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Background:Standard medical castration reduces muscle mass. We sought to characterize body composition changes in men undergoing maximal androgen suppression with and without exogenous gluocorticoids.Methods:Cross-sectional areas of total fat, visceral fat and muscle were measured on serial CT scans in a post-hoc analysis of patients treated in Phase I/II trials with abiraterone followed by abiraterone and dexamethasone 0.5 mg daily. Linear mixed regression models were used to account for variations in time-on-treatment and baseline body mass index (BMI).Results:Fifty-five patients received a median of 7.5 months abiraterone followed by 5.4 months abiraterone and dexamethasone. Muscle loss was observed on single-agent abiraterone (maximal in patients with baseline BMI >30, −4.3%), but no further loss was observed after addition of dexamethasone. Loss of visceral fat was also observed on single-agent abiraterone, (baseline BMI >30 patients −19.6%). In contrast, addition of dexamethasone led to an increase in central visceral and total fat and BMI in all the patients.Interpretation:Maximal androgen suppression was associated with loss of muscle and visceral fat. Addition of low dose dexamethasone resulted in significant increases in visceral and total fat. These changes could have important quality-of-life implications for men treated with abiraterone. [ABSTRACT FROM AUTHOR]

Background: New or worsening bone lesions in patients responding to treatment, known as the flare phenomenon is well described on (99m)Tc-MDP bone scintigraphy, but to our knowledge has not previously been described on CT. The appearance of new or worsening bone sclerosis on CT in patients with prostate cancer may therefore be erroneously classified as disease progression.Purpose: To assess the incidence of osteoblastic healing flare response at 3-month CT assessment in patients with castrate-resistant prostate cancer and to identify associated features that enable differentiation from progressive metastatic bone disease at 3 months.Material and Methods: CT scans of 67 patients with castrate-resistant prostate cancer undergoing treatment were reviewed by a radiologist blinded to clinical outcome. Changes in number, size, and density of metastatic bone lesions were documented and Response Evaluation Criteria in Solid Tumours (RECIST) in soft tissue lesions, alkaline phosphatase, prostate specific antigen, and (99m)Tc-MDP bone scans were used for correlation.Results: Of the 39 patients who had 3- and 6-month follow-up, eight patients (21%) demonstrated an increase in number, size, or density of sclerotic lesions on the 3-month CT scan despite improvement in PSA and soft tissue lesions. Three out of eight patients (8%) maintained partial response/remained stable at follow-up and were defined as showing a flare response: in this group bone metastases evident on CT showed a qualitative and quantitative increase in density and no lesions faded at 3 months. In contrast, in all patients who progressed at 3 months by PSA/RECIST criteria (n = 8) bone lesions showed a mixed pattern with some lesions increasing and others decreasing in density.Conclusion: The incidence of flare response of metastatic bone disease evident at 3-month post-treatment CT in patients with prostate cancer undergoing systemic treatment is 8%. In patients with falling PSA and stable/responding soft tissue disease at 3 months an increase in bone sclerosis in the absence of fading bone metastases can be interpreted as flare and is likely to represent a response. [ABSTRACT FROM AUTHOR]

Background: The discovery of ERG/ETV1 gene rearrangements and PTEN gene loss warrants investigation in a mechanism-based prognostic classification of prostate cancer (PCa). The study objective was to evaluate the potential clinical significance and natural history of different disease categories by combining ERG/ETV1 gene rearrangements and PTEN gene loss status.Methods: We utilised fluorescence in situ hybridisation (FISH) assays to detect PTEN gene loss and ERG/ETV1 gene rearrangements in 308 conservatively managed PCa patients with survival outcome data.Results: ERG/ETV1 gene rearrangements alone and PTEN gene loss alone both failed to show a link to survival in multivariate analyses. However, there was a strong interaction between ERG/ETV1 gene rearrangements and PTEN gene loss (P<0.001). The largest subgroup of patients (54%), lacking both PTEN gene loss and ERG/ETV1 gene rearrangements comprised a 'good prognosis' population exhibiting favourable cancer-specific survival (85.5% alive at 11 years). The presence of PTEN gene loss in the absence of ERG/ETV1 gene rearrangements identified a patient population (6%) with poorer cancer-specific survival that was highly significant (HR=4.87, P<0.001 in multivariate analysis, 13.7% survival at 11 years) when compared with the 'good prognosis' group. ERG/ETV1 gene rearrangements and PTEN gene loss status should now prospectively be incorporated into a predictive model to establish whether predictive performance is improved.Conclusions: Our data suggest that FISH studies of PTEN gene loss and ERG/ETV1 gene rearrangements could be pursued for patient stratification, selection and hypothesis-generating subgroup analyses in future PCa clinical trials and potentially in patient management. [ABSTRACT FROM AUTHOR]

Background: Histone deacetylase blockade can promote heat shock protein 90 (HSP90) acetylation, abrogating androgen receptor signaling. A phase II trial of the histone deacetylase inhibitor (HDACi) romidepsin was conducted in patients with progressing, metastatic, castration-resistant prostate cancer (CRPC). [ABSTRACT FROM PUBLISHER]

Background: This study was performed to test the hypothesis that expression of small heat shock protein Hsp-27 is, at diagnosis, a reliable predictive biomarker of clinically aggressive prostate cancer.Methods: A panel of tissue microarrays constructed from a well-characterised cohort of 553 men with conservatively managed prostate cancer was stained immunohistochemically to detect Hsp-27 protein. Hsp-27 expression was compared with a series of pathological and clinical parameters, including outcome.Results: Hsp-27 staining was indicative of higher Gleason score (P<0.001). In tissue cores having a Gleason score >7, the presence of Hsp-27 retained its power to independently predict poor clinical outcome (P<0.002). Higher levels of Hsp-27 staining were almost entirely restricted to cancers lacking ERG rearrangements (chi2 trend=31.4, P<0.001), although this distribution did not have prognostic significance.Interpretation: This study has confirmed that, in prostate cancers managed conservatively over a period of more than 15 years, expression of Hsp-27 is an accurate and independent predictive biomarker of aggressive disease with poor clinical outcome (P<0.001). These findings suggest that apoptotic and cell-migration pathways modulated by Hsp-27 may contain targets susceptible to the development of biologically appropriate chemotherapeutic agents that are likely to prove effective in treating aggressive prostate cancers. [ABSTRACT FROM AUTHOR]

The discovery of ETS gene fusions as common events in prostate cancer represents a paradigmatic shift in the significance attributed to chromosomal translocations as a key mechanistic player in carcinogenesis. However, these chromosomal fusion events are poorly understood, as their functional significance and therapeutic potential remain unclear. Nonetheless, they have generally been used as novel molecular handles to sub-categorise the broad diversity of prostate cancers mainly via the use of fluorescence in-situ hybridisation-based "break-apart assays". Thus, the potential roles of these ETS gene fusion events are being actively explored and are discussed in this review within the context of the existing scientific and clinical climates. Examples include their possible utilities as screening tools, markers for risk stratification and predictors of responses to therapies (in particular hormonal manipulation), biomarkers to guide early phase clinical trials, as well as therapeutic targets. Work is ongoing to address the many questions surrounding these pursuits in a very rapidly evolving area of research, and it is believed that an improved understanding of the biology underpinning these genetic events is vital in order to optimise their use in anticancer drug development. [ABSTRACT FROM AUTHOR]

A fluorescence in situ hybridisation (FISH) assay has been used to screen for ETV1 gene rearrangements in a cohort of 429 prostate cancers from patients who had been diagnosed by trans-urethral resection of the prostate. The presence of ETV1 gene alterations (found in 23 cases, 5.4%) was correlated with higher Gleason Score (P=0.001), PSA level at diagnosis (P=<0.0001) and clinical stage (P=0.017) but was not linked to poorer survival. We found that the six previously characterised translocation partners of ETV1 only accounted for 34% of ETV1 re-arrangements (eight out of 23) in this series, with fusion to the androgen-repressed gene C15orf21 representing the commonest event (four out of 23). In 5'-RACE experiments on RNA extracted from formalin-fixed tissue we identified the androgen-upregulated gene ACSL3 as a new 5'-translocation partner of ETV1. These studies report a novel fusion partner for ETV1 and highlight the considerable heterogeneity of ETV1 gene rearrangements in human prostate cancer. [ABSTRACT FROM AUTHOR]

Castration-resistant prostate cancer (CRPC) is now the second most common cause of male cancer-related mortality. Although docetaxel has recently been shown to extend the survival of patients with CRPC in two large randomised phase III studies, subsequent treatment options remain limited for these patients. A greater understanding of the molecular causes of castration resistance is allowing a more rational approach to the development of new drugs and many new agents are now in clinical development. Therapeutic targets include the adrenal steroid synthesis pathway, androgen receptor signalling, the epidermal growth factor receptor family, insulin growth factor-1 receptor, histone deacetylase, heat shock protein 90 and the tumour vasculature. Drugs against these targets are giving an insight into the molecular pathogenesis of this disease and promise to improve patient quality of life and survival. Finally, the recent discovery of chromosomal translocations resulting in the upregulation of one of at least 3 ETS genes (ERG, ETV1, ETV4) may lead to novel agents for the treatment of this disease. [ABSTRACT FROM AUTHOR]

The prostate gland is the site of the most commonly diagnosed cancer in men in USA and UK, accounting for one in five of new cases of male cancer. Common with many other cancer types, prostate cancer is believed to arise from a stem cell that shares characteristics with the normal stem cell. Normal prostate epithelial stem cells were recently identified and found to have a basal cell phenotype together with expression of CD133. Preliminary data have now emerged for a prostate cancer stem cell that also expresses cell surface CD133 but lacks expression of the androgen receptor. Here we examine the evidence supporting the existence of prostate cancer stem cells and discuss possible mechanisms of stem cell maintenance. [ABSTRACT FROM AUTHOR]

To assess toxicity and patient quality of life after stereotactic body radiotherapy (SBRT) to oligoprogressive disease (OPD) in patients with metastatic castrate-resistant prostate cancer (CRPC) on androgen receptor targeted agents (ARTA). This phase II trial enrolled patients with metastatic CRPC with ≤ 2 oligoprogressive lesions in bone, lymph node, lung, or prostate. All patients were receiving systemic treatment with abiraterone or enzalutamide at the time of oligoprogression. All patients received SBRT to the OPD site(s) and continued the current ARTA. Patients received 30 Gy in 5 fractions (alternate days) to the OPD site. The primary endpoint of the trial is to assess if SBRT to OPD sites results in progression free survival of >6 months. The primary endpoint for this toxicity analysis is the rate of grade 3 or higher adverse events at any timepoint up to 6 months after SBRT. Secondary endpoints included comparing pre- and post-SBRT patient-related outcomes reported using visual analogue scale scores and EQ-5D health questionnaire. Forty enrolled patients had at least 6 months of follow-up at the time of analysis. Grade 3 or higher toxicity from any cause recorded using common terminology criteria for adverse events and radiation therapy oncology group was found in 8/40 (20%) of patients, but only 1/40 (2.5%) was deemed possibly related to SBRT. There was no significant difference in mean EQ5D visual analogue scale score from baseline to each timepoint after SBRT (p = 0.449). In this prospective phase II clinical trial for OPD whilst on ARTA in the CRPC setting, we report low grade ≥ 3 toxicity after SBRT. There is no discernible change in patient-reported quality of life due to SBRT treatment. The final results of progression-free survival and toxicity of SBRT treatment will be reported once further follow-up is complete. • Stereotactic radiotherapy to oligoprogressive disease in metastatic prostate cancer patients on targeted agents is feasible. • Stereotactic body radiotherapy is well tolerated in patients with castrate-resistant prostate cancer. • There is minimal treatment-related effect on quality of life and patient-reported outcomes. [ABSTRACT FROM AUTHOR]

Fusion of the hormone-regulated gene TMPRSS2 with ERG occurs in 50-70% of prostate cancers; fusions of ETV1 with one of several partners occur in approximately 10% of prostate cancers. These two translocations are mutually exclusive. The presence of subclasses of these chromosomal rearrangements may indicate worse prognosis, with the subclass 2+Edel, which has duplication of TMPRSS2:ERG fusion sequences, indicating particularly poor survival. However as this case shows, significant heterogeneity can exist with ERG and ETV1 rearrangements occurring in both prostate intra-epithelial neoplasia and cancer in the same prostatectomy specimen and with adjacent cancer areas containing a single copy, duplication and even triplication of the rearranged locus. As the majority of ETS gene fusions are hormone regulated, they could explain the pathogenesis underlying exquisitely hormone-sensitive prostate cancer. This is exemplified by the case presented here of a patient diagnosed in 1991 who remains asymptomatic and chemotherapy-naïve after having long-lasting tumour responses to multiple lines of systemic hormonal treatments. [ABSTRACT FROM AUTHOR]

The phase III CHAARTED trial established upfront androgen-deprivation therapy (ADT) plus docetaxel (D) as a standard for metastatic hormone-sensitive prostate cancer (mHSPC) based on meaningful improvement in overall survival (OS). Biological prognostic markers of outcomes and predictors of chemotherapy benefit are undefined. Whole transcriptomic profiling was performed on primary PC tissue obtained from patients enrolled in CHAARTED prior to systemic therapy. We adopted an a priori analytical plan to test defined RNA signatures and their associations with HSPC clinical phenotypes and outcomes. Multivariable analyses (MVAs) were adjusted for age, Eastern Cooperative Oncology Group status, de novo metastasis presentation, volume of disease, and treatment arm. The primary endpoint was OS; the secondary endpoint was time to castration-resistant PC. The analytic cohort of 160 patients demonstrated marked differences in transcriptional profile compared with localized PC, with a predominance of luminal B (50%) and basal (48%) subtypes, lower androgen receptor activity (AR-A), and high Decipher risk disease. Luminal B subtype was associated with poorer prognosis on ADT alone but benefited significantly from ADT + D [OS: hazard ratio (HR) 0.45; P = 0.007], in contrast to basal subtype which showed no OS benefit (HR 0.85; P = 0.58), even in those with high-volume disease. Higher Decipher risk and lower AR-A were significantly associated with poorer OS in MVA. In addition, higher Decipher risk showed greater improvements in OS with ADT + D (HR 0.41; P = 0.015). This study demonstrates the utility of transcriptomic subtyping to guide prognostication in mHSPC and potential selection of patients for chemohormonal therapy, and provides proof of concept for the possibility of biomarker-guided selection of established combination therapies in mHSPC. • Gene expression profiles of mHSPC show divergent prognoses and differential benefit from chemohormonal therapy. • High Decipher, luminal B and AR-low profiles define subgroups associated with shorter survival on androgen deprivation alone. • Expression profiling prior to therapy forms a basis for biomarker-guided selection of therapy combinations in mHSPC. [ABSTRACT FROM AUTHOR]

Plasma tumor DNA fraction is prognostic in metastatic cancers. This could improve risk stratification before commencing a new treatment. We hypothesized that a second sample collected after one cycle of treatment could refine outcome prediction of patients identified as poor prognosis based on plasma DNA collected pre-treatment. Plasma DNA [128 pre-treatment, 134 cycle 2 day 1 (C2D1), and 49 progression] from 151 chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC) patients in a phase II study of abiraterone acetate (NCT01867710) were subjected to custom targeted next-generation sequencing covering exons of these genes: TP53 , AR , RB1 , PTEN , PIK3CA , BRCA1, BRCA2 , ATM , CDK12 , CHEK2 , FANCA HDAC2 and PALB2. We also captured 1500 pan-genome regions enriched for single nucleotide polymorphisms to allow detection of tumor DNA using the rolling B-allele method. We tested associations with overall survival (OS) and progression-free survival (PFS). Plasma tumor DNA detection was associated with shorter OS [hazard ratio (HR): 2.89, 95% confidence intervals (CI): 1.77-4.73, P ≤ 0.0001] and PFS (HR: 2.05; 95% CI: 1.36-3.11, P < 0.001). Using a multivariable model including plasma tumor DNA, patients who had a TP53 , RB1 or PTEN gene alteration pre-treatment and at C2D1 had a significantly shorter OS than patients with no alteration at either time point (TP53 : HR 7.13, 95% CI 2.37-21.47, P < 0.001; RB1 : HR 6.24, 95% CI 1.97-19.73, P = 0.002; PTEN : HR 11.9, 95% CI 3.6-39.34, P < 0.001). Patients who were positive pre-treatment and converted to undetectable had no evidence of a difference in survival compared with those who were undetectable pre-treatment (P = 0.48, P = 0.43, P = 0.5, respectively). Progression samples harbored AR gain in all patients who had gain pre-treatment (9/49) and de novo AR somatic point mutations were detected in 8/49 patients. Plasma gene testing after one cycle treatment refines prognostication and could provide an early indication of treatment benefit. • The rolling B-allele method applied to a clinical assay allows detection of plasma tumor DNA independent of mutation calls. • Patients with TP53 , RB1 or PTEN alterations persisting after one cycle of treatment have the worst outcomes. • Conversion of alterations after one cycle is associated with similar outcomes as patients negative before treatment. • Plasma AR gain pre-treatment persists at progression while AR point mutations appear de novo in ∼16%. [ABSTRACT FROM AUTHOR]

Standard of care management for metastatic castration sensitive prostate cancer (mCSPC) includes androgen deprivation therapy (ADT) with docetaxel or second-generation anti-androgen therapy. Recently, randomized data has demonstrated radiotherapy to the prostate is associated with an improvement in overall survival among patients with low-volume metastatic disease. Tumor genomics represents an additional dimension to understand the clinical trajectory of patients with mCSPC. Herein we aim to evaluate a high-risk genomic signature for its ability to predict response to prostate directed therapy (PDT). We performed a single institution retrospective review of men with low-volume mCSPC who underwent next-generation sequencing of their tumor. Patients were classified according to the presence of high-risk (HiRi) mutation including pathogenic mutations in either TP53, ATM, BRCA1/2 , or Rb1. Our primary endpoint was to determine the effect of PDT on overall survival (OS) in patients with and without a HiRi mutation. Survival analysis was performed with the Kaplan-Meier method compared with log-rank test and multivariable cox regression. Interaction between HiRi mutation and PDT was evaluated. A total of 101 patients with synchronous low-volume CSPC were included in our analysis with a median follow-up of 44 months. Approximately half of patients were found to have a HiRi pathogenic mutation (48.5%) with TP53 mutations accounting for 75.5% of HiRi mutations. On multivariable cox regression PDT was associated with improvement in OS (HR = 0.37, 95% CI 0.16-0.88; p = 0.03). When stratified by presence of HiRi mutation, PDT was not associated with any clinical outcome. Patients with HiRi mutations demonstrated a median OS of 73 vs 66.8 months (p = 0.28) for no PDT and PDT, respectively. Conversely, patients without a HiRi mutation demonstrated a significant improvement in median OS of 60 vs 105.3 months (p<0.01) for no PDT and PDT, respectively. The p-value for interaction for OS between PDT and HiRi mutation was statistically significant (p<0.01). Here we have identified a high-risk genomic biomarker that appears predictive for response to PDT in men with synchronous low-volume mCSPC. Further work validating these results with prospective randomized data is warranted. [ABSTRACT FROM AUTHOR]

Decipher is a prognostic genomic classifier (GC) validated in several prospective NRG Oncology Phase III trials. Herein, we validate the GC in pre-treatment biopsy samples for risk stratification in a cohort of high-risk men treated with definitive radiotherapy and androgen suppression with or without docetaxel chemotherapy. As per a pre-specified and approved NCI analysis plan (Navigator #1061), we obtained available formalin-fixed paraffin-embedded tissue from biopsy specimens from the NRG biobank from patients enrolled on the NRG/RTOG 0521 randomized phase III trial. After central review, the highest-grade tumors were profiled on clinical-grade whole-transcriptome arrays (Veracyte, San Diego, CA) and GC scores were obtained. Pre-specified categorical GC scores, adjusted for archival tissue analysis, were used to define higher (>0.46) and lower (≤0.46) risk groups. The primary objective was to validate the independent prognostic ability of GC for metastasis-free survival (MFS) with Cox multivariable analyses (MVA). Samples were obtained from 283 consented, evaluable patients with tissue (50% of trial) yielding 183 (65%) GC scores that passed quality metrics, 91 from control and 92 from the interventional arm. Median age was 66 years, median PSA was 19.3 ng/uL (IQR: 8.1-41.4), 81% had clinical stage ≥T2 and 80% had Gleason score ≥8 (47% ≥9). Median GC score was 0.55 (IQR: 0.38-0.78) and overall the arms were balanced for key covariates. With a median follow-up of 9.9 years (IQR: 9.3, 10.7), 67 MFS events including 34 distant metastases (DM) were observed. On MVA, only the GC (per 0.1 unit) was independently associated with MFS (HR 1.12, 95% CI 1.01-1.25) as well as DM (sHR 1.22, 95% CI 1.06-1.41), whereas the 4 pre-defined trial risk groups used for stratification (based on Gleason score, T-stage and PSA), randomization and patient age were not. For categorical GC, on MVA, higher-risk GC patients (65%) had worse DM (sHR 2.82, 95% CI 1.1-7.3) compared to those with lower GC. Cumulative incidence of DM at 10-years was 27% for higher GC vs 9% (95% CI 7-18%) for lower GC. No biomarker-by-treatment interaction with GC and the addition of docetaxel was detected. In pre-treatment biopsy samples from a randomized Phase 3 trial cohort, GC demonstrated its ability to further risk stratify clinically high-risk men demonstrating an independent association of GC score with DM and MFS. High-risk prostate cancer is a heterogeneous disease state and GC can improve risk stratification to help personalize shared decision-making. NRG-GU009/PREDICT-RT (NCT04513717) aims to determine the optimal therapy based on GC score for high-risk prostate cancer. [ABSTRACT FROM AUTHOR]

Background STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients. Methods We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional. Results Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n  = 724) or SOC + docetaxel (n  = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69–0.95, P  = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P  = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57–0.76, P  < 0.001) and progression-free survival (HR = 0.69, 95% CI 0.59–0.81, P  < 0.001) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P  > 0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression). Conclusions The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden. [ABSTRACT FROM AUTHOR]

Prostate cancer progression and treatment relapse is associated with changes in the androgen receptor axis, and analysis of alternations of androgen receptor signaling is valuable for prognostics and treatment optimization. The profile of androgen receptor axis is currently obtained from biopsy specimens, which are not always easy to obtain. Moreover, the information acquired only provides a snapshot of the tumor biology, with strict spatial and temporal limitations. On the other hand, circulation is easily accessible source of both circulating tumor cells and circulating tumor DNA, which can be sampled at numerous time points. This Review will explore the potential use of androgen receptor axis alternations detectable in the blood in therapeutic decision-making and precision medicine for advancing metastatic castration-resistant prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Abiraterone and cabazitaxel improve survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We conducted an open-label phase I/II trial of cabazitaxel plus abiraterone to assess the antitumor activity and tolerability in patients with progressive mCRPC after docetaxel (phase I), and after docetaxel and abiraterone (phase II) (NCT01511536). Patients and methods: The primary objectives were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel plus abiraterone (phase I), and the prostate-specific antigen (PSA) response defined as a≥50% decrease confirmed ≥3 weeks later with this combination (phase II). Results: Ten patients were enrolled in the phase I component; nine were evaluable. No DLTs were identified. The MTD was established as the approved doses for both drugs (cabazitaxel 25 mg/m2 every 3 weeks and abiraterone 1000mg once daily). Daily abiraterone treatment did not impact on cabazitaxel clearance. Twenty-seven patients received cabazitaxel plus abiraterone plus prednisone (5mg twice daily) in phase II. The median number of cycles administered (cabazitaxel) was seven (range: 1-28). Grade 3-4 treatment-emergent adverse events included asthenia (in 5 patients; 14%), neutropenia (in 5 patients; 14%) and diarrhea (in 3 patients; 8%). Nine patients (24%) required dose reductions of cabazitaxel. Of 26 evaluable patients, 12 achieved a PSA response [46%; 95% confidence interval (CI): 26.6-66.6%]. Median PSA-progression-free survival was 6.9 months (95% CI: 4.1-10.3 months). Of 14 patients with measurable disease at baseline, 3 (21%) achieved a partial response per response evaluation criteria in solid tumors. Conclusions: The combination of cabazitaxel and abiraterone has a manageable safety profile and shows antitumor activity in patients previously treated with docetaxel and abiraterone. [ABSTRACT FROM AUTHOR]

Aim To test the hypothesis that computed tomography (CT)-based signs might precede symptomatic malignant spinal cord compression (MSCC) in men with metastatic castration-resistant prostate cancer (mCRPC). Materials and methods A database was used to identify suitable mCRPC patients. Staging CT images were retrospectively reviewed for signs preceding MSCC. Signs of malignant paravertebral fat infiltration and epidural soft-tissue disease were defined and assessed on serial CT in 34 patients with MSCC and 58 control patients. The presence and evolution of the features were summarized using descriptive statistics. Results In MSCC patients, CT performed a median of 28 days prior to the diagnostic magnetic resonance imaging (MRI) demonstrated significant epidural soft tissue in 28 (80%) patients. The median time to MSCC from a combination of overt malignant paravertebral and epidural disease was 2.7 (0–14.6) months. Conversely, these signs were uncommon in the control cohort. Conclusions Significant malignant paravertebral and/or epidural disease at CT precede MSCC in up to 80% of mCRPC patients and should prompt closer patient follow-up and consideration of early MRI evaluation. These CT-based features require further prospective validation. [ABSTRACT FROM AUTHOR]

Abiraterone is a new hormonal drug for metastatic castration resistant prostate cancer. In a retrospective analysis, neutrophil/lymphocyte ratio (NLR) ≤ 5 and restricted metastatic spread to either bones or lymph nodes were associated with PSA response to abiraterone. These two variables were combined to a score that was associated with PSA response and OS, in both a training and a validation cohort.Background Abiraterone acetate (abiraterone) prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC). This study's objective was to retrospectively identify factors associated with prostate-specific antigen (PSA) response to abiraterone and validate them in an independent cohort. We hypothesized that the neutrophil/lymphocyte ratio (NLR), thought to be an indirect manifestation of tumor-promoting inflammation, may be associated with response to abiraterone. Patients and methods All patients receiving abiraterone at the Princess Margaret (PM) Cancer Centre up to March 2013 were reviewed. The primary end point was confirmed PSA response defined as PSA decline ≥50% below baseline maintained for ≥3 weeks. Potential factors associated with PSA response were analyzed using univariate and multivariable analyses to generate a score, which was then evaluated in an independent cohort from Royal Marsden (RM) NHS foundation. Results A confirmed PSA response was observed in 44 out of 108 assessable patients (41%, 95% confidence interval 31%–50%). In univariate analysis, lower pre-abiraterone baseline levels of lactate dehydrogenase, an NLR ≤ 5 and restricted metastatic spread to either bone or lymph nodes were each associated with PSA response. In multivariable analysis, only low NLR and restricted metastatic spread remained statistically significant. A score derived as the sum of these two categorical variables was associated with response to abiraterone (P = 0.007). Logistic regression analysis on an independent validation cohort of 245 patients verified that this score was associated with response to abiraterone (P = 0.003). It was also associated with OS in an exploratory analysis. Conclusions A composite score of baseline NLR and extent of metastatic spread is associated with PSA response to abiraterone and OS. Our data may help understand the role of systemic inflammation in mCRPC and warrant further research. [ABSTRACT FROM PUBLISHER]

Background A number of genomic alterations detected in plasma DNA have been associated with worse outcome in mCRPC (Jayaram et al Cancer Discov). We hypothesized that patients (pts) who harbored a genomic alteration that decreased after 1C of treatment derive treatment benefit and this would distinguish them from truly resistant pts. Methods Plasma DNA (128 C1 day (D) 1,134 C2 D1, and 41 progression [PD] from chemotherapy-naïve mCRPC pts in a phase 2 study of AA (NCT01867710), recently reported (Attard et al, Jama Onc) were subjected to custom targeted-capture NGS. Assay was optimised and validated to detect pathogenic point mutations (PM), deletions and copy number alterations (CNA) inAR, TP53, RB1, PIK3CA and DNA repair deficient genes (DRD): BRCA1, BRCA2, FANCA, ATM, CHEK2, HDAC2, BRIP1, and PALB2. Pts were followed up for overall survival (OS) and radiographic progression-free survival (rPFS) (48 months). Results Pts were classified into 4 groups based on whether a gene alteration was detectable (+) or not (-) at C1D1 and C2D1 respectively. At C1D1, 49 pts (37.5%) had + alterations. Pts who converted from + to - (+/-) had similar outcomes as pts who remained - (-/-) and those that did not convert had worst outcomes (+/+) (Table). In matched C1D1 and PD samples pts with ARgain (G) at C1D1 were more ARG at PD (p = <0.01) while ARPM were only detected in PD samples that were ARnormal (N) at C1D1. DRD + pts at C1D1 were more likely DRD + at PD (p = <0.1). Table: 9P Gene conversion (N)  C2 conversion (%)  rPFS   OS   p  HR  95.0% CI  p  HR  95.0% CI  C1D1 + vs -    <0.01  2.0  1.23  3.30  <0.01  2.5  1.51  4.27    TP53  -/- (85) vs +/- (16)  60.7  0.23  1.4  0.74  2.77  0.7  1.2  0.55  2.51  +/ + (8) vs +/-  0.07  2.2  0.73  6.7  <0.01  4.2  1.10  16.44    AR  -/-(88) vs +/-(16)  69.6  0.46  1.3  0.61  2.7  0.09  1.8  0.79  3.91  +/ + (7) vs +/-  <0.01  3.3  0.9  11.4  0.07  2.5  0.65  9.84    RB1    -/-(92) vs +/- (12)  66.67  0.79  1.1  0.5  2.4  0.37  1.4  0.60  3.27  +/+6) vs +/-  <0.01  5.7  1.11  29.1  <0.01  5.6  0.92  34.26    DRD  -/-(96) vs +/-(10)  73.3  0.85  0.9  0.44  2.0  1.0  1.0  0.43  2.36  +/ + (4) vs +/-  0.03  4.4  0.29  69.1  <0.01  4.7  0.72  30.39    PIK3CA  +/ + (100) vs +/-(5)  50  0.02  2.7  0.65  11.37  0.06  2.6  0.54  12.33  +/ + (5) vs +/-  0.29  1.9  0.51  6.85  0.7  1.3  0.32  5.2  Gene conversion (N)  C2 conversion (%)  rPFS   OS   p  HR  95.0% CI  p  HR  95.0% CI  C1D1 + vs -    <0.01  2.0  1.23  3.30  <0.01  2.5  1.51  4.27    TP53  -/- (85) vs +/- (16)  60.7  0.23  1.4  0.74  2.77  0.7  1.2  0.55  2.51  +/ + (8) vs +/-  0.07  2.2  0.73  6.7  <0.01  4.2  1.10  16.44    AR  -/-(88) vs +/-(16)  69.6  0.46  1.3  0.61  2.7  0.09  1.8  0.79  3.91  +/ + (7) vs +/-  <0.01  3.3  0.9  11.4  0.07  2.5  0.65  9.84    RB1    -/-(92) vs +/- (12)  66.67  0.79  1.1  0.5  2.4  0.37  1.4  0.60  3.27  +/+6) vs +/-  <0.01  5.7  1.11  29.1  <0.01  5.6  0.92  34.26    DRD  -/-(96) vs +/-(10)  73.3  0.85  0.9  0.44  2.0  1.0  1.0  0.43  2.36  +/ + (4) vs +/-  0.03  4.4  0.29  69.1  <0.01  4.7  0.72  30.39    PIK3CA  +/ + (100) vs +/-(5)  50  0.02  2.7  0.65  11.37  0.06  2.6  0.54  12.33  +/ + (5) vs +/-  0.29  1.9  0.51  6.85  0.7  1.3  0.32  5.2  Table: 9P Gene conversion (N)  C2 conversion (%)  rPFS   OS   p  HR  95.0% CI  p  HR  95.0% CI  C1D1 + vs -    <0.01  2.0  1.23  3.30  <0.01  2.5  1.51  4.27    TP53  -/- (85) vs +/- (16)  60.7  0.23  1.4  0.74  2.77  0.7  1.2  0.55  2.51  +/ + (8) vs +/-  0.07  2.2  0.73  6.7  <0.01  4.2  1.10  16.44    AR  -/-(88) vs +/-(16)  69.6  0.46  1.3  0.61  2.7  0.09  1.8  0.79  3.91  +/ + (7) vs +/-  <0.01  3.3  0.9  11.4  0.07  2.5  0.65  9.84    RB1    -/-(92) vs +/- (12)  66.67  0.79  1.1  0.5  2.4  0.37  1.4  0.60  3.27  +/+6) vs +/-  <0.01  5.7  1.11  29.1  <0.01  5.6  0.92  34.26    DRD  -/-(96) vs +/-(10)  73.3  0.85  0.9  0.44  2.0  1.0  1.0  0.43  2.36  +/ + (4) vs +/-  0.03  4.4  0.29  69.1  <0.01  4.7  0.72  30.39    PIK3CA  +/ + (100) vs +/-(5)  50  0.02  2.7  0.65  11.37  0.06  2.6  0.54  12.33  +/ + (5) vs +/-  0.29  1.9  0.51  6.85  0.7  1.3  0.32  5.2  Gene conversion (N)  C2 conversion (%)  rPFS   OS   p  HR  95.0% CI  p  HR  95.0% CI  C1D1 + vs -    <0.01  2.0  1.23  3.30  <0.01  2.5  1.51  4.27    TP53  -/- (85) vs +/- (16)  60.7  0.23  1.4  0.74  2.77  0.7  1.2  0.55  2.51  +/ + (8) vs +/-  0.07  2.2  0.73  6.7  <0.01  4.2  1.10  16.44    AR  -/-(88) vs +/-(16)  69.6  0.46  1.3  0.61  2.7  0.09  1.8  0.79  3.91  +/ + (7) vs +/-  <0.01  3.3  0.9  11.4  0.07  2.5  0.65  9.84    RB1    -/-(92) vs +/- (12)  66.67  0.79  1.1  0.5  2.4  0.37  1.4  0.60  3.27  +/+6) vs +/-  <0.01  5.7  1.11  29.1  <0.01  5.6  0.92  34.26    DRD  -/-(96) vs +/-(10)  73.3  0.85  0.9  0.44  2.0  1.0  1.0  0.43  2.36  +/ + (4) vs +/-  0.03  4.4  0.29  69.1  <0.01  4.7  0.72  30.39    PIK3CA  +/ + (100) vs +/-(5)  50  0.02  2.7  0.65  11.37  0.06  2.6  0.54  12.33  +/ + (5) vs +/-  0.29  1.9  0.51  6.85  0.7  1.3  0.32  5.2  Conclusions These findings suggest that tracking gene aberrations in plasma DNA could be an early marker of treatment efficacy. Clinical trial identification NCT01867710. Legal entity responsible for the study The authors. Funding Janssen Pharmaceuticals. Disclosure D. Shen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen Research and Development. A. Wingate: Honoraria (self), Research grant / Funding (self), Travel / Accommodation / Expenses: Janssens. C. Sternberg: Honoraria (self): Astellas Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Sanofi; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: Eisai; Advisory / Consultancy, Research grant / Funding (institution): Clovis Oncology; Advisory / Consultancy, Research grant / Funding (institution): Incyte; Advisory / Consultancy: Roche; Advisory / Consultancy: Ipsen; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Medscape; Advisory / Consultancy: UroToday; Advisory / Consultancy: Genentech; Advisory / Consultancy: Medivation; Research grant / Funding (institution): Exelixis. R. Jones: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas Pharma; Honoraria (self), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Travel / Accommodation / Expenses: MSD Oncology; Honoraria (self): BMS; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Travel / Accommodation / Expenses: Ipsen; Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Exelixis; Honoraria (self): Sanofi; Honoraria (self): Genentech; Honoraria (self): Eusa Pharma; Honoraria (self): Pharmacyclics. A. Berruti: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen-Cilag; Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma; Travel / Accommodation / Expenses: Sanofi. F. Lefresne: Honoraria (self), Research grant / Funding (self), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Johnson & Johnson. M. Lahaye: Honoraria (self), Advisory / Consultancy, Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen-Cilag. S. Thomas: Leadership role, Research grant / Funding (self), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Janssen Research and Development. S. Joshi: Honoraria (self), Travel / Accommodation / Expenses, Full / Part-time employment: Janssen Research and Development. M. Gormley: Travel / Accommodation / Expenses, Licensing / Royalties, Full / Part-time employment: Janssen Research and Development. B. Tombal: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas Pharma; Honoraria (institution), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Ferring; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: Takeda; Advisory / Consultancy: Steba Biotech; Honoraria (self): Myovant Sciences. A. Merseburger: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen-Cilag; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas Pharma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Honoraria (self): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (self): Eisai; Honoraria (self): Takeda; Honoraria (self): Pfizer; Honoraria (self), Research grant / Funding (self): Novartis; Research grant / Funding (institution): Clovis Oncology. D. Ricci: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Janssen. G. Attard: Honoraria (self), Honoraria (institution), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astellas Pharma; Advisory / Consultancy: Janssen-Cilag; Research grant / Funding (institution): Innocrin; Research grant / Funding (institution): Arno; Advisory / Consultancy, Travel / Accommodation / Expenses: Ventana Medical Systems; Travel / Accommodation / Expenses: Abbott Laboratories; Licensing / Royalties: ICR Rewards to Inventors; Honoraria (self), Travel / Accommodation / Expenses: Abbott; Advisory / Consultancy, Travel / Accommodation / Expenses: ESSA; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Tumour DNA circulates in the plasma of cancer patients admixed with DNA from non-cancerous cells. The genomic landscape of plasma tumour DNA has been characterised in metastatic castration-resistant prostate cancer (mCRPC) but the plasma methylome in mCRPC has not been extensively explored. Methods mCRPC plasma samples collected from three different centres were concurrently subject to targeted genomic and pan-genome methylation profiling. The treatment courses and outcomes were also obtained. Tumour fraction of each plasma sample was estimated based on heterogyzous SNPs located in two truncal genomic deletions (8q21 and 21q22). Targeted methylome was performed using pre-designed capture panel followed by deep sequencing. We integrated genomic information with methylation data to extract methylation signatures associated with genomically-determined tumour fraction or private to individual's tumour. Results Principal component analysis on the mCRPC plasma methylome indicated that the main contributor to methylation variance (principal component one, or PC1) was strongly correlated with genomically-determined tumour fraction (r=-0.96; P < 10-9), characterised by hypermethylation of targets of the polycomb repressor complex 2 components. Further deconvolution of the top PC1 correlated segments revealed that these segments comprised of methylation patterns specific to either prostate cancer or prostate normal epithelium. To extract information specific to an individual's cancer, we then focused on an orthogonal methylation signature which revealed enrichment for androgen receptor (AR) binding sequences and where hypomethylation of these segments associated with AR copy number gain. Individuals harbouring this methylation pattern had a more aggressive clinical course, including a significantly shorter overall survival (HR = 8.18, 95% CI = 1.93–34.76, P = 0.0044). Conclusions Plasma methylome analysis can accurately quantitate tumour fraction and identify distinct biologically-relevant mCRPC phenotypes associated with worse clinical outcome. Clinical trial identification Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Italy (REC 2192/2013) Royal Marsden, London, UK (REC 04/Q0801/6) PREMIERE trial (EudraCT: 2014-003192-28, NCT02288936). Legal entity responsible for the study The authors. Funding Cancer Research UK (CRUK), Prostate Cancer Foundation (PCF). Disclosure V. Conteduca: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Janssen-Cilag; Honoraria (self), Advisory / Consultancy: Sanofi-Aventis. E. Gonzalez-Billalebeita: Honoraria (self): Astellas; Honoraria (self): Janssen-Cilag; Honoraria (self): Sanofi-Aventis. U.D. Giorgi: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Janssen-Cilag,; Honoraria (self), Advisory / Consultancy: Sanofi-Aventis. G. Attard: Honoraria (self): Institute of Cancer Research; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Medivation; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Arno. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]