Hormone Therapy For Prostate Cancer Research Articles

Addition of abiraterone to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Model to estimate long-term survival, quality-adjusted survival, and cost-effectiveness.

204 Background: Results from randomised trials show adding abiraterone acetate plus prednisolone (AAP) to standard of care (SOC) improves disease-free and overall survival in men with prostate cancer (PC) starting long-term hormone therapy for first time. Formal assessment is required of whether funding AAP here shows appropriate use of resources. This cost-effectiveness decision model tests if giving AAP to these patients is cost-effective using costs from English National Health Service, the largest nation where STAMPEDE recruited. Methods: Health outcomes and costs were modelled using patient data from AAP comparison of STAMPEDE (recruitment 2011-14). This included 1917 men with high-risk, locally advanced metastatic or recurrent PC starting 1st-line hormone therapy. SOC was hormone therapy for ≥2 years with radiotherapy in pre-selected patients. If allocated to research group, AAP (AA 1000mg/day, P 5mg/day) was added to SOC. The model makes lifetime predictions of survival, costs and quality-adjusted lifeyears (QALYs), with costs and QALYs discounted at 3.5% annually. Sensitivity analyses were performed. Results: The model predicted AAP would extend survival (discounted quality-adjusted survival) by 2.68y (1.46 QALYs) for metastatic patients and 0.30y (0.29 QALYs) for non-metastatic. The cost of AAP means it is not currently cost-effective in this setting, including with Patient Access Scheme costs for AAP and enzalutamide and similar reductions for cabazitaxel and Ra. If AAP’s price reduces after patent expiry as expected (90% reduction on BNF cost), it would be cost-effective in both patient groups, with incremental cost-effectiveness ratios below £10,000 (US$12,665) per QALY. AAP could also dominate in non-metastatic patients (i.e. lower costs and higher QALYs than SOC alone). Conclusions: AAP could be cost-effective for patients with non-metastatic and metastatic disease with expected future pricing and may be cost-saving in the former. Policymakers should encourage license submissions and generic price reductions to facilitate use of AAP given cost-saving potential in addition to improving survival. Clinical trial information: NCT00268476.

Family history in primary hormone therapy for prostate cancer: Analysis from a community-based multi-institutional Japan-wide database.

To determine the association between hormone therapy and outcomes in a cohort of prostate cancer patients with a family history of prostate cancer. Data of patients with prostate cancer who had received hormone therapy were extracted from a nationwide community-based database established by the Japan Study Group for Prostate Cancer. Family history of prostate cancer was available for 13346 of these patients, who thus comprised the study cohort. Prognostic variables, including progression-free survival, cancer-specific survival and overall survival, were compared between men with familial and men with sporadic prostate cancer. A positive family history was identified in 220 patients (1.6%). Patients with a positive family history were younger than those without; however, other clinicopathological characteristics and prognoses were comparable. In subgroup analysis, family history was identified as a possible favorable prognostic factor for overall survival among patients with a prostate-specific antigen level at diagnosis <100ng/mL and those with low or intermediate Japan Cancer of the Prostate Risk Assessment. Our findings show that familial prostate cancer has an early-onset feature or is diagnosed earlier than sporadic prostate cancer. However, the prognosis of individuals with familial prostate cancer undergoing hormone therapy is comparable to those with sporadic prostate cancer.

Editorial Comment to Family history in primary hormone therapy for prostate cancer: Analysis from a community-based multi-institutional Japan-wide database.

Editorial Comment to Family history in primary hormone therapy for prostate cancer: Analysis from a community-based multi-institutional Japan-wide database.

Erectile dysfunction in prostate cancer patients treated with intensity-modulated radiation therapy.

Sexual dysfunction is an important side-effect after radiotherapy (RT) for prostate cancer (PCa). The aim of this study was to compare sexual functions of PCa patients before and after intensity-modulated RT and to analyze their correlation with penile bulb (PB) doses and patient characteristics. Forty-two patients who underwent RT ± hormone therapy for PCa between 2010 and 2013 were analyzed. Sexual functions assessed by patient-reported questionnaire and physician reported scale before and 3 years after treatment. The effect of patients' age, prostate volume, testosterone levels, comorbidity, smoking status, tumor stage, RT technique, hormone therapy, and PB doses to sexual functions were investigated. After 3 years of RT, 64.3% of all patients had a lower erectile score; and 75% of patients who were previously potent (n = 24) had become impotent after treatment. However sexual desire still remained in 75.8% of patients who had desire before treatment (n = 33). Statistical analysis showed that two parameters were correlated with postradiotherapy impotency outcome; PB mean radiation dose (P = 0.033) and testosterone levels (P = 0.032). RT, despite modern techniques, affects the sexual function of PCa patients in varying degrees. Reducing radiation doses to penile structures may play a role in preventing erectile dysfunction.

E. J. Pavlik, ed. Estrogens, progestins and their antagonists. - Vol. 2. Functions and mechanisms of action. - Boston, Basel, Berlin: Bikhauser, 1996 .-- 632 p.

The book under review is part of a lengthy and interesting series for specialists, published by the Birkhauser Publishing House and having the common title Hormones in Normal and Pathological Conditions. The first volume of the book, a review of which is published in Issue 3 of the journal “Oncology Issues” for 1997, deals mainly with the degree of oncological risk of estrogen replacement therapy in menopause, about the not always unambiguous anticarcinogenic properties of phytoestrogens and food indoles, and about modern approaches to hormone therapy for prostate cancer, etc., i.e., mainly about the problems of oncological endocrinology. The 2nd volume of this publication, as its editor E. Pavlik writes in the introduction to the book, is devoted to the physiological and molecular mechanisms of action of estrogens, progestins and their antagonists, and is primarily focused on the discussion of the effect of various and often even opposite effects these compounds in different cells and tissues. A highly qualified team of authors, assembled by the editor, was able to ensure the implementation of this difficult and responsible task.

Practically scheduling hormone therapy for prostate cancer using a mathematical model

Hormone therapy is one of the popular therapeutic methods for prostate cancer. Intermittent androgen suppression (IAS) is the method which stops and resumes hormone therapy repeatedly. The efficacy of IAS differs depending on patients; both the cases have been reported where the relapse of cancer happened and did not happen, for the patients who had undergone IAS. For the patients who cannot avoid the relapse of cancer by IAS, we should delay the relapse of cancer as later as possible. Here we compared some practical methods of determining when to stop and restart hormone therapy for IAS using an existing mathematical model of prostate cancer. The method we suggest is to determine the ratio of on-treatment period and off-treatment period sparsely for each cycle, namely the “sparse search.” We also compared the performance of the sparse search with the exhaustive search and the model predictive control. We found that the sparse search can find a good treatment schedule without failure, and the computational cost is not so high compared to the exhaustive method. In addition, we focus on the model predictive control (MPC) method which has been applied to the scheduling of IAS in some existing studies. The MPC is computationary efficient, although it does not always find an optimal schedule in the numerical experiments here. We believe that the MPC method might be also promising because of its reasonable computational costs and its possibility of expanding of the model.

Highlights of This Issue

Metastatic head and neck cancer (HNSCC) represents a major clinical challenge, and the molecular underpinnings of HNSCC metastasis are poorly defined. Here, Lakshmanachetty and colleagues demonstrate that TP63, which is overexpressed in some primary HNSCC, is downregulated exclusively in advanced and metastatic disease. Loss of TP63 expression was causative of increased progression and metastasis in vivo, and was shown to be acutely reliant on activation of MAPK signaling. This finding is supported by the observation that the MEK inhibitor trametinib significantly reduced metastasis of TP63-deficient HNSCC. Taken together, the data uncover a novel role for TP63 in the progression of HNSCC and highlight a potential avenue to improve patient survival outcomes.Constitutively active androgen receptor splice variants (AR-V) have emerged as a clinically relevant mechanism of disease progression and resistance to hormone therapy in prostate cancer. However, it remains unclear whether AR-V rely on the same chromatin remodeling factors as full-length AR to execute their transcriptional program. In this article, Chaytor and colleagues show that GATA2 regulates AR-V chromatin binding, and that the GATA2/AR-V cistromes overlap considerably with bromodomain and extraterminal (BET) cistromes in castration-resistant prostate cancer cells. BET inhibitors were shown to impede the pioneering role of GATA2 and by extension AR-V activity, thereby exposing a potential weakness in AR-V function which has thus far evaded targeted therapy.Cancer cells extensively rewire their metabolism to meet increased demands on their cellular energetics, but emerging evidence has suggested that altered metabolic states play roles in other aspects of tumor biology as well. Here, Efimova and colleagues expand on their novel observations that the hexosamine biosynthetic pathway can regulate the DNA damage response. Inhibition of O-GlcNAc transferase (OGT) significantly impeded radiation-induced DNA double strand break repair both in vitro and in vivo, whereas ablation of O-GlcNAcase or supplementation with GlcNAc enhanced the efficiency of the DNA damage response. These observations provide compelling preclinical data to support a novel means of enhancing or restoring sensitivity to ionizing radiation.Kinase inhibitors are a cornerstone of clinical cancer management, but current methods of evaluating patient responses present considerable lag time. Here, Lee and colleagues demonstrate metabolic quantification of the cancer cell response, or lack thereof, to ibrutinib, an inhibitor of BTK. Responsive cells experienced marked inhibition of key metabolic pathways, with decreases in lactate and alanine concentrations serving as potential biomarkers of response. Resistant cells maintained their metabolic flux largely through glutaminolysis; accordingly, inhibition of glutamine metabolism potently inhibited cell growth in ibrutinib-resistant cells. Overall, the authors demonstrate precise and expedient evaluation of response to a kinase inhibitor using fluxomic quantification, allowing for early determination of drug sensitivity as well as highlighting potential vulnerabilities in resistant cells that can be exploited therapeutically.

Family history in primary hormone therapy for prostate cancer from a community-based multi-institutional Japan-wide database.

e16549 Background: Although a positive family history is known to increase the risk of morbidity of prostate cancer, little is known about the prognoses with hormone therapy of individuals with familial prostate cancer. Thus, in this study we aimed to determine the associations between hormone therapy and outcomes of a cohort of men with familial prostate cancer from a large community-based multi-institutional Japan-wide registry. Methods: Data of patients with prostate cancer who had received hormone therapy were extracted from a nationwide community-based database established by the Japan Study Group for Prostate Cancer. Family history of prostate cancer was available for 15,873 of these patients, who thus comprised the study cohort. Prognostic variables, including progression-free survival, cancer-specific survival, and overall survival, were compared between men with familial and men with sporadic prostate cancer. Results: A positive family history was identified in 247 patients (1.6%). Patients with a positive family history were younger than those without; however, other clinicopathological characteristics and prognoses were comparable. In subgroup analysis, family history was identified as a significant favorable prognostic factor for progression-free survival among patients treated by castration, as was overall survival among patients with PSA level at diagnosis less than 100 ng/mL and those with low or intermediate J-CAPRA risk. Conclusions: Our findings indicate that familial prostate cancer has an early-onset feature or is diagnosed earlier than sporadic prostate cancer. However, with hormone therapy the prognoses of individuals with familial prostate cancer are comparable to those of individuals with sporadic prostate cancer.

Steroid 5-alpha reductase 1 is negatively regulated by Homeobox gene D10 in prostate cancer LNCaP cells

Objective To investigate the relationship between homeobox gene D10 (HOXD10) and steroid 5-alpha reductase 1 (SRD5A1) and the effect of the former on the latter in prostate cancer cells. Methods Expression of HOXD10 and SRD5A1 and their correlation was analyzed basing on Taylor and TCGA database. Then HOXD10-overexpressing prostate cancer LNCaP cells was constructed, and the effect of HOXD10 on SRD5A1 was detected by real-time quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR) and Western blotting. Immunohistochemistry was used to analyze the expression of HOXD10 and SRD5A1 in human prostate cancer tissues.Statisticalanalysis of data using the GraphPad Prism Version 6 software. Results mRNA expression of HOXD10 decreased gradually with the progression of prostate cancer (Taylor: Benign: 8.94±0.09, Primary: 7.93±0.05, Met: 7.66±0.11, F=43.72, P<0.05), while SRD5A1 increased gradually (Taylor: Benign: 7.75±0.02, Primary: 7.79±0.02, Met: 7.98±0.01, F=5.306, P<0.05), and demonstrated a significant negative correlation (TCGA: HOXD10: 80.72±1.60, SRD5A1: 231.60±2.48; r=-0.220, P<0.01). Moreover, the expression of SRD5A1 in prostate cancer cells or patients was significantly reduced in which with higher expression of HOXD10 (Immunohistochemistry: χ2=5.868, P<0.05). (RT-qPCR: overexpressing HOXD10-LNCaP SRD5A1: 0.66±0.02, vector-LNCaP SRD5A1: 0.99±0.00, t=11.31, P<0.01; Western blotting: overexpressing HOXD10-LNCaP SRD5A1: 0.58±0.00, vector-LNCaP SRD5A1: 0.82±0.02, t=11.31, P<0.01). Conclusion HOXD10 negatively regulates SRD5A1 in prostate cancer and may provide a new strategy for endocrine therapy of prostate cancer. Key words: Homeobox gene D10; Steroid 5-alpha reductase 1; Prostate cancer

Analysis of Anatomical Factors Contributing to Urinary Incontinence After Radical Prostatectomy (Literature Review)

The objective: to conduct a thorough analysis of the main anatomical mechanisms underlying postprostatectomic urinary incontinence.Collect evidence. The analysis of works published in PubMed and EmBAse on the topic of postprostratectomic urinary incontinence is performed. Initially, 212 papers were investigated. Animal studies, publications on operations for benign prostatic hyperplasia, analysis of the results of radio- and hormone therapy for prostate cancer were excluded from the review. Surgical aspects of postprostatectomic incontinence were also not considered in this work.Synthesis of evidence. Numerous works emphasize the important influence of anatomical elements and pelvic support on the development of postprostatectomic urinary incontinence. Anatomical factors included the analysis of modern approaches to the structure of the urethral sphincter complex, the study of the supporting components of the membranous urethra, the role of fibrosis and neural structures, as well as the importance of urothelial features.Conclusion. Anatomical support and pelvic innervation, as it turned out, are important factors in the etiology of postprostatectomic urinary incontinence. Taking into account the anatomical features of the urethral sphincter in combination with the additional study of the surgical aspects of postprostatectomic urinary incontinence can improve the level of continence in patients who have undergone radical prostatectomy.

PT395 - Hormone therapy for prostate cancer increases the risk of new-onset hypertension: A nationwide propensity score-matched four-year longitudinal cohort study

PT395 - Hormone therapy for prostate cancer increases the risk of new-onset hypertension: A nationwide propensity score-matched four-year longitudinal cohort study

A Phase II Trial of Triamcinolone with Hormone Therapy for Prostate Cancer (TRICREST) in Chemotherapy Naive Metastatic Castration Resistant Prostate Cancer

A Phase II Trial of Triamcinolone with Hormone Therapy for Prostate Cancer (TRICREST) in Chemotherapy Naive Metastatic Castration Resistant Prostate Cancer

Halogen-substituted anthranilic acid derivatives provide a novel chemical platform for androgen receptor antagonists

Androgen receptor (AR) antagonists are used for hormone therapy of prostate cancer (PCa). However resistance to the treatment occurs eventually. One possible reason is the occurrence of AR mutations that prevent inhibition of AR-mediated transactivation by antagonists. To offer in future more options to inhibit AR signaling, novel chemical lead structures for new AR antagonists would be beneficial. Here we analyzed structure-activity relationships of a battery of 36 non-steroidal structural variants of methyl anthranilate including 23 synthesized compounds. We identified structural requirements that lead to more potent AR antagonists. Specific compounds inhibit the transactivation of wild-type AR as well as AR mutants that render treatment resistance to hydroxyflutamide, bicalutamide and the second-generation AR antagonist enzalutamide. This suggests a distinct mode of inhibiting the AR compared to the clinically used compounds. Competition assays suggest binding of these compounds to the AR ligand binding domain and inhibit PCa cell proliferation. Moreover, active compounds induce cellular senescence despite inhibition of AR-mediated transactivation indicating a transactivation-independent AR-pathway. In line with this, fluorescence resonance after photobleaching (FRAP) - assays reveal higher mobility of the AR in the cell nuclei. Mechanistically, fluorescence resonance energy transfer (FRET) - assays indicate that the amino-carboxy (N/C)-interaction of the AR is not affected, which is in contrast to known AR-antagonists. This suggests a mechanistically novel mode of AR-antagonism. Together, these findings indicate the identification of a novel chemical platform as a new lead structure that extends the diversity of known AR antagonists and possesses a distinct mode of antagonizing AR-function.

Controllability of hybrid PDE‐ODE systems with structural instability and applications to mathematical models on intermittent hormonal therapy for prostate cancer

Several mathematical models on intermittent androgen suppression (IAS) therapy for prostate cancer are classified into hybrid PDE‐ODE system with structural instability. The purpose of this paper is to give a unified strategy to prove the controllability of the mathematical models on the IAS therapy. For this aim, we prove that (1) a generalized hybrid PDE‐ODE system is controllable for any initial data and (2) the result given by (1) is applicable to the mathematical models on the IAS therapy. Finally, we conclude that the mathematical models on the IAS therapy for prostate cancer are controllable for any initial data.

Addition of Docetaxel to First-line Long-term Hormone Therapy in Prostate Cancer (STAMPEDE): Modelling to Estimate Long-term Survival, Quality-adjusted Survival, and Cost-effectiveness

BackgroundResults from large randomised controlled trials have shown that adding docetaxel to the standard of care (SOC) for men initiating hormone therapy for prostate cancer (PC) prolongs survival for those with metastatic disease and prolongs failure-free survival for those without. To date there has been no formal assessment of whether funding docetaxel in this setting represents an appropriate use of UK National Health Service (NHS) resources. ObjectiveTo assess whether administering docetaxel to men with PC starting long-term hormone therapy is cost-effective in a UK setting. Design, setting, and participantsWe modelled health outcomes and costs in the UK NHS using data collected within the STAMPEDE trial, which enrolled men with high-risk, locally advanced metastatic or recurrent PC starting first-line hormone therapy. InterventionSOC was hormone therapy for ≥2 yr and radiotherapy in some patients. Docetaxel (75mg/m2) was administered alongside SOC for six three-weekly cycles. Outcome measurements and statistical analysisThe model generated lifetime predictions of costs, changes in survival duration, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). Results and limitationsThe model predicted that docetaxel would extend survival (discounted quality-adjusted survival) by 0.89 yr (0.51) for metastatic PC and 0.78 yr (0.39) for nonmetastatic PC, and would be cost-effective in metastatic PC (ICER £5514/QALY vs SOC) and nonmetastatic PC (higher QALYs, lower costs vs SOC). Docetaxel remained cost-effective in nonmetastatic PC when the assumption of no survival advantage was modelled. ConclusionsDocetaxel is cost-effective among patients with nonmetastatic and metastatic PC in a UK setting. Clinicians should consider whether the evidence is now sufficiently compelling to support docetaxel use in patients with nonmetastatic PC, as the opportunity to offer docetaxel at hormone therapy initiation will be missed for some patients by the time more mature survival data are available. Patient summaryStarting docetaxel chemotherapy alongside hormone therapy represents a good use of UK National Health Service resources for patients with prostate cancer that is high risk or has spread to other parts of the body.

Compositional differences in gastrointestinal microbiota in prostate cancer patients treated with androgen axis-targeted therapies

BackgroundIt is well known that the gastrointestinal (GI) microbiota can influence the metabolism, pharmacokinetics, and toxicity of cancer therapies. Conversely, the effect of cancer treatments on the composition of the GI microbiota is poorly understood. We hypothesized that oral androgen receptor axis-targeted therapies (ATT), including bicalutamide, enzalutamide, and abiraterone acetate, may be associated with compositional differences in the GI microbiota.MethodsWe profiled the fecal microbiota in a cross-sectional study of 30 patients that included healthy male volunteers and men with different clinical states of prostate cancer (i.e., localized, biochemically recurrent, and metastatic disease) using 16S rDNA amplicon sequencing. Functional inference of identified taxa was performed using PICRUSt.ResultsWe report a significant difference in alpha diversity in GI microbiota among men with versus without a prostate cancer diagnosis. Further analysis identified significant compositional differences in the GI microbiota of men taking ATT, including a greater abundance of species previously linked to response to anti-PD-1 immunotherapy such as Akkermansia muciniphila and Ruminococcaceae spp. In functional analyses, we found an enriched representation of bacterial gene pathways involved in steroid biosynthesis and steroid hormone biosynthesis in the fecal microbiota of men taking oral ATT.ConclusionsThere are measurable differences in the GI microbiota of men receiving oral ATT. We speculate that oral hormonal therapies for prostate cancer may alter the GI microbiota, influence clinical responses to ATT, and/or potentially modulate the antitumor effects of future therapies including immunotherapy. Given our findings, larger, longitudinal studies are warranted.

Abstract 5499: A potent BH3 mimetic targeting BCL-XL induces apoptosis regulated by PTEN loss and integrin alpha 5 in prostate cancer cells

Abstract Background: PTEN-loss is a highly prevalent genomic event associated with higher risk of metastatic progression and resistance to hormonal therapy in prostate cancer. Akt inhibitor therapy in combination with abiraterone demonstrates early promise in the clinical control of PTEN-deficient prostate cancers. We have previously implicated BCL-XL in the survival of PTEN-null PC-3 prostate cancer cells in vitro, regulated by integrin alpha 5 (ITGA5) (Ren, MCR 2016). Toward advancing therapeutic strategies in PTEN-deficient prostate cancer we further assessed the link between PTEN and BCL-XL mediated prostate cancer cell survival. Methods: Isogenic PTEN knockdown stable cell lines (VCAP and DU145) were generated by lentiviral transduction of pLKO-control-shRNA and two pLKO-PTEN-shRNAs, respectively. PTEN was exogenously expressed in PTEN-null prostate cancer cell lines (PC-3, LNCaP and C4-2B) by 1) transfecting cells with pCMV-Flag-vector or pCMV-Flag-PTEN 2) transfecting cells with pcDNA3-GFP-PTEN and then sorting GFP-PTEN-negative and GFP-PTEN-positive cells by flow cytometry. Cells were then treated with a single agent BCL-XL inhibitor (A1331852 or navitoclax (ABT263); AbbVie), PI3K (buparlisib; Selleck Chem) or Akt (ipatasertib, Selleck Chem) inhibitors or combined PI3K and BCL-2 family inhibitors. Cell survival was assessed by cell viability assay. Expression of pAkt, ITGA5 and apoptotic markers was assayed by Western blot analysis and/or flow cytometry. Results: Notwithstanding the reduction of phospho-bad expression with PI3K inhibition, the potent BCL-XL-targeting BH3 mimetic, A1331852, compared to single agent PI3K or Akt inhibitors in titrated doses was alone sufficient to induce apoptosis and loss of cell viability in all PTEN-null prostate cancer lines tested. PTEN expression reversed the apoptotic response to BCL-XL targeting and blocked the anti-proliferative effect of PI3K or Akt inhibition in PTEN-mutant cells. PTEN knockdown induced membrane expression of ITGA5 whereas PTEN overexpression diminished ITGA5 expression. Conclusions: PTEN regulates the apoptotic threshold in prostate cancer cells via BCL-XL independent of the PI3K/Akt pathway. The induction of ITGA5 membrane localization by PTEN loss defines a potential upstream signaling mechanism for the BCL-XL regulated apoptotic threshold in these cells. Highly potent BCL-XL inhibition requires further investigation as a therapeutic strategy in PTEN-deficient prostate cancer. Citation Format: Wenying Ren, Raghav Joshi, Paul Mathew. A potent BH3 mimetic targeting BCL-XL induces apoptosis regulated by PTEN loss and integrin alpha 5 in prostate cancer cells [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 5499.

Heterogeneous Flare in Prostate-specific Membrane Antigen Positron Emission Tomography Tracer Uptake with Initiation of Androgen Pathway Blockade in Metastatic Prostate Cancer

BackgroundProstate-specific membrane antigen (PSMA)-based positron emission tomography (PET) imaging is a highly sensitive tool for the detection of prostate cancer metastases. However, the effect of primary and secondary androgen deprivation therapy (ADT) on PSMA PET uptake has not been described. ObjectiveTo prospectively evaluate changes in 68Ga-PSMA-11 PET uptake on initiation of androgen receptor (AR)-targeted therapy. Design, setting, and participantsProspective single-institution study of patients with metastatic castration-sensitive (n=4) and castration-resistant prostate cancer (n=4) starting treatment with ADT and enzalutamide, respectively, who underwent serial 68Ga-PSMA-11 PET imaging before and after treatment initiation. Outcome measurements and statistical analysisThe percentage change in 68Ga-PSMA-11 PET uptake from baseline was descriptively reported and graphically represented. Results and limitationsEarly increases in PSMA PET tracer uptake in at least one metastatic lesion were observed in six out of seven patients who achieved subsequent prostate-specific antigen declines of >50% from baseline. Overall, 22 of 45 metastatic lesions (49%) exhibited early increases in PSMA uptake that were indicative of a flare effect rather than disease progression. Considerable intra- and interpatient heterogeneity was observed in the temporal pattern of PSMA uptake on treatment initiation. Study limitations include the sample size, the variable timing for scan acquisition, and limited long-term follow up. ConclusionsTumor flare in PSMA PET tracer uptake in the absence of disease progression is variably observed on initiation of AR-targeted treatment. Further studies are needed to delineate the factors controlling PSMA expression to optimize the diagnostic yield. Patient summaryFlares of increased prostate-specific membrane antigen (PSMA) tracer uptake on positron emission tomography scans are variably observed following initiation of hormone therapy for prostate cancer and do not necessarily represent disease progression. There was considerable variability in PSMA expression between patients, and further studies are needed to understand the factors controlling PSMA expression.

Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol

BackgroundAdding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC+AAP versus SOC+DocP. MethodRecruitment to SOC+DocP and SOC+AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for≥2years and RT to the primary tumour. Stratified randomisation allocated pts 2:1:2 to SOC; SOC+docetaxel 75mg/m2 3-weekly×6+prednisolone 10mg daily; or SOC+abiraterone acetate 1000mg+prednisolone 5mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC+AAP, and HR>1 favours SOC+DocP. ResultsA total of 566 consenting patients were contemporaneously randomised: 189 SOC+DocP and 377 SOC+AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8–10; 449 (79%) WHO performance status 0; median age 66years and median PSA 56ng/ml. With median follow-up 4years, 149 deaths were reported. For overall survival, HR=1.16 (95% CI 0.82–1.65); failure-free survival HR=0.51 (95% CI 0.39–0.67); progression-free survival HR=0.65 (95% CI 0.48–0.88); metastasis-free survival HR=0.77 (95% CI 0.57–1.03); prostate cancer-specific survival HR=1.02 (0.70–1.49); and symptomatic skeletal events HR=0.83 (95% CI 0.55–1.25). In the safety population, the proportion reporting≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC+DocP, and 40%, 7% and 1% SOC+AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm. ConclusionsThis direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs. Trial registrationClinicaltrials.gov: NCT00268476.

The predictive role of the expression ratio of androgen receptor splice variant-7 and androgen receptor in the prognosis of prostate cancer treated by castration therapy

Objective To evaluate the prognostic value of the ratio of AR and AR-V7 expression in prostate cancer treated by castration therapy. Methods Immunohistochemical staining was performed in biopsy specimen of 136 prostate cancer patients received hormone therapy in Tongji Hospital of Huazhong University of Science and Technology from January 2010 to December 2015. Expression was determined using modified H score method. Patients aged from 53-96, the median age was 71, median tPSA value at diagnosed was 110.00 ng/ml(2.61-4 003.4 ng/ml), median fPSA value was 14.62 ng/ml(0.12-640.19 ng/ml), median PSA density was 1.15 ng/(ml·cm3) [0.02-62.63 ng/(ml·cm3)]. Among these, 88(64.7%)patients were diagnosed Gleason score≥8, 39(28.7%) patients with Gleason score 7, while 7(6.6%) patients Gleason score <7. There were 54(39.7%) patients diagnosed T4 stage, 57(41.9%) patients T3 stage and 25(18.4%) patients Tx stage; 62(45.6%) patients were diagnosed N1 stage, 46(33.8%) N0 stage and 28(20.6%) patients Nx stage; 97(71.3%) patients were diagnosed M1 stage, 30(22.1%) M0 stage, 9(6.6%) patients Mx stage. Cause-specific Cox regression and Kaplan-Meier Analysis were used to analyze the prognosis risk. Results The median follow-up time was 44 months, ranged 15-71 months. During the surveillance, the disease progression-free survival time ranged from 5-59 month, median 19 months. The overall survival time ranged from 12-61 months, median 31 months. Among these, 79(58.1%) patients were AR positive and 26(19.1%) patients were AR-V7 positive, while AR and AR-V7 expression had no significant correlation (Spearman-test r=0.042, P=0.629). The AR-V7 positive patients showed significantly lower CRPC progression free survival (10.8 months vs. 25.0 months, P<0.001) and much lower overall survival (20.3 months vs. 42.8 months, P<0.001). The high AR-V7/AR expression ratio group showed significantly lower CRPC progression free survival (12.0 months vs. 24.8 months, P<0.001) and much lower overall survival (22.5 months vs. 42.8 months, P<0.001). In univariate Cox regression analyses, Gleason score at diagnosis, T stage, tPSA, PSA density and high AR-V7/AR expression ratio could predict the prognosis of hormonal therapy. While in multivariate Cox regression analyses, T stage(HR=2.597, 95% CI 1.351-4.995, P=0.004)and high AR-V7/AR expression ratio(HR=5.788, 95% CI 2.530-13.242, P<0.001)could effectively and independently predict the prognosis of hormonal therapy. Conclusion High AR-V7/AR HS ratio is the independent predictor of the prognosis of prostate cancer hormone therapy. AR-V7 positive and high AR-V7/AR HS ratio patients may have shorter PFS and overall survival time than AR-V7 negative and low AR-V7/AR HS ratio patients. Key words: Prostatic neoplasm; Androgen receptor; Androgen receptor splice variant-7; castration therapy; Prognosis