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]

Prognostic impact of prior local therapy in castration-resistant prostate cancer

2021 ◽  
Author(s):  
Mikifumi Koura ◽  
Masaki Shiota ◽  
Shohei Ueda ◽  
Takashi Matsumoto ◽  
Satoshi Kobayashi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Local Therapy ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Free Survival ◽  
First Line Therapy ◽  
Castration Resistant ◽  
Line Therapy

Abstract Objective This study aimed to reveal the prognostic values of prior local therapy in first-line therapy using androgen receptor-axis targeting agents (abiraterone or enzalutamide) or docetaxel for castration-resistant prostate cancer (CRPC). Methods The study included 303 patients treated with first-line therapy for non-metastatic and metastatic CRPC. The association between prior local therapy and therapeutic outcome including progression-free survival and overall survival was investigated by univariate and multivariate analyses as well as propensity score-matched analysis. Results In univariate analysis, local prior therapy was associated with a lower risk of all-cause mortality (hazard ratio, 0.56, 95% confidence interval, 0.40–0.79; P = 0.0009). Overall survival, but not progression-free survival, was better among patients with prior local therapy compared with patients without prior local therapy even after multivariate analysis and propensity score-matched analysis. Conclusions This study robustly indicated that prior local treatment was prognostic for overall survival among patients with CRPC. This finding is useful to predict patient prognosis in CRPC.

scholarly journals The Heterogeneity of Intraductal Carcinoma of the Prostate Is Associated With Different Efficacy of Standard First-Line Therapy for Patients With Metastatic Castration-Resistant Prostate Cancer

2020 ◽  
Author(s):  
Zhipeng Wang ◽  
Sha Zhu ◽  
Jinge Zhao ◽  
Ling Nie ◽  
Xueqin Chen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Therapeutic Efficacy ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Free Survival ◽  
Carcinoma Of The Prostate ◽  
First Line Therapy ◽  
Castration Resistant ◽  
Line Therapy

Abstract BackgroundTo explore whether patients with distinct intraductal carcinoma of the prostate (IDC-P) subtypes respond differently to standard first-line therapy among patients with metastatic castration resistant prostate cancer (mCRPC).MethodsWe retrospectively analyzed data of 170 mCRPC patients receiving abiraterone (ABI) or docetaxel (DOC) as first-line therapy between 2014 and 2019. PSA response, PSA progression-free survival (PSA-PFS), radiographic progression-free survival (rPFS), and overall survival (OS) were analyzed and compared based on the presence of IDC-P and its sub-patterns.ResultsTotally, IDC-P was confirmed in 91/170 (53.5%) patients. Among them, 36/91 (39.6%) and 55/91 (60.4%) harbored IDC-P pattern 1 and pattern 2, respectively. The presence of IDC-P was confirmed to be associated with poor prognosis in the whole cohort. Patients with IDC-P pattern 1 shared similar clinical outcomes to those without IDC-P in both ABI and DOC treatment. However, compared to patients with IDC-P pattern 1 and without IDC-P, IDC-P pattern 2 had markedly poorer prognosis in either ABI (PSA-PFS: P<0.001; rPFS: P<0.001) or DOC (PSA-PFS: P<0.001; rPFS: P<0.001) treatment. For patients without IDC-P, DOC had comparable therapeutic efficacy with ABI. In contrast, the therapeutic efficacy of DOC in patients with either IDCP pattern 1 (PSA-PFS: P=0.021; rPFS: P=0.027) or pattern 2 (PSA-PFS: P=0.003; rPFS: P=0.007) was significantly inferior to ABI.ConclusionCompared to DOC, ABI exhibited better efficacy in patients with IDC-P of either pattern. However, IDC-P pattern 2 still responded unsatisfactorily to either ABI or DOC therapy. Novel therapeutic strategies appropriate for IDC-P pattern 2 need to be further investigated in the future.

scholarly journals Efficacy and safety of abiraterone acetate plus prednisolone in patients with early metastatic castration-resistant prostate cancer who failed first-line androgen-deprivation therapy: a single-arm, phase 4 study

2020 ◽  
Author(s):  
K Kobayashi ◽  
N Okuno ◽  
G Arai ◽  
H Nakatsu ◽  
A Maniwa ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prostate Specific Antigen ◽  
Androgen Deprivation Therapy ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Abiraterone Acetate ◽  
Androgen Deprivation ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Castration Resistant

Abstract Aim The aim was to evaluate the efficacy and safety of abiraterone acetate plus prednisolone in patients with chemotherapy-naïve early metastatic castration-resistant prostate cancer who failed first-line androgen deprivation therapy. Methods Patients with early metastatic castration-resistant prostate cancer with confirmed prostate-specific antigen progression within 1-year or prostate-specific antigen progression without having normal prostate-specific antigen level (&lt;4.0 ng/mL) during first-line androgen deprivation therapy were enrolled and administered abiraterone acetate (1000 mg) plus prednisolone (10 mg). A minimum of 48 patients were required according to Simon’s minimax design. The primary endpoint was prostate-specific antigen response rate (≥50% prostate-specific antigen decline by 12 weeks), secondary endpoints included prostate-specific antigen progression-free survival and overall survival. Safety parameters were also assessed. Results For efficacy, 49/50 patients were evaluable. Median age was 73 (range: 55–86) years. The median duration of initial androgen deprivation therapy was 32.4 (range: 13.4–84.1) weeks and 48 patients experienced prostate-specific antigen progression within 1-year after initiation of androgen deprivation therapy. prostate-specific antigen response rate was 55.1% (95% confidence interval: 40.2%–69.3%), median prostate-specific antigen–progression-free survival was 24.1 weeks, and median overall survival was 102.9 weeks (95% confidence interval: 64.86 not estimable [NE]). Most common adverse event was nasopharyngitis (15/50 patients, 30.0%). The most common ≥grade 3 adverse event was alanine aminotransferase increased (6/50 patients, 12.0%). Conclusions Abiraterone acetate plus prednisolone demonstrated a high prostate-specific antigen response rate of 55.1%, suggesting tumor growth still depends on androgen synthesis in patients with early metastatic castration-resistant prostate cancer. However, prostate-specific antigen–progression-free survival was shorter than that reported in previous studies. Considering the benefit–risk profile, abiraterone acetate plus prednisolone would be a beneficial treatment option for patients with chemotherapy-naive metastatic prostate cancer who show early castration resistance.

Management of Castration-Resistant Prostate Cancer: First-Line Therapy

2019 ◽  
Author(s):  
Simon Y.F. Fu ◽  
Kim N. Chi
Keyword(s):  
Prostate Cancer ◽  
Abiraterone Acetate ◽  
Chemotherapeutic Agents ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
First Line Therapy ◽  
Castration Resistant ◽  
Radium 223 ◽  
Incurable Condition ◽  
Line Setting

The development of castration-resistant prostate cancer (CRPC) heralds significant morbidity and an incurable condition. Since 2004, there are now six proven life-prolonging therapies available, including androgen receptor pathway inhibitor (ARPI) , chemotherapeutic agents, radiopharmaceutical, and immunotherapy for the first-line management of metastatic CRPC. Recent advances have seen enzalutamide and apalutamide approved by US FDA for the treatment of nonmetastatic CRPC, with darolutamide the latest ARPI demonstrating efficacy in nonmetastatic CRPC. ARPI is the treatment of choice in the first-line setting for most CRPC patients, and this approach has been endorsed by clinical guidelines and expert consensus, although treatment must be individualized. Advances in the molecular profiling of CRPC promise to select suitable patients for trials involving targeted therapy and identify biomarkers to guide treatment selection. This review contains 2 figures, 1 table, and 54 references. Keywords: abiraterone acetate, apalutamide, cabazitaxel, castration-resistant prostate cancer, docetaxel, enzalutamide, first-line treatment, radium-223, sipuleucel-T

Does abiraterone withdrawal syndrome (AWS) exist also in metastatic castration-resistant prostate cancer (mCRPC) first-line setting?

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 344-344
Author(s):  
Francesca Maines ◽  
Orazio Caffo ◽  
Chiara Trentin ◽  
Antonello Veccia ◽  
Enzo Galligioni
Keyword(s):  
Withdrawal Syndrome ◽  
Small Sample Size ◽  
Objective Response ◽  
Clinical History ◽  
Abiraterone Acetate ◽  
Small Sample ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Clinical Role ◽  
Clinical Records

344 Background: AWS is a recently phenomenon observed in mCRPC patients (pts) characterized by a PSA reduction with or without objective response after abiraterone acetate (AA) discontinuation. This syndrome has clinical features similar to antiandrogen withdrawal syndrome and was described in pts who treated with AA in the post-docetaxel setting. At the best of our knowledge, to date AWS was never described in chemo-naïve mCRPC pts. Methods: We retrospectively reviewed clinical records of mCRPC pts treated with first-line AA at our Institution. All pts were treated with AA 1,000 mg + prednisone (PDN) 10 mg po daily; the treatment was continued until progression disease (PD) which required an imaging confirmation too. After PD, we also discontinued the PDN administration. For each pt we recorded pre and post-AA clinical history, treatment details and outcomes. AWS was defined by PSA reduction ≥ 25% compared to the AA-end values observed in the first month after AA stop. Results: From September 2014, eight pts received first-line AA and, to date, 6 patients (75%) who discontinued the treatment due to PD are evaluable for AWS occurrence. We observed an AWS in 2/6 (33.3%). The first patient, a 76 year-old man, who experienced a PD after 12 wks AA treatment, had a 69% reduction in PSA with PSA dropping from 60 ng/mL to 19.47 ng/mL after about 30 days from the discontinuation. The second patient, 83 years old, treated with AA for 12 weeks, had a reduction in PSA from 112.2 ng/mL to 55 ng/mL at one-month (51% reduction) and to 35.36 ng/mL at two months (68.5% reduction) after AA and PDN discontinuation; after 9 wks the AWS is still ongoing. Conclusions: Notwithstanding the limits of the small sample size, our data shows for the first time that AWS can be observed also in mCRPC patients receiving AA as first-line treatment. Larger observations are needed to establish frequency and clinical role of this phenomenon. Although pathogenetic mechanisms and predictive factors are still unclear, AWS may represent a possibility to delay the second line start for mCRPC pts.

Cabazitaxel in the Management of Metastatic Castration-resistant Prostate Cancer Progressing After Docetaxel-based Chemotherapy

2012 ◽  
Vol 08 (01) ◽  
pp. 42 ◽  
Author(s):  
Axel Heidenreich ◽  
David Pfister ◽  
◽  
Keyword(s):  
Prostate Cancer ◽  
Side Effects ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Abiraterone Acetate ◽  
Metastatic Progression ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Patient Counselling ◽  
Castration Resistant

Docetaxel is the guideline-recommended first-line chemotherapy in men with castration-resistant prostate cancer (CRPC). Despite its proven survival benefit, however, all patients will progress after a mean interval of six to eight months. Recently, the FDA approved cabazitaxel and abiraterone acetate as effective second-line treatment options in this clinical scenario. By comparison with mitoxantrone, cabazitaxel improves progression-free survival, overall survival, time to prostate surface antigen (PSA) progression and time to metastatic progression. On the other hand, cabazitaxel (Sanofi) is asscociated with a significantly higher frequency of grade 3 and 4 haematotoxic and gastrointestinal side effects than mitoxantrone. In experienced hands, and with the use of proactive therapeutic measures – such as weekly monitoring, adequate patient counselling and appropriate application of the guidelines on management and prophylaxis of neutropenia and diarrhoea — all side effects can be handled easily without harming the patient, as has been shown recently by the analysis of the results of the German and European compassionate use programmes. Cabazitaxel is one of the key components in the management of disease progression after docetaxel, and might be of benefit in men with high metastatic burden, rapid PSA doubling time and minimal side effects during first-line docetaxel therapy.

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.

High-exosomal AKR1C3 mRNA expression as a marker of poor efficacy of abiraterone in metastatic PCa patients.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 196-196
Author(s):  
Sha Zhu ◽  
Guangxi Sun ◽  
Xingming Zhang ◽  
Jindong Dai ◽  
Junru Chen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Mrna Expression ◽  
Progression Free Survival ◽  
Study Endpoint ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Free Survival ◽  
First Line Therapy ◽  
Castration Resistant ◽  
Line Therapy

196 Background: Aldo-keto reductase family 1 member C3 (AKR1C3) has been proved to be an important part in the androgen biosynthesis process. Previous researches have showed that immunohistochemical (IHC) AKR1C3 expression is a prognosticator in prostate cancer (PCa) patients treated with abiraterone. This study is to find out the relationship between exosomal AKR1C3 mRNA expression and the efficacy of abiraterone in metastatic PCa patients. Methods: Blood samples of metastatic prostate cancer patients during different disease stages were collected. We isolated the exosomes and extracted the RNA for analysis of AKR1C3 by ddPCR. Absolute target mRNA concentration was measured by ddPCR as copies per milliliter (copies/20ul). Clinical data were collected for all patients. Primary study endpoint was progression-free survival (PFS). Statistical analyses were performed with SPSS 25.0. Results: Exosomal AKR1C3 mRNA expression was positive in 71.9% (41/57) patients, and high expression (defined as ≥ 20 copies/20μl) was found in 12.3% (7/57) patients. High exosomal AKR1C3 mRNA expression was not related to positive IHC AKR1C3 expression ( P=0.723). Patients with high exosomal AKR1C3 expression and negative IHC AKR1C3 expression harbored only 4.866 months’ median progression-free survival (PFS) compared with the whole cohort (9.37 months). High exosomal AKR1C3 expression is significantly associated with shorter PFS (median PFS 8.036 months, p<0.001). Multivariate Cox regression analysis revealed that high exosomal AKR1C3 expression was an independent prognosticator of abiraterone treatment efficacy (OR: 8.891, 95%CI: 1.309-61.631, P=0.026). In subsequently subgroup analyses, high exosomal AKR1C3 expression demonstrates particularly high hazard ratio in multiple subgroups (patients with baseline PSA >100 ng/mL, ALP >71 IU/L, HGB >120 g/L, and patients receiving abiraterone as first-line therapy in castration resistant prostate cancer). Conclusions: Exosomal AKR1C3 level is an independent adverse prognosticator in metastatic PCa patients receiving abiraterone treatment, especially when abiraterone was used as first-line therapy in castration resistant prostate cancer.

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