Abiraterone Acetate In Men Research Articles

Serum Androgens as Predictive Biomarkers: Results From a Randomized Clinical Trial Comparing Enzalutamide and Abiraterone Acetate in Men With Metastatic Castration-Resistant Prostate Cancer

IntroductionThe purpose of this study was to investigate the association between baseline androgen concentrations and outcomes in men with metastatic castration-resistant prostate cancer (mCRPC) treated with first-line enzalutamide or abiraterone acetate plus prednisone (AAP). Materials and MethodsWe previously randomized men with mCRPC to enzalutamide or AAP to compare side-effects and measured androgen concentrations. In this post-hoc analysis, patients were grouped in quartiles (Q) based on their serum androgen values. Kaplan-Meier and Cox regression were used to analyze progression-free and overall survival for baseline androgen groups, treatment subgroups and their interaction. The trial was registered at clinicaltrialsregister.eu (2017-000099-27). ResultsEighty-four patients received enzalutamide and 85 AAP. Overall, higher (Q4) compared with lower (Q1) baseline serum testosterone was associated with longer progression-free survival (24.8 vs. 10.7 months, hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.33; 0.84) and overall survival (52.8 vs. 31.5 months, HR 0.49, 95% CI 0.28; 0.85). The risk reduction in death seemed to be treatment dependent (treatment subgroup interaction P = .04). For men in the AAP subgroup, the Q4 compared with Q1 group had a significant lower risk of death (HR 0.30, 95% CI 0.13; 0.73), while no difference was found for enzalutamide (HR 0.77, 95% CI 0.35; 1.69). Similar results were found for the other androgens. ConclusionPre-treatment serum testosterone levels may be a clinically useful biomarker for predicting mCRPC treatment responses and guiding treatment selection.

Relugolix in combination with abiraterone acetate, apalutamide, or docetaxel in men with advanced prostate cancer (aPC): A phase 1, three-part, open-label, parallel-cohort study.

TPS207 Background: Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) analogs or receptor antagonists is a cornerstone of prostate cancer treatment. As disease progresses, agents with complementary mechansims are co-prescribed with ADT to suppress extra-testicular testosterone production or block androgen receptors on cancer cells. Relugolix (120 mg) is an oral non-peptide GnRH receptor antagonist approved in the US for the treatment of aPC. In the phase 3 study, relugolix maintained suppression of testosterone to castration levels in 96.7% of men for up to 48 weeks (wks), with superiority to leuprolide acetate. Relugolix was well tolerated and associated with a 54% lower risk of major adverse cardiovascular events relative to leuprolide acetate (Shore N, NEJM 2020;382;23). To formally assess the safety and tolerability of combination treatment with relugolix, a phase 1 study in men with aPC has been undertaken. Methods: This is a three-part, open-label, parallel-cohort safety and tolerability study of relugolix in combination with abiraterone acetate in men with metastatic castration-sensitive prostate cancer (mCSPC) or metastatic castration-resistant prostate cancer (mCRPC) (Part 1), apalutamide in men with mCSPC or non-metastatic catration-resistant prostate cancer (nmCRPC) (Part 2), or docetaxel in men with mCSPC or mCRPC (Part 3). Each part of the study consists of a 45-day screening period, a 12-wk primary study treatment period and a 40-wk safety extension treatment period. All of the men are required to have been treated with leuprolide acetate or a GnRH receptor antagonist (eg, degarelix) in combination with abiraterone acetate for a minimum of 12 wks, apalutamide for a minimum of 6 wks, or docetaxel for a minimum of one treatment cycle prior to the baseline (Day 1) visit. Men will be transitioned from leuprolide acetate or degarelix to relugolix (120 mg [Part 1 and 3] or 240 mg [Part 2] once daily after a single loading dose of 360 mg); on the approximate date the next analog or antagonist injection is scheduled; treatment with each combination treatment will continue as previously prescribed. Hence, the study will provide safety and tolerability of relugolix and the three different combination agents for up to 1 year and in addition, will provide safety and tolerability data as men transition from injectable leuprolide acetate or degarelix to oral treatment with relugolix. Enrollment into the study began in March 2021. A protocol amendment was approved in July 2021 to include Part 2 and Part 3 of the study and to add the 40-wk safety extension treatment period. Screening for Part 2 was initiated in August 2021 and for Part 3 it is expected to initiate in January 2022. Clinical trial information: NCT04666129.

649P Abiraterone acetate in men with metastatic castration-resistant prostate cancer and no prior chemotherapy: A double-arm, multiple-centre, phase III clinical study

649P Abiraterone acetate in men with metastatic castration-resistant prostate cancer and no prior chemotherapy: A double-arm, multiple-centre, phase III clinical study

Liver tests increase on abiraterone acetate in men with metastatic prostate cancer: Natural history, management and outcome

BackgroundAbiraterone acetate (abiraterone) combined with prednisone is a standard of care in metastatic castration-resistant prostate cancer. Recently, benefit in overall survival was reported in metastatic castration-sensitive prostate cancer also, and an extension of indication has been granted. Abiraterone is seldom associated with liver toxicity. The clinical management and the outcome of patients with transaminase increase while on abiraterone have not been described. Patients and methodWe identified 25 men with metastatic prostate cancer and liver function test disorders occurring while on abiraterone treatment from December 2009 to September 2017 in three oncology centres in France. ResultsForty-six liver disorder events occurred in 25 patients while on abiraterone treatment. The median age at liver function test increase was 67 (55–85) years. The incidence of aspartate aminotransférase (AST) (24 events) and that of alanine aminotransférase (ALT) (22 events) increases were similar. Liver toxicity was of grade 1, 2 and 3 (Common Terminology Criteria for Adverse Events. version 4) in 7 (32%), 6 (27%) and 9 (41%) patients for ALT, and in 12 (50%), 6 (25%) and 6 (25%) for AST, respectively. The median time from abiraterone initiation to the detection of liver toxicity was 7.1 (4–95) weeks. The median time from highest ALT/AST increase to normalisation was 6.2 [2–14] weeks. In 13 patients (52%), liver tests spontaneously returned to baseline values, while abiraterone was continued at full dose. ConclusionLiver function test increase is a rare event that typically occurs within the first two months on abiraterone. Most patients experience normalisation of the tests, either spontaneously or after dose reduction/discontinuation.

A candidate androgen signalling signature predictive of response to abiraterone acetate in men with metastatic castration-resistant prostate cancer

BackgroundThe unmet need for predictive biomarkers emerged from the unpredictable pattern of response to androgen signalling inhibition in metastatic castration-resistant prostate cancer (mCRPC). Here, we report on the testing of a previously identified candidate androgen signalling signature associated with response to androgen signalling inhibition. Patients and methodsWe report on the outcome of the first module of a phase II trial on abiraterone acetate (AA) followed by combination with dasatinib or sunitinib. Bone marrow biopsies (BMBs) with matched bone marrow aspirate and blood samples were collected at baseline and upon progression. End-points included assessment of a prespecified molecular signature consisting of nuclear androgen receptor (AR) overexpression, cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17) expression, and AR-C-/N terminal expression ratio of ≥0.8 by immunohistochemistry (IHC) in patients with benefit versus primary resistance to AA (i.e. progression within 4 months). Tumour markers also included v-ets avian erythroblastosis virus E26 oncogene homologue (ERG), androgen receptor splice variant (ARV7) by IHC and steroids by liquid chromatography-tandem mass spectrometry. ResultsOf 170 patients accrued from 03/2011 to 02/2015, 44 (26%) were primary resistant to AA. Forty-eight patients had tumour infiltrated BMB at baseline. Pretreatment androgen signalling signature was linked to benefit from AA (p < 0.001). Presence of ERG was associated with benefit (p = 0.05), whereas nuclear ARV7 presence and 20 or more bone lesions at baseline with primary resistance (p = 0.04 and p = 0.0006, respectively). ConclusionTesting of a prespecified androgen signalling signature was highly supportive of its predictive value in maximal androgen deprivation strategies in mCRPC. Further validation is under way. Trial registrationClinicalTrials.gov NCT01254864.

Germline Variant in SLCO2B1 and Response to Abiraterone Acetate Plus Prednisone (AA) in New-onset Metastatic Castration-resistant Prostate Cancer (mCRPC).

There are many treatment options available for men with metastatic castration-resistant prostate cancer (mCRPC). Yet, biomarkers predictive of differential response to treatment are currently unavailable. A recent translational study suggested that SLCO2B1 genotype could predict response to abiraterone acetate for men with advanced prostate cancer. Here, we investigate whether germline variants in SLCO2B1 are predictive of response to first-line abiraterone acetate in men with new mCRPC. Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah (Salt Lake City, UT). Genotyping was performed using the Illumina OmniExpress genotyping platform. Primary endpoint was progression-free survival (PFS) on first-line abiraterone acetate in men with mCRPC. We performed a prespecified multivariate Cox regression analysis to assess the independent predictive value of rs12422149 and rs1789693 on PFS on abiraterone acetate. Of 401 men with advanced prostate cancer genotyped, 323 were homozygous wild-type for rs12422149 (80.5%), 74 were heterozygous (18.5%), and 4 were homozygous variant (1.0%). In a multivariate analysis of 79 men treated with first-line abiraterone acetate for mCRPC, men heterozygous for rs12422149 had significantly improved median PFS compared with the homozygous wild-type group (8.9 months vs. 6.3 months; HR, 0.46; 95% confidence interval, 0.23-0.94; P = 0.03). No significant difference in median PFS was seen by rs1789693 genotype. In this first clinical validation of translational data reported by Mostaghel and colleagues, germline variant alleles in rs12422149 of SLCO2B1 are common and predict improved response to first-line abiraterone acetate in men with mCRPC.

Neutrophil-to-lymphocyte Ratio as a Predictive Marker of Response to Abiraterone Acetate: A Retrospective Analysis of the COU302 Study

BackgroundThe neutrophil-lymphocyte ratio (NLR) is an inexpensive and accessible prognostic marker for many cancers, including metastatic castration-resistant prostate cancer (mCRPC). ObjectiveIn this study, we assess the role of NLR as a predictive biomarker through a retrospective analysis of the pivotal COU302 study of abiraterone acetate (AA) as first-line therapy for men with asymptomatic or minimally symptomatic mCRPC. Design, setting, and participantsThe COU302 study randomized asymptomatic or minimally symptomatic men with mCRPC to receive AA plus prednisone or prednisone as first-line treatment. Baseline NLR, overall survival, radiographic progression-free survival, and prostate-specific antigen (PSA) progression-free survival were evaluated. Outcome measurements and statistical analysisDescriptive statistics, as well as Kaplan-Meier and Cox survival models were used to assess the effect of baseline NLR and changes in NLR on response to AA plus prednisone versus prednisone, with adjustment for important covariates. Results and limitationsAmong the 1082 patients who received treatment, baseline NLR values showed no significant differences according to baseline covariates except for albumin. Baseline variables were similar between dichotomous groups with an NLR cutoff of 2.5, except for a lower proportion of patients with >10 bone metastases in the NLR <2.5 group. Our survival results demonstrate that higher NLR values corresponded to poorer overall survival and PSA response to AA but not to placebo, which was confirmed in our adjusted regression models. No significant differences were seen in time to radiographic progression. In separate analyses, an increase or decrease in NLR by 2 from treatment baseline did not clearly signal subsequent lack of benefit with continued AA. ConclusionsOur results suggest that baseline NLR may be able to predict response to AA in men with asymptomatic mCRPC but that changes in NLR during treatment are insufficient to guide treatment. Further validation studies are warranted. Patient summaryIn this report, we look at the ratio of circulating immune cells as a predictor of response to abiraterone acetate (AA), using data from a large trial. Our results suggest that this ratio derived from routinely obtained bloodwork can predict which patients respond better to AA.

Abstract 4929: A PK/PD study of Delta-4 abiraterone metabolite in metastatic castration-resistant prostate cancer patients

Abstract Background : Abiraterone (ABI), a steroidal CYP17A1 inhibitor, blocks the DHT synthesis from adrenal precursor steroids in castration resistant prostate cancer (mCRPC) patients. ABI is converted by 3β-hydroxysteroid dehydrogenase (HSD3B) into D4-abiraterone (D4-ABI). In a previous preclinical study, D4-ABI was shown to block multiple steroidogenic enzymes and antagonize the androgen receptor. Besides, it appeared more active than ABI itself (Li Z et al. Nature 2015). However, the contribution of D4-ABI to the clinical antitumoral activity of abiraterone acetate in men with mCRPC remains unknown. Methods : From 12/2012 to 10/2014, 61 consecutive mCRPC patients were treated with ABI (1000 mg, once daily) concomitantly with 10 mg of prednisone (Carton et al Eur J Cancer 2017). The study population represents a subgroup of these patients for whom trough plasma ABI and D4-ABI concentrations were assayed using liquid chromatography with fluorescence detection and LC/MS/MS, respectively. The trough plasma concentration of ABI and D4-ABI was assayed one (M1), two (M2) and three (M3) months after treatment initiation. ABI and D4-ABI Cmin were defined as the mean of trough concentrations measured during the first 3 months of treatment. This prospective analysis was in compliance with the Declaration of Helsinki and approved by the local medical ethical board (N°9166). All patients gave their written informed consent to participate in the study. Results : Thirty-six mCRPC patients were included. Mean plasma ABI and D4-ABI Cmin were 12.6 ± 6.8 ng/mL (coefficient of variation, CV= 54.0%) and 1.6 ± 1.3 ng/mL (CV= 81.3%), respectively. Intra-individual variability for ABI and D4-ABI Cmin was 23.8% and 60.7%, respectively. The mean metabolic ratio (D4-ABI / ABI) was of 0.18 ± 0.25 (CV=140.4%). In regards with in vitro data previously reported for IC50% of ABI and D4-ABI, we estimated that total plasma Cmin enabled to achieve these IC50% in 30 patients (83.3%) and only 2 patients (5.6%), respectively. The univariate Cox proportional-hazard regression model showed that higher D4-ABI Cmin was associated with shorter OS (Hazard ratio, HR 1.54; CI95% 1.06-2.22; p=0.022) but not with PFS. As previously reported, patients with ABI Cmin &amp;gt;8.3 ng/mL exhibited a longer PFS than patients underexposed (322 vs 237 days, p=0.05). The HR associated with the metabolic D4-ABI / ABI ratio for PFS and OS were 7.80 (CI 95% 1.63-37.38; p = 0.010) and 12.52 (CI 95% 1.95-80.47, p = 0.0078), respectively. Conclusion : It is unlikely that pharmacologic activity of D4-ABI contributes significantly to abiraterone acetate clinical activity for a daily dosing of 1,000 mg. The poor prognosis of higher D4-ABI Cmin / ABI Cmin ratio could be further in relation with a high activity of HSD3B1 enzyme which drive castration resistance by enhancing the DHT synthesis from non-gonadal precursors. Citation Format: Benoit Blanchet, Edith Carton, Mohammad Alyamani, Lisa Golmard, Olivier Huillard, Audrey Thomas, Michel Vidal, Francois Goldwasser, Nima Sharifi, Jerome Alexandre. A PK/PD study of Delta-4 abiraterone metabolite in metastatic castration-resistant prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4929.

Germline Variant in HSD3B1 (1245 A > C) and Response to Abiraterone Acetate Plus Prednisone in Men With New-Onset Metastatic Castration-Resistant Prostate Cancer.

The HSD3B1 gene encodes the enzyme 3β-hydroxysteroid dehydrogenase-1 (3βHSD1), which catalyzes adrenal androgen precursors into dihydrotestosterone, the most potent androgen. Recently, the HSD3B1 (1245C) variant was shown to predict shorter duration of response to androgen deprivation therapy with medical or surgical castration in the setting of castration-sensitive prostate cancer (CSPC). The HSD3B1 (1245C) variant also predicts longer duration of response to ketoconazole in men with castration-resistant prostate cancer (CRPC). We hypothesized that the HSD3B1 (1245C) variant predicts response to treatment with abiraterone acetate (AA) and can help personalize treatment in men with advanced prostate cancer. Clinical data and samples were from a prospectively maintained prostate cancer registry at the University of Utah. Genotyping was performed. The primary study end point was progression-free survival in first-line AA in men with metastatic CRPC. We performed prespecified multivariate analyses to assess the independent predictive value of HSD3B1 genotype on progression-free survival on AA. Seventy-six men with metastatic CRPC treated with first-line AA were included. In multivariate analysis, the HSD3B1 (1245C) variant did not predict response to first-line AA. The HSD3B1 (1245C) variant does not predict response to first-line AA in metastatic CRPC. This finding could be due to the ability of AA metabolites to act as both agonist (3-keto-5α-abiraterone) and antagonist (Δ4-abiraterone) on androgen signaling.

Independent assessment of TP53 and PTEN as predictors of response to enzalutamide (ENZ) or abiraterone acetate (AA) in men with metastatic castration-resistant prostate cancer (mCRPC).

351 Background: Alterations in androgen receptor signaling are well-established mechanisms of resistance to medical castration. Pre-clinical studies suggest that alterations to key tumor suppressor genes, such as TP53 or PTEN, may also be associated with development of androgen independence as an alternate mechanism of castration-resistance. Previous studies have shown that TP53 inactivation and PTEN loss are predictive of response to novel androgen axis inhibitors. Here, we independently assess whether TP53 and PTEN genomic alterations are predictive of response to ENZ and AA in men with mCRPC. Methods: Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah (Salt Lake City, UT). Next-generation sequencing (NGS) was performed on predominantly primary tumor tissue for 343 somatic and germline genetic alterations using FoundationOne. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Patients with mCRPC who were treated with any line AA or enzalutamide were included. We performed a univariate analysis to assess the predictive value of TP53 and PTEN. Only patients treated with single-agent therapy were included. Results: Of 141 men with prostate cancer and NGS available, 56 were included. Most patients were treated with abiraterone (n = 50), and only 6 with enzalutamide. 28.6% had PTEN loss and 35.7% had a TP53 mutation. OS and PFS did not differ significantly according to PTEN or TP53 status. Median OS was 40.9 months and not reached for men with and without TP53 mutation (HR 1.85, p = 0.31). Median PFS was 7.5 months and 9.5 months for men with and without TP53 mutation (HR 1.18, p = 0.60). Median PFS was 7.2 months and 9.5 months for men with and without PTEN loss (HR 1.15, p = 0.66). Median OS for PTEN was not mature enough to analyze. Conclusions: In our independent cohort, neither TP53 mutation nor PTEN loss is predictive of response to androgen-directed therapy in men with mCRPC patients. However, this is a relatively small retrospective sample with few events. These results should be considered exploratory only.

Frequency of liver test increases on abiraterone acetate in men with castrate-resistant prostate cancer (CRPC): Natural history, management, and outcome.

332 Background: Abiraterone acetate (abiraterone) in combination with prednisone is a standard of care for patients with metastatic CRPC. Abiraterone is seldom associated with liver toxicity and systematic monitoring of ALT and AST is required. Clinical management and outcome of these patients have not been described. Methods: We retrospectively identified 22 men with mCRPC with liver tests disorder occurring during abiraterone therapy from December 2009 to September 2017 from three oncology centers in France. Results: Thirty nine liver disorder events occurred in 22 patients during abiraterone therapy. The median age was 62 (50-80) years. Only one patient had liver metastasis. No patient had a history of chronic alcoholism. Accountability of the liver tests increase to abiraterone was doubtful in two patients who were receiving antibiotics when the event occurred. The incidence of AST increase (19 events) and that of ALT (20 events) were similar. Liver toxicity was of grade 1, 2, and 3 (CTCAEv4) in 5 (22.7%), 5 (22.7%), and 9 (40.9%) patients for ALT, and in 9 (40.9%), 6 (27.3%), and 5 (22.7%) for AST, respectively. The median time from abiraterone initiation to the detection of liver toxicity was 15.8 (4-95) weeks. The median time from highest ALT/AST increase to normalization was 7.7 (2-15) weeks. Normalization of liver test was observed in 19 (86.4%) patients, and 3 patients died of cancer progression before their liver tests had normalized. In 12 patients (54.4%), liver tests spontaneously returned to baseline values, while abiraterone was continued at full dose. Abiraterone was discontinued in 6 patients (27.7%) due to liver test increase. It was reintroduced after a break in four patients and then discontinued in two for a subsequent liver disorder event. No patient reported symptoms clearly related to liver test increase. Conclusions: Liver tests increase is a quite rare event that typically occurs within the first 4 months on abiraterone, though it can also happen up to 20 months later. It is typically asymptomatic and most patients experience normalization of tests, either spontaneously or after dose reduction/discontinuation.

Predictors of duration of abiraterone acetate in men with castration-resistant prostate cancer.

Androgen receptor signaling remains important in castration-resistant prostate cancer (CRPC) as demonstrated by the efficacy of abiraterone acetate (henceforth abiraterone) in phase III trials. Given that heterogeneous patient responses are observed, we sought to identify clinical factors associated with duration of abiraterone. We retrospectively identified patients with CRPC treated with abiraterone in our database. Patient characteristics and types and duration of prostate cancer (PC) therapies were analyzed. These parameters were analyzed with duration of abiraterone in univariate and multivariable analyses. We identified 161 patients who had received abiraterone. All had received primary androgen-deprivation therapy (ADT), 86% prior secondary hormone therapy (SHT) and 33% prior chemotherapy. The median duration of primary ADT was 23 months, duration of SHT (excluding abiraterone) was 17 months and duration of chemotherapy was 8 months. We demonstrated that lower PSA at abiraterone initiation, longer primary ADT duration, no prior ketoconazole, no prior chemotherapy and longer chemotherapy duration were associated with a longer duration on abiraterone in univariate analysis. In multivariable analysis, duration of primary ADT (duration of abiraterone 9 versus 13 months for ⩽12 versus >12 months, P=0.03) and no use of prior chemotherapy (duration of abiraterone 16 versus 7 months for no versus yes prior chemotherapy, P<0.01) were associated with duration of abiraterone. Several clinical parameters, including type and duration of prior therapy, are predictive of responsiveness to abiraterone. These parameters are logical and correlate with smaller disease burden or less exposure to PC therapies. This information can help physicians counsel patients about the potential durability of efficacy of abiraterone. Identifying predictive biomarkers that inform patient selection for therapy is critical to optimizing treatment outcomes.

Open-label phase II study evaluating the efficacy of concurrent administration of radium Ra 223 dichloride and abiraterone acetate in men with castration-resistant prostate cancer patients with symptomatic bone metastases.

Open-label phase II study evaluating the efficacy of concurrent administration of radium Ra 223 dichloride and abiraterone acetate in men with castration-resistant prostate cancer patients with symptomatic bone metastases.

Inherited Variants in SULT1E1 and Response to Abiraterone Acetate by Men with Metastatic Castration Refractory Prostate Cancer

Germline variations in genes involved in androgen biosynthesis and metabolic pathways may predict the response to abiraterone acetate in men with metastatic, castration refractory prostate cancer. The variations may serve as prognostic and predictive biomarkers to allow for more individualized therapy. We evaluated 832 single nucleotide polymorphisms from the OmniExpress genotyping platform (Illumina®) in the boundaries of 61 candidate genes reported to be involved in the androgen metabolic pathway. The purpose was to investigate them for an association with time to treatment failure in 68 white men with metastatic, castration refractory prostate cancer undergoing treatment with abiraterone acetate. Cox proportional hazard analysis was used with Gleason score, age, level of alkaline phosphatase and prostate specific antigen at treatment initiation as covariates. Each single nucleotide polymorphism was assessed using an allele carriage genetic model in which carriage of 1 or more minor alleles contributes to increased risk. Subset analyses were done to determine whether metastasis site, or prior treatment with ketoconazole or docetaxel would interact with the single nucleotide polymorphisms investigated. Six single nucleotide polymorphisms in the estrogen sulfotransferase gene SULT1E1 were associated with time to treatment failure on abiraterone acetate therapy after false discovery rate (q value) correction for multiple testing while controlling for Gleason score, age, level of alkaline phosphatase and prostate specific antigen at treatment initiation (q <0.05). Single nucleotide polymorphisms in SULT1E1 were significantly associated with time to treatment failure in men on abiraterone acetate therapy. The single nucleotide polymorphisms may serve as predictive markers for treatment with abiraterone acetate.

Association of single nucleotide polymorphisms (SNPs) in SULT1E1 with response to treatment with abiraterone acetate (AA) in men with metastatic castration refractory prostate cancer (mCRPC).

222 Background: Germline variations in genes involved in androgen biosynthesis and metabolic pathways may predict response to AA in men with mCRPC, serve as prognostic and predictive biomarkers, and guide towards more individualized therapy. Methods: 836 single nucleotide polymorphisms (SNPs) from the Illumina OmniExpress genotyping platform within the boundaries of 61 genes reported to be involved in the androgen metabolic pathway were investigated for association with time to treatment failure (TTF) in 68 Caucasian men with mCRPC undergoing treatment with AA. Cox proportional hazard analysis was employed using Gleason score as a covariate and assessing each SNP under an additive genetic model in which the number of minor alleles contributes increasing risk (or protection). Results: Three SNPs in SULT1E1 were associated with TTF on AA therapy after correcting for multiple testing (p &lt; .00007) while controlling for Gleason Score (Table). Conclusions: SNPs in SULT1E1(estrogen sulfotransferase gene) were significantly associated with TTF on AA therapy, and may serve as predictive markers to treatment with AA. Further validation is being performed in a larger cohort of men with mCRPC. [Table: see text]

Association of single nucleotide polymorphisms (SNPs) in ESR1 and PRMT8 and response to treatment with abiraterone acetate (AA) in men with metastatic castration refractory prostate cancer (mCRPC).

5048 Background: Germline variations in genes involved in androgen biosynthesis and metabolic pathways may predict response to AA in men with mCRPC, serve as prognostic and predictive biomarkers, a...

Predictors of response to abiraterone acetate in men with metastatic castrate resistant prostate cancer: Retrospective analysis of a large number of clinical and laboratory variables.

e16073 Background: A number of effective treatments exist for men with metastatic castrate resistant prostate cancer. Predicting response to a given drug is desirable. We retrospectively reviewed p...

From trial to practice: The Northern Ireland cancer center experience with abiraterone acetate in men with metastatic castration resistant prostate cancer.

e16101 Background: Treatment with Abiraterone acetate (AA) combined with prednisolone has proven benefit in overall survival compared with prednisolone alone in men with metastatic castration resis...

Clinical activity of abiraterone acetate in patients with castration-resistant prostate cancer who received prior ketoconazole therapy.

99 Background: Studies have shown activity of Abiraterone acetate (AA) in patients (pts) with castration-resistant prostate cancer (CRPC) who have received prior ketoconazole. Prostate-specific antigen (PSA) response to AA in relation to previous PSA response to ketoconazole was investigated. Methods: A retrospective analysis was conducted to determine the clinical activity of AA in men with CRPC who have received prior ketoconazole therapy at our institution. Time to PSA progression (PSA TTP) was defined by PCWG2 criteria, a PSA reduction of 50% or more was considered as PSA response. Results: Thirty four pts were identified. Nineteen pts (56%) had previous PSA responses on ketoconazole, with a median PSA TTP of 11 months (95% confidence interval [CI] 6.8-19.9). Subsequently, 11 of 34 (33%) of pts achieved a PSA response on AA, with a median PSA TTP of 6 months (95% CI 4.9-9.5). Among the 19 pts having a PSA response on ketoconazole, only four (21%) pts subsequently had PSA response to AA. Two of these pts had transient PSA response with PSA TTP less than 3 months on kKetoconazole, one patient discontinued Ketoconazole due to side effects, one patient had intermittent non-castrate testosterone levels. In contrast, 7 of 15 (46.7%) pts without prior PSA response to ketoconazole subsequently achieved PSA response on AA (p=0.11). Of note, PSA reduction of less than 50% on AA was observed in 9 of 34 pts (26%), which was associated with a longer median PSA TTP compared to pts who had PSA-progressive disease (5.9 months [95% CI 3.5-7.3] vs.1.5 months [95% CI 1.0-3.5], p=0.028). Five of these nine patients had a prior PSA response to ketoconazole but required drug discontinuation for reasons other than disease progression. Conclusions: PSA response to prior ketoconazole therapy is associated with lower PSA response rate to subsequent AA. The observation suggests that there is a biologically distinct subset of patients who are ketoconazole-resistant but abiraterone-sensitive, the underlying mechanism needs to be further investigated.

Single‐dose pharmacokinetic studies of abiraterone acetate in men with hepatic or renal impairment

Three open-label, single-dose studies investigated the impact of hepatic or renal impairment on abiraterone acetate pharmacokinetics and safety/tolerability in non-cancer patients. Patients (n = 8 each group) with mild/moderate hepatic impairment or end-stage renal disease (ESRD), and age-, BMI-matched healthy controls received a single oral 1,000 mg abiraterone acetate (tablet dose); while patients (n = 8 each) with severe hepatic impairment and matched healthy controls received 125- and 2,000-mg abiraterone acetate (suspension doses), respectively (systemic exposure of abiraterone acetate suspension is approximately half to that of tablet formulation). Blood was sampled at specified timepoints up to 72 or 96 hours postdose to measure plasma abiraterone concentrations. Abiraterone exposure was comparable between healthy controls and patients with mild hepatic impairment or ESRD, but increased by 4-fold in patients with moderate hepatic impairment. Despite a 16-fold reduction in dose, abiraterone exposure in patients with severe hepatic impairment was about 22% and 44% of the Cmax and AUC∞ of healthy controls, respectively. These results suggest that abiraterone pharmacokinetics were not changed markedly in patients with ESRD or mild hepatic impairment. However, the capacity to eliminate abiraterone was substantially compromised in patients with moderate or severe hepatic impairment. A single-dose administration of abiraterone acetate was well-tolerated.