index date. Men were followed until death, disenrollment, or end of study and were 1:1 propensity score matched (PSM). All-cause and PC-related resource use and costs per patient per month (PPPM) in the 12 months post index were compared between matched cohorts.. We identified 1229 men with mCRPC prescribed enzalutamide and 1945 prescribed abiraterone with mean ages of 74 and 73 years, respectively. After PSM, each cohort had 1160 patients. The enzalutamide cohort had fewer all-cause (2.51 vs 2.86; p < 0.0001) and PC-related outpatient visits (0.86 vs 1.03; p < 0.0001), with corresponding lower all-cause ($2588 vs $3115; p < 0.0001) and PC-related ($1356 vs $1775; p < 0.0001) PPPM outpatient costs compared with the abiraterone cohort. All-cause total costs (medical and pharmacy) PPPM ($8085 vs $9092; p = 0.0002) and PC-related total costs PPPM ($6321 vs $7280; p < 0.0001) were significantly lower in the enzalutamide cohort compared with the abiraterone cohort.. Enzalutamide-treated men with chemotherapy-naïve mCRPC had significantly lower resource utilization and healthcare costs compared with abiraterone-treated men.. Prostate cancer (PC) is the second leading cause of death among men with cancer in the USA. Healthcare costs associated with PC, including hospitalizations, outpatient visits, and medications prescribed to treat adverse effects, depend on the severity of the disease and intensity of treatment, but are generally very high. Enzalutamide and abiraterone acetate with prednisone (abiraterone) are both approved treatments for men with PC that does not respond to treatments that reduce the male hormone testosterone, known as castration-resistant PC (CRPC). These drugs are associated with varying treatment duration and different adverse effects, and therefore could result in differences in the use of healthcare resources and overall cost of treatment. Here we evaluated the healthcare resource utilization (HCRU), which was calculated as the average number of healthcare encounters, including inpatient stays, outpatient visits, and pharmacy visits, and length of inpatient stays, and treatment costs associated with use of enzalutamide or abiraterone by men with metastatic CRPC (mCRPC), who had not received prior chemotherapy in the Veterans Health Administration. We found that men with chemotherapy-naïve mCRPC treated with enzalutamide used less healthcare resources and incurred lower total healthcare costs than men treated with abiraterone. On average, all-cause total healthcare costs were $1007 per patient per month lower and PC-related total healthcare costs were $959 per patient per month lower for patients treated with enzalutamide than those treated with abiraterone. These results support the hypothesis that the long-term HCRU and costs of enzalutamide may be lower compared with abiraterone.

Topics: Abiraterone Acetate; Adult; Aged; Androstenes; Antineoplastic Agents, Hormonal; Benzamides; Cohort Studies; Drug Administration Schedule; Health Care Costs; Humans; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prednisone; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies

It is projected that approximately 50,000 new cases of prostate cancer will be diagnosed in 2020 in India. Survival has improved because of the development of effective drugs such as abiraterone acetate, but universal accessibility to treatment is not always possible because of cost constraints in lower- and middle-income countries. Recently, the National Comprehensive Cancer Network (NCCN) has included low-dose abiraterone (250 mg/day) with food as an alternative treatment option to full-dose abiraterone (1,000 mg/day) fasting.. The Science and Cost Cancer Consortium conducted a survey to evaluate the use of abiraterone in India and the opinions of medical oncologists about using low-dose treatment. Modeling was used to estimate potential financial benefits to individual patients and to estimate overall costs of health care in India if low-dose abiraterone is prescribed.. Of 251 Indian medical oncologists who were invited to participate in the survey, 125 provided their e-mail address and received the survey; 118 responded (47% of the total). Of these, 25% were not aware of the recent NCCN recommendation, 55% were already prescribing low-dose abiraterone when resources were limited, 7% had already changed their practice, and 29% agreed to switch to a universal practice of using low-dose abiraterone with food; 9% of practitioners would not use low-dose abiraterone. Estimated mean per patient savings was US$3,640, with annual savings of US$182 million in India.. Use of lower-dose abiraterone would increase access to treatment in India and globally and lead to large cost savings.

Topics: Abiraterone Acetate; Androstenes; Humans; India; Male; Prostatic Neoplasms

In men with castration-sensitive prostate cancer (CSPC), the HSD3B1 c.1245A>C variant has been reported to be associated with shorter responses to first-line androgen-deprivation therapy (ADT). Here, we evaluated the association between the inherited HSD3B1 c.1245A>C variant and outcomes from metastatic castration-resistant prostate cancer (mCRPC) after first-line treatment with abiraterone (Abi) or enzalutamide (Enza).. Patients with mCRPC (n = 266) were enrolled from two centers at the time of starting first-line Abi/Enza. Outcomes after Abi/Enza included best prostate-specific antigen (PSA) response, treatment duration, and overall survival (OS). Outcomes after first-line ADT were determined retrospectively, and included treatment duration and OS. As was prespecified, we compared patients with the homozygous variant HSD3B1 genotype (CC genotype) versus the combined group with the heterozygous (AC) and homozygous wild-type (AA) genotypes.. Among the 266 patients, 22 (8.3%) were homozygous for the HSD3B1 variant (CC). The CC genotype had no association with PSA response rate; the median Abi/Enza treatment duration was 7.1 months for the CC group and 10.3 months for the AA/AC group (log rank P = 0.34). Patients with the CC genotype had significantly worse OS, with median survival at 23.6 months for the CC group and 30.7 months for the AA/AC group (log rank P = 0.02). In multivariable analysis adjusting for age, Gleason score, PSA, prior chemotherapy, and M1 disease, the association between the CC genotype and OS remained significant (hazard ratio 1.78, 95% confidence interval 1.03-3.07, P = 0.04). Poor outcome after first-line ADT in the CC group was also observed when evaluating retrospective ADT duration data for the same combined cohort.. In this large two-center study evaluating the HSD3B1 c.1245 genotype and outcomes after first-line Abi/Enza, homozygous variant (CC) HSD3B1 genotype was associated with worse outcomes. Novel therapeutic strategies are needed to enable treatment selection based on this genetic marker.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstenes; Benzamides; Genotype; Germ Cells; Humans; Male; Multienzyme Complexes; Nitriles; Phenylthiohydantoin; Progesterone Reductase; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Steroid Isomerases; Treatment Outcome

Topics: Abiraterone Acetate; Androstenes; Humans; Male; Prostatic Neoplasms

Topics: Abiraterone Acetate; Androstenes; Humans; Male; Metformin; Pilot Projects; Prostatic Neoplasms, Castration-Resistant

Results from the ERA 223 trial of abiraterone combined with radium-223 among men with chemotherapy-naïve castration-resistant prostate cancer and bone metastases show no improvement in survival free from symptomatic skeletal events. We hypothesize that this finding might be attributable to bone loss induced by the concomitantly administered prednisone.

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Fractures, Bone; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant; Radium; Treatment Outcome

Topics: Abiraterone Acetate; Androstenes; Artifacts; Clinical Laboratory Techniques; Humans; Immunoassay; Male; Prostatic Neoplasms, Castration-Resistant; Testosterone

Topics: Abiraterone Acetate; Androstenes; Double-Blind Method; Humans; Male; Prednisolone; Prednisone; Prostatic Neoplasms, Castration-Resistant; Radium

Topics: Abiraterone Acetate; Androstenes; Double-Blind Method; Humans; Male; Prednisolone; Prednisone; Prostatic Neoplasms, Castration-Resistant; Radium

This study examined the inter- and intra-patient variability in pharmacokinetics of AA and its metabolites abiraterone and Δ(4)-abiraterone (D4A), and potential contributing factors.. AA administered daily for ≥4 weeks concurrently with androgen deprivation therapy (ADT) for mCRPC were included. Pharmacokinetic evaluation was performed at two consecutive visits at least 4 weeks apart. Plasma samples were collected 24 h after last dose of AA to obtain drug trough level (DTL) of two active metabolites, abiraterone and D4A.. 39 plasma samples were obtained from 22 patients, with 17 patients had repeat DTL measurement. Considerable inter-patient variability in DTL was seen, with initial DTL for abiraterone ranging between 1.5 and 25.4 ng/ml (CV 61%) and for D4A between 0.2 and 2.5 ng/ml (CV 61%). Intra-patient variability in DTL for abiraterone varied between 0.85 and 336% and for D4A between 1.14 and 199%. There was no increase in AA exposure with use of dexamethasone (n = 5; DTL 13.9) compared with prednisone (n = 17; DTL 11.0 p = 0.5), dosing in fasted state (n = 13, DTL 12.1) compared to dosing in fed state (n = 9; DTL 11.1, p = 0.8), or chemotherapy-exposed (n = 10; DTL 8.9) compared to chemotherapy naïve (n = 12; DTL 14.0, p = 0.1).. Our cohort demonstrated high inter- and intra-patient variability in both abiraterone and D4A with fixed dosing of AA, with no effect from choice of corticosteroids, prior use of chemotherapy, or dosing in fasting state. Monitoring DTL of AA may be necessary to minimise risk of patients being under-dosed and earlier development of resistance.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Fasting; Humans; Longitudinal Studies; Male; Middle Aged; Neoplasm Metastasis; Prednisone; Prospective Studies; Prostatic Neoplasms, Castration-Resistant

Topics: Abiraterone Acetate; Aged; Androstenes; Feasibility Studies; Humans; Liver Transplantation; Male; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Topics: Abiraterone Acetate; Androgen Antagonists; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Taxoids

Topics: Abiraterone Acetate; Androstenes; Cell Cycle; Cell Proliferation; Genome-Wide Association Study; Humans; Male; Prednisone; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Wnt Signaling Pathway

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant

Androgen deprivation therapy (ADT) has been the standard of care for the treatment of newly diagnosed metastatic prostate cancer for the past 70 years. Furthermore, adding docetaxel chemotherapy to ADT significantly improved patient survival, and thus became the new standard for patients with high volume disease. However, recent evidence has called this treatment strategy into question since a published study has shown that the drug abiraterone has a similar benefit to docetaxel in a similar patient population group but with less toxicity. The following article considers this key paper and its implications. Areas covered: In this key paper evaluation, the authors discuss the rational, trial design and results of the LATITUDE trial. Furthermore, the past and current standard of care of metastatic castrate-naïve prostate cancer (mCNPC) is discussed, while the authors also compare abiraterone and docetaxel in terms of benefit, safety profile, and affordability. Expert opinion: Abiraterone is highly effective and has an excellent safety profile for the treatment of metastatic castrate-naïve prostate cancer. It is the authors' opinion that it should now be considered the new standard of care.

Topics: Abiraterone Acetate; Androstenes; Anti-Inflammatory Agents; Docetaxel; Drug Therapy, Combination; Humans; Male; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms, Castration-Resistant; Taxoids

Topics: Abiraterone Acetate; Androstenes; Humans; Male; Prospective Studies; Prostatic Neoplasms, Castration-Resistant

Topics: Abiraterone Acetate; Androstenes; Humans; Male; Prospective Studies; Prostatic Neoplasms, Castration-Resistant

Topics: Abiraterone Acetate; Androstenes; Humans; Male; Prospective Studies; Prostatic Neoplasms, Castration-Resistant

Topics: Abiraterone Acetate; Androstenes; Humans; Male; Prospective Studies; Prostatic Neoplasms, Castration-Resistant

Topics: Abiraterone Acetate; Androstenes; Drug Monitoring; Humans; Male; Prospective Studies; Prostatic Neoplasms, Castration-Resistant

Topics: Abiraterone Acetate; Androstenes; Humans; Male; Prospective Studies; Prostatic Neoplasms, Castration-Resistant

Treatment of metastatic castration-resistant prostate cancer (mCRPC) has evolved significantly during the past decade, and the preferred combination and/or sequence of these treatments remains controversial. In this retrospective study, we explored clinical and pathologic factors that could predict response to consecutive treatment with enzalutamide (ENZA) after disease progression (PD) on abiraterone acetate and prednisone (AA/P).. Data were collected from 40 consecutive patients with mCRPC who were treated with ENZA without other interim therapy after progression on AA/P.. The median time from prostate cancer initial diagnosis to AA/P treatment was 6.2 (range, 0.9-16.3) years. The median prostate-specific antigen (PSA) progression-free survival (PSA-PFS) from treatment initiation was 8.5 months (95% confidence interval [CI], 7.1-10.1 months) and 2.3 months (95% CI, 1.8-3.4 months) on AA/P and ENZA, respectively. The median time to PD from treatment initiation was 9.7 months (95% CI, 7.1-12.4 months) and 3 months (95% CI, 2.3-4.1 months) on AA/P and ENZA, respectively. The correlations were weak between the best percent change in PSA on ENZA and time from diagnosis to AA/P initiation, best absolute or percentage change in PSA on AA/P, time to PSA progression or PD on AA/P. Patients with longer than the median duration of treatment with AA/P (11.73 months) had longer PSA-PFS on ENZA (median 2.8 vs. 1.9 months; P = .035).. In this retrospective analysis, we did not find any clinical or pathologic factors associated with response to ENZA administered consecutively after AA/P. Patients with longer than median AA/P treatment duration had longer PSA-PFS on ENZA. Further evaluations and validation are greatly needed.

Topics: Abiraterone Acetate; Aged; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Disease Progression; Drug Resistance, Neoplasm; Humans; Kallikreins; Kaplan-Meier Estimate; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prednisone; Progression-Free Survival; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Time Factors; Treatment Failure; Treatment Outcome

Abiraterone acetate plus prednisone is a standard treatment option for mCRPC. The phase II SWITCH trial showed that further prostate-specific antigen (PSA) responses can be obtained in a subset of patients when prednisone was switched to dexamethasone at progression. Here, we discuss the potential underlying mechanisms, including the activation of glucocorticoid receptors (GR) in progressive mCRPC and the implications for clinical practice.

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Glucocorticoids; Humans; Male; Pilot Projects; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Castration; Disease-Free Survival; Humans; Male; Neoplasm Metastasis; Prednisolone; Prednisone; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Taxoids

Topics: Abiraterone Acetate; Androstenes; Androstenols; Humans; Male; Prostatic Neoplasms; Treatment Outcome

Abiraterone acetate is a potent and irreversible inhibitor of cytochrome p450 17A1 that suppresses androgen synthesis. It is approved for chemotherapy-naive and docetaxel-treated patients with metastatic castration-resistant prostate cancer. We describe the protocol for use of abiraterone in metastatic castration-resistant prostate cancer chemotherapy naive patients has been implanted in our centre and we review the cases of those patients whose adverse effects have forced the discontinuation of treatment. The side effects fit the safety profile of abiraterone, speed of their appearance and severity indicate that you should perform a thorough follow-up of these patients especially in the early phases of treatment.

Topics: Abiraterone Acetate; Aged, 80 and over; Androstenes; Disease Progression; Docetaxel; Humans; Male; Middle Aged; Prostatic Neoplasms, Castration-Resistant; Safety-Based Drug Withdrawals; Taxoids; Time Factors; Treatment Outcome

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Humans; Male; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

Topics: Abiraterone Acetate; Androstenes; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant

Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis. Abiraterone is metabolized in patients to Δ(4)-abiraterone (D4A), which has even greater anti-tumour activity and is structurally similar to endogenous steroidal 5α-reductase substrates, such as testosterone. Here, we show that D4A is converted to at least three 5α-reduced and three 5β-reduced metabolites in human serum. The initial 5α-reduced metabolite, 3-keto-5α-abiraterone, is present at higher concentrations than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abiraterone and downstream metabolites were depleted by the addition of dutasteride, while D4A concentrations rose, showing that dutasteride effectively blocks production of a tumour-promoting metabolite and permits D4A accumulation. Furthermore, dutasteride did not deplete the three 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 5α-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy.

Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; 5-alpha Reductase Inhibitors; Abiraterone Acetate; Administration, Oral; Androgen Antagonists; Androgens; Androstenes; Animals; Cell Line, Tumor; Disease Progression; Dutasteride; Humans; Male; Mice; Oxidation-Reduction; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Xenograft Model Antitumor Assays

Topics: Abiraterone Acetate; Androstenes; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Substance Withdrawal Syndrome

Topics: Abiraterone Acetate; Androstenes; Humans; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen

Abiraterone acetate (AA) has demonstrated improved outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). However, data are lacking on the effect of AA on subsequent efficacy of enzalutamide or docetaxel.. We included men with mCRPC who received AA and subsequent enzalutamide or docetaxel by August 12, 2013. Patients were separated into 3 groups: group A, treated with AA then enzalutamide before chemotherapy; group B, treated with AA then docetaxel; and group C, treated with AA and enzalutamide after chemotherapy. The primary objective was to describe the response and overall survival with subsequent therapy.. There were 28 evaluable patients who received enzalutamide after AA (9 in group A and 19 in group C) and 13 patients who received docetaxel after AA (group B). Group A patients had more visceral disease and higher baseline prostate-specific antigen (PSA) levels, and group C men had a higher level of pain and multiple poor prognostic features. Median progression-free survival was 3.6, 5.1, and 2.8 months, respectively, and median overall survival was 8.5, not reached, and 9.6 months, respectively. A ≥ 50% PSA decline was achieved in 11%, 63%, and 5% of group A, B, and C patients, respectively. Radiographic or clinical progression as best response was noted in 55.5%, 30.8%, and 68.4% in each respective group.. In this chart review of consecutive men with progressive mCRPC after AA, we found modest activity for enzalutamide and docetaxel, with clear cross-resistance for AA and enzalutamide. These data might inform the complex treatment decisions after AA treatment.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androstenes; Antineoplastic Agents; Benzamides; Disease Progression; Disease-Free Survival; Docetaxel; Drug Resistance, Neoplasm; Humans; Kallikreins; Kaplan-Meier Estimate; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prednisone; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Radiography; Retrospective Studies; Taxoids; Treatment Outcome

Abiraterone acetate(AA)has been approved in more than 80 countries for the treatment of patients with metastatic castration-resistant prostate cancer(mCRPC). In July 2013, a marketing approval application for AA was submitted to the Japanese Ministry of Health, Labour, and Welfare. AA is a selective inhibitor of CYP17A1, a crucial enzyme for androgen biosynthesis. AA exerts its anti-tumor activity by directly inhibiting androgen production at all three sources, i. e., the testes, adrenal glands, and tumor itself. Data from international phase III studies and phase I and II studies in Japan have indicated that AA improves the overall survival and quality of life(QoL)of patients with mCRPC. Herein, we have summarized the development of AA and the results of important international and local clinical trials in Japan. In addition, the effect of food on AA bioavailability, concomitant steroid use, and liver function test abnormalities have been discussed regarding the appropriate use of AA.

Topics: Abiraterone Acetate; Androstadienes; Androstenes; Androstenols; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Enzyme Inhibitors; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Steroid 17-alpha-Hydroxylase

A novel spectrofluorimetric method to determine abiraterone acetate and its active metabolite, abiraterone was developed, based on the fact that fluorescence intensity of abiraterone acetate and abiraterone could be enhanced in β-cyclodextrin (β-CD) due to the formation of the inclusion complex. The inclusion interaction of β-CD and abiraterone acetate and the β-cyclodextrin sensitized spectrofluorimetry was examined. The various factors influencing fluorescence were discussed in details. The results showed that under the optimized conditions, the linear range of calibration curve for the determination of biraterone acetate and abiraterone was 0.20 ~ 6.0 μg/mL, and the detection limit (LOD) was 6.8 (r = 0.997) or 6.6 ng/mL (r = 0.996), respectively. No interference was observed from common co-existing substances or pharmaceutical excipient. The method was successfully applied to the analysis of abiraterone acetate in pharmaceutical formulation and abiraterone in human serum/urine.

Topics: Abiraterone Acetate; Androstadienes; Androstenes; Androstenols; beta-Cyclodextrins; Fluorescent Dyes; Healthy Volunteers; Humans; Hydrogen-Ion Concentration; Molecular Structure; Osmolar Concentration; Spectrometry, Fluorescence; Temperature; Time Factors

Medical or surgical castration for the treatment of prostatic cancers prevents androgen production by the testes, but not by the adrenals. Inhibition of the key enzyme for androgen biosynthesis, cytochrome P450(17) alpha, could prevent androgen production from both sources. The in vivo effects of 17-(3-pyridyl)androsta-5,16-dien-3 beta-ol (CB7598) and 17-(3-pyridyl)androsta-5,16-dien-3-one (CB7627), novel potent steroidal inhibitors of this enzyme, on WHT mice were compared with those of castration and two clinically active compounds, ketoconazole and flutamide. Flutamide and surgical castration caused significant reductions in the weights of the ventral prostate and seminal vesicles. CB7598, in its 3 beta-O-acetate form (CB7630), and CB7627 caused significant reductions in the weights of the ventral prostate, seminal vesicles, kidneys and testes when administered once daily for 2 weeks. Ketoconazole, given on the same schedule, caused no reductions. Plasma testosterone was reduced to < or = 0.1 nM by CB7630, despite a 3- to 4-fold increase in the plasma level of luteinizing hormone. Adrenal weights were unchanged following treatment with CB7630 or CB7627 but were markedly increased following ketoconazole, indicating no inhibition of corticosterone production by these steroidal compounds. These results indicate that CB7598, CB7630 or CB7627 may be useful in the treatment of hormone-dependent prostatic cancers.

Topics: Abiraterone Acetate; Adrenal Glands; Aldehyde-Lyases; Androgens; Androstadienes; Androstenes; Androstenols; Animals; Cytochrome P-450 Enzyme Inhibitors; Flutamide; Guinea Pigs; Ketoconazole; Kidney; Luteinizing Hormone; Male; Mice; Orchiectomy; Organ Size; Prostate; Seminal Vesicles; Steroid 17-alpha-Hydroxylase; Testis; Testosterone