CYP17A1 Polymorphisms and Clinical Outcome of Castration-Resistant Prostate Cancer Patients Treated with Abiraterone

2016 ◽  
Vol 31 (3) ◽  
pp. 264-269 ◽  
Author(s):  
Samanta Salvi ◽  
Valentina Casadio ◽  
Salvatore Luca Burgio ◽  
Vincenza Conteduca ◽  
Lorena Rossi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Outcome ◽  
Small Sample Size ◽  
Progression Free Survival ◽  
Small Sample ◽  
Nucleotide Polymorphisms ◽  
Castration Resistant Prostate Cancer ◽  
Single Nucleotide ◽  
Castration Resistant

Background We evaluated the role of single nucleotide polymorphisms in the CYP17A1 gene for predicting clinical outcome in castration-resistant prostate cancer (CRPC) patients treated with abiraterone. Methods Sixty-four patients were genotyped for the selected polymorphisms (rs743572, rs10883783, rs17115100 and rs284849) in CYP17A1. We hypothesized that different genotypes could be associated with progression-free survival (PFS) and overall survival (OS). Results Statistical analyses highlighted no significant associations between these polymorphisms and clinical outcome. However, individuals with the most common TT genotype for rs10883783 had a 3 months’ longer PFS than individuals with the TA + AA genotype. Conclusions With the limitation of the retrospective study design and the small sample size, the analyzed polymorphisms do not seem to be correlated with clinical outcome of CRPC patients treated with abiraterone.

scholarly journals Efficacy and safety of darolutamide in Japanese patients with nonmetastatic castration-resistant prostate cancer: a sub-group analysis of the phase III ARAMIS trial

2020 ◽  
Author(s):  
Hiroji Uemura ◽  
Hisashi Matsushima ◽  
Kazuki Kobayashi ◽  
Hiroya Mizusawa ◽  
Hiroaki Nishimatsu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Small Sample Size ◽  
Group Analysis ◽  
Specific Antigen ◽  
Japanese Patients ◽  
Small Sample ◽  
Phase Iii ◽  
Efficacy And Safety ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

Abstract Background Darolutamide, an oral androgen receptor inhibitor, has been approved for treating nonmetastatic castration-resistant prostate cancer (nmCRPC), based on significant improvements in metastasis-free survival (MFS) in the ARAMIS clinical trial. Efficacy and safety of darolutamide in Japanese patients are reported here. Methods In this randomized, double-blind, placebo-controlled phase III trial, 1509 patients with nmCRPC and prostate-specific antigen (PSA) doubling time ≤ 10 months were randomized 2:1 to darolutamide 600 mg twice daily or matched placebo while continuing androgen deprivation therapy. The primary endpoint was MFS. Results In Japan, 95 patients were enrolled and randomized to darolutamide (n = 62) or placebo (n = 33). At the primary analysis (cut-off date: September 3, 2018), after 20 primary end-point events had occurred, median MFS was not reached with darolutamide vs. 18.2 months with placebo (HR 0.28, 95% CI 0.11–0.70). Median OS was not reached due to limited numbers of events in both groups but favored darolutamide in the Japanese subgroup. Time to pain progression, time to PSA progression, and PSA response also favored darolutamide. Among Japanese patients randomized to darolutamide vs. placebo, incidences of treatment-emergent adverse events (TEAEs) were 85.5 vs. 63.6%, and incidences of treatment discontinuation due to TEAEs were 8.1 vs. 6.1%. Conclusions Efficacy outcomes favored darolutamide in Japanese patients with nmCRPC, supporting the clinical benefit of darolutamide in this patient population. Darolutamide was well tolerated; however, due to the small sample size, it is impossible to conclude with certainty whether differences in the safety profile exist between Japanese and overall ARAMIS populations.

scholarly journals Angiogenesis genotyping and clinical outcome during regorafenib treatment in metastatic colorectal cancer patients.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 595-595 ◽  
Author(s):  
Riccardo Giampieri ◽  
Lisa Salvatore ◽  
Michela Del Prete ◽  
Tiziana Prochilo ◽  
Marco D'Anzeo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Outcome ◽  
Cancer Patients ◽  
Progression Free Survival ◽  
Therapeutic Index ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Colorectal Cancer Patients ◽  
Ecog Ps

595 Background: The introduction of regorafenib for the treatment of colorectal cancer represented a sure medical achievement though at a cost of relevant toxicity. As a consequence the lack of predictive factors made the use of regorafenib in the clinical practice challenging. Previous observations suggested that polymorphisms of VEGF and its receptor (VEGFR) genes may regulate angiogenesis and lymphangiogenesis and potentially influence outcome during anti-angiogenesis treatment. Aim of our study was to evaluate the role of VEGF and VEGFR genotyping in determining clinical outcome for colorectal cancer patients receiving regorafenib. Methods: From a multicentre experience 138 samples (tumour or blood samples) of colorectal cancer patients receiving regorafenib were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients’ progression-free survival (PFS) and overall survival (OS) were analysed. Results: Results from angiogenesis genotyping showed that only VEGF-A rs2010963 maintained an independent correlation with PFS and OS (respectively HR: 0.49, 95% CI: 0.33-0.81, p=0.003 and HR: 0.52, 95% CI: 0.34-0.99, p=0.04). A correlation with disease control rate (DCR) was also observed (DCR 55% vs. 26%, p=0.02). Among clinical factors only ECOG PS was independently correlated with OS (HR: 0.52, 95% CI: 0.21-0.81, p=0.009), whereas no correlation with PFS was evident. Grouping together observations from angiogenesis genotyping and ECOG PS allowed further patients stratification into 3 prognostic groups: favourable, intermediate and unfavourable. Median OS resulted progressively decreased across these groups (OS not reached, 7.8 and 3.9 months respectively in the favourable, intermediate and unfavourable group, p<0.0001). Conclusions: VEGF-A rs2010963 genotyping may represent an important tool for a more accurate selection of candidates for regorafenib. This selection opportunity will ultimately improve the therapeutic index of such a treatment approach by limiting treatment to potentially responding patients and sparing unnecessary toxicity to those unlikely to benefit.

Outcomes of prechemotherapy (pCHT) abiraterone (AA) or enzalutamide (E) for metastatic castration-resistant prostate cancer (mCRPC) after androgen deprivation therapy (ADT) + docetaxel (D) or ADT alone for metastatic hormone sensitive prostate cancer (mHSPC) in a hospital-based registry.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16515-e16515
Author(s):  
Edoardo Francini ◽  
Kathryn P. Gray ◽  
Carolyn Evan ◽  
Marina D. Kaymakcalan ◽  
Grace Katherine Shaw ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
De Novo ◽  
Small Sample Size ◽  
Small Sample ◽  
Castration Resistant Prostate Cancer ◽  
Start Time ◽  
Time To Death ◽  
Castration Resistant ◽  
Kaplan Meier ◽  
Hormone Sensitive

e16515 Background: The E3805: CHAARTED trial noted use of D at time of commencing ADT for mHSPC was associated with an improvement in time to CRPC (PSA rise or clinical progression [CP]) or time to CP and resulted in a prolongation of overall survival (OS). Therefore, we postulated that pCHT AA or E maintained activity after ADT+D. Methods: A cohort of CRPC patients (pts) treated with pCHT AA or E for CRPC between 2010 and 2016 was selected from the Dana-Farber Cancer Institute IRB approved database. Patients were grouped by use of D and whether they had prior localized therapy (PLT) or de novo (DN) metastatic disease, at time of ADT start for mHSPC. The analysis endpoints included OS (time to death from all causes) from ADT start, time to AA/E start from ADT start, OS from AA/E start. Kaplan-Meier method estimated the time to events distribution with median (95% CI). Results: Of the 147 pts selected, 134 (91.2%) had previously received ADT alone, while 13 (8.8%) had ADT+D. Once stratified by PLT or DN, the distributions of the 4 groups are 33.3% (ADT/PLT), 57.8% (ADT/DN), 0.7% (ADT+D/PLT), and 8.2% (ADT+D/DN). In the ADT alone group, the median OS with pCHT AA or E for CRPC was approximately 3 years from the AA/E start, regardless of PLT or DN. In the smaller cohort of pts selected for treatment with ADT+D, both the OS from ADT start and from AA/E start were shorter than the ADT alone cohort. However, even in this group with shorter time to AA/E start, the median OS from AA/E start was still 1.5 years despite prior chemotherapy. Conclusions: Within limitations of a hospital-based registry, small sample size for ADT+D and lack of volume of metastases data, pts selected for ADT+D show poorer outcomes but still have an OS of 1.5 yrs from AA/E start. [Table: see text]

Germline variant in HSD3B1 (1245 A>C) and response to abiraterone acetate plus prednisone (AA) in men with new onset metastatic castration-resistant prostate cancer (mCRPC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 173-173
Author(s):  
Andrew W Hahn ◽  
David Michael Gill ◽  
Roberto Nussensveig ◽  
Austin Poole ◽  
James M. Farnham ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Small Sample Size ◽  
Progression Free Survival ◽  
Abiraterone Acetate ◽  
Small Sample ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Adrenal Androgen ◽  
University Of Utah ◽  
First Line Therapy

173 Background: The HSD3B1 gene encodes the enzyme 3β-hydroxysteroid dehydrogenase-1 (3βHSD1), which catalyzes adrenal androgen precursors into dihydrotestosterone, the most potent androgen. Recently, multiple reports validated the role of HSD3B1 (1245 A>C) variant in predicting response to androgen deprivation therapy (ADT) in castration sensitive prostate cancer. The objective of this study was to correlate HSD3B1 variantwith response AA in first-line therapy for men with mCRPC. Methods: Clinical data and samples were from a prospectively maintained prostate cancer registry at the University of Utah. Genotyping was performed as described by Hearn at al (Lancet Oncology, 2016). Primary endpoint was progression-free survival in first-line AA in men with mCRPC. We performed pre-specified multivariate analyses to assess the independent predictive value of HSD3B1 genotype on PFS on AA (Table). Results: 76 men with mCRPC treated with first-line AA were included. In multivariate analysis, HSD3B1 (1245 A>C) did not predict response to first-line AA (Table). Conclusions: This hypothesis-generating data shows that inherited variant alleles in HSD3B1 do not predict response to first-line AA in mCRPC. 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 or our small sample size. [Table: see text]

scholarly journals Consecutive Prostate Cancer Specimens Revealed Increased Aldo–Keto Reductase Family 1 Member C3 Expression with Progression to Castration-Resistant Prostate Cancer

2019 ◽  
Vol 8 (5) ◽  
pp. 601 ◽  
Author(s):  
Yu Miyazaki ◽  
Yuki Teramoto ◽  
Shinsuke Shibuya ◽  
Takayuki Goto ◽  
Kosuke Okasho ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Immunohistochemical Expression ◽  
Free Survival ◽  
Castration Resistant ◽  
Psa Progression ◽  
Prostatic Epithelium

Aldo-keto reductase family 1 member C3 (AKR1C3) is an enzyme in the steroidogenesis pathway, especially in formation of testosterone and dihydrotestosterone, and is believed to have a key role in promoting prostate cancer (PCa) progression, particularly in castration-resistant prostate cancer (CRPC). This study aims to compare the expression level of AKR1C3 between benign prostatic epithelium and cancer cells, and among hormone-naïve prostate cancer (HNPC) and CRPC from the same patients, to understand the role of AKR1C3 in PCa progression. Correlation of AKR1C3 immunohistochemical expression between benign and cancerous epithelia in 134 patient specimens was analyzed. Additionally, correlation between AKR1C3 expression and prostate-specific antigen (PSA) progression-free survival (PFS) after radical prostatectomy was analyzed. Furthermore, we evaluated the consecutive prostate samples derived from 11 patients both in the hormone-naïve and castration-resistant states. AKR1C3 immunostaining of cancer epithelium was significantly stronger than that of the benign epithelia in patients with localized HNPC (p < 0.0001). High AKR1C3 expression was an independent factor of poor PSA PFS (p = 0.032). Moreover, AKR1C3 immunostaining was significantly stronger in CRPC tissues than in HNPC tissues in the same patients (p = 0.0234). Our findings demonstrate that AKR1C3 is crucial in PCa progression.

Safety and clinical outcome of a cohort of patients (pts) with castration resistant prostate cancer (CRPC) treated with abiraterone acetate (AA) in a named patient program (NPP): Updated results of a retrospective study from an Italian cooperative group.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 253-253 ◽  
Author(s):  
Orazio Caffo ◽  
Lucia Fratino ◽  
Giovanni Lo Re ◽  
Umberto Basso ◽  
Alessandro D'Angelo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Retrospective Study ◽  
Clinical Outcome ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Abiraterone Acetate ◽  
Consecutive Series ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Clinical Records

253 Background: Abiraterone acetate (AA) provided a survival advantage compared to placebo in patients (pts) with castration resistant prostate cancer (CRPC) who had received docetaxel (de Bono JS et al, NEJM 2011). The present retrospective study is aimed to assess safety and clinical outcome in an unselected CRPC population which received AA in a named patient program (NPP). Methods: We retrospectively reviewed the clinical records of all pts treated with AA for CRPC by NPP in our institutions. All pts have been previously treated with a docetaxel-based first-line chemotherapy and received the standard AA dose of 1,000 mg daily plus prednisone 10 mg daily. For each pt we recorded the pre- and post-AA clinical history, the AA treatment details toxicities and clinical outcomes. Results: To date we have collected a consecutive series of 245 pts from 18 Italian hospitals. The median age was 73 (range 45 to 91). The median baseline prostate-specific antigen (PSA) level was 100 ng/ml (range 0.33->100.000); 79% of the pts had bone metastases, while nodal, lung and liver metastases were observed in 52%, 9%, and 7% of the pts, respectively. The median duration of AA treatment was 5 months (range, 1 to 26). Grade 3 to 4 toxicities were anemia (11 pts), fatigue (nine pts), bone pain (four pts), constipation (two pts), thrombocytopenia (two pts), nausea (one pt), diarrhea (one pt), dyspnea (one pt), edema (one pt), hypertension (one pt), hyperbilirubinemia (one pt), and hypokaliemia (one pt). A PSA reduction of more than 50% was observed in 50.9% of the pts. The median progression-free survival (PFS) and overall survival (OS) were 6 months and 15 months, respectively; the 1 year PFS and OS rates were 24.3% and 56.9%, respectively. Conclusions: Our results have confirmed the safety and efficacy of AA in an unselected population of pts with pre-treated CRPC outside clinical trials and provided further support concerning the good safety profile of the drug.

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