Ignite Creation Date:
2024-05-06 @ 1:38 AM
Last Modification Date:
2024-10-26 @ 11:07 AM
Study NCT ID:
NCT01858441
Status:
COMPLETED
Last Update Posted:
2020-12-04
First Post:
2013-05-02
Brief Title:
Pharmacogenetic Study in Castration-resistant Prostate Cancer Patients Treated With Abiraterone Acetate
Sponsor:
Centre Antoine Lacassagne
Organization:
Centre Antoine Lacassagne
Study Overview
Official Title:
Pharmacogenetic Study in Castration-resistant Prostate Cancer Patients Treated With Abiraterone Acetate
Status:
COMPLETED
Status Verified Date:
2019-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ABIGENE
Brief Summary:
Prostate cancer is the 2nd leading cause of mortality in men in developed countries For metastatic prostate cancer patients the 1st-line treatment relies on hormone therapy However the efficacy of androgen deprivation therapy remains limited in time and most patients eventually develop castration-resistant prostate cancer CRPC while remaining androgen-dependent
Docetaxel is currently the standard of care for metastatic CPRC It has been shown that testosterone levels within metastatic tumoral tissue from men receiving hormone therapy were significantly higher than those from primitive tumors of untreated prostate cancers Among the mechanistic explanations for this observation it has been shown that CYP17A1 a key enzyme in de novo steroid synthesis localized in testis and adrenal gland is up-regulated in CRPC metastases The existence of de novo CYP17A1-dependent androgen biosynthesis at the tumor level has supported the development of novel antiandrogens including abiraterone acetate AA an irreversible CYP17A1 inhibitor Based on a placebo-controlled phase III trial demonstrating that abiraterone prolonged overall survival 148 vs 109 months and increased PSA response rate 29 vs 6 in patients with metastatic CRPC who previously received docetaxel AA was recently approved by the FDA and French Health Authorities AA is well-tolerated and main toxicities are urinary tract infections 2 and a syndrome of secondary mineralocorticoid excess characterized by fluid overload hypertension and hypokaliema 1 to 4 of grade 3-4
Almost concomitantly a novel taxane-class cytotoxic agent cabazitaxel has proven efficacy in CRPC treatment after failure to docetaxel and has recently been approved by the FDA and French Health Authority Although cabazitaxel exhibits a less favorable toxicity profile this precise context creates a need to dispose of objective individual criteria so as to orientate patients to treatment towards AA or towards cabazitaxel To this purpose several approaches are of potential interest for identifying good candidates for a treatment by AA tumor-specific TMPRSS2-ERG gene fusion measurement circulating tumor cell analysis tumoral CYP17A1 expression analysis of splicing forms of the androgen receptor However the clinical relevance of these potential predictive factors remains to be established in this setting
Pharmacogenetics examines germinal gene polymorphisms likely to influence the pharmacodynamics of anticancer agents Encouraging results have recently been reported by our group for irinotecan pharmacogenetics with concrete possibilities of individual dose adaptations and very recently by other investigators for sunitinib pharmacogenetics Concerning AA one can hypothesize that tumors with elevated CYP17A1 expression will be more likely to respond better to AA This hypothesis is indirectly supported by the observation that in CPRC patients receiving AA PSA-based response is higher in patients with elevated pre-treatment blood concentration of DHEA and androstenedione
The CYP17A1 gene presents numerous single nucleotide polymorphisms SNPs whose frequencies of rare alleles are at least 12 Their functional impact has been suggested for nine of them which were linked either to the risk of developing prostate cancer or to survival of prostate cancer patients So far no study has examined the links between these polymorphisms and the efficacy of a CYP17A1 inhibitor Also relationships with the efficacy of androgen deprivation therapy have recently been reported for SNPs of genes involved in the membrane-transport testosterone and dehydroepiandrosterone namely SLCO2B1 and SLCO1B3 One can make the hypothesis that gene polymorphisms of these transporters may play a role for the intratumoral concentration of testosterone locally-produced through the mediation of CYP17A1 activity
To resume two second-line treatments of metastatic CRPC cancers are currently available thus is raising the question in practice of which treatment is more appropriate for a given patient Herein the present study proposes an original pharmacogenetic approach in order to highlight a relationship between AA activity and patients genetic profile Ultimately this could reveal evidences of genetic predispositions for potentially good responders to AA treatment
Docetaxel is currently the standard of care for metastatic CPRC It has been shown that testosterone levels within metastatic tumoral tissue from men receiving hormone therapy were significantly higher than those from primitive tumors of untreated prostate cancers Among the mechanistic explanations for this observation it has been shown that CYP17A1 a key enzyme in de novo steroid synthesis localized in testis and adrenal gland is up-regulated in CRPC metastases The existence of de novo CYP17A1-dependent androgen biosynthesis at the tumor level has supported the development of novel antiandrogens including abiraterone acetate AA an irreversible CYP17A1 inhibitor Based on a placebo-controlled phase III trial demonstrating that abiraterone prolonged overall survival 148 vs 109 months and increased PSA response rate 29 vs 6 in patients with metastatic CRPC who previously received docetaxel AA was recently approved by the FDA and French Health Authorities AA is well-tolerated and main toxicities are urinary tract infections 2 and a syndrome of secondary mineralocorticoid excess characterized by fluid overload hypertension and hypokaliema 1 to 4 of grade 3-4
Almost concomitantly a novel taxane-class cytotoxic agent cabazitaxel has proven efficacy in CRPC treatment after failure to docetaxel and has recently been approved by the FDA and French Health Authority Although cabazitaxel exhibits a less favorable toxicity profile this precise context creates a need to dispose of objective individual criteria so as to orientate patients to treatment towards AA or towards cabazitaxel To this purpose several approaches are of potential interest for identifying good candidates for a treatment by AA tumor-specific TMPRSS2-ERG gene fusion measurement circulating tumor cell analysis tumoral CYP17A1 expression analysis of splicing forms of the androgen receptor However the clinical relevance of these potential predictive factors remains to be established in this setting
Pharmacogenetics examines germinal gene polymorphisms likely to influence the pharmacodynamics of anticancer agents Encouraging results have recently been reported by our group for irinotecan pharmacogenetics with concrete possibilities of individual dose adaptations and very recently by other investigators for sunitinib pharmacogenetics Concerning AA one can hypothesize that tumors with elevated CYP17A1 expression will be more likely to respond better to AA This hypothesis is indirectly supported by the observation that in CPRC patients receiving AA PSA-based response is higher in patients with elevated pre-treatment blood concentration of DHEA and androstenedione
The CYP17A1 gene presents numerous single nucleotide polymorphisms SNPs whose frequencies of rare alleles are at least 12 Their functional impact has been suggested for nine of them which were linked either to the risk of developing prostate cancer or to survival of prostate cancer patients So far no study has examined the links between these polymorphisms and the efficacy of a CYP17A1 inhibitor Also relationships with the efficacy of androgen deprivation therapy have recently been reported for SNPs of genes involved in the membrane-transport testosterone and dehydroepiandrosterone namely SLCO2B1 and SLCO1B3 One can make the hypothesis that gene polymorphisms of these transporters may play a role for the intratumoral concentration of testosterone locally-produced through the mediation of CYP17A1 activity
To resume two second-line treatments of metastatic CRPC cancers are currently available thus is raising the question in practice of which treatment is more appropriate for a given patient Herein the present study proposes an original pharmacogenetic approach in order to highlight a relationship between AA activity and patients genetic profile Ultimately this could reveal evidences of genetic predispositions for potentially good responders to AA treatment
Detailed Description:
None
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None