bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical events associated with cumulative corticosteroid use in patients with castration-resistant prostate cancer: An administrative claims analysis.
Authors: Lowentritt Benjamin H , Penson David F. , Wilson Samuel C. , Song Yan , Yang Hongbo , Ramaswamy Krishnan , Schultz Neil M.
Published: March 2019

236

Background: Corticosteroids (CSs) are used in the treatment of castration-resistant prostate cancer (CRPC) to manage adverse events and tumor-related symptoms. This study evaluated the impact of cumulative CS use on the risk of developing specific clinical events in men with CRPC. Methods: Adult chemotherapy-naïve patients who initiated a CRPC treatment following surgical or medical castration were identified from the MarketScan database (2007–2016). Patients were grouped into 4 cohorts based on their cumulative CS dose since 1 year before initiating their CRPC treatment: no use (0 g); low use ( < 0.5 g); medium use (0.5–2.0 g); and high use ( > 2.0 g). Time-dependent Cox proportional hazards models adjusting for baseline characteristics were used to evaluate the association between CS use and the risk of events (fracture, infection, endocrine disorders, acute cardiovascular [CV] events, peptic ulcer, and mental health conditions), with no CS use as the reference group. Results: This study included 9425 patients: 6765 no CS use; 1660 low use; 655 medium use; and 345 high use. On average, the no-CS-use cohort was older and had a lower comorbidity burden than the other 3 cohorts. During the study period, cumulative CS exposure (across all categories) was associated with a significantly higher risk of developing an infection (comparing high-use vs. no-use cohort, adjusted hazard ratio [HR] = 2.55; p for trend < 0.001), fracture (HR = 1.59; p for trend < 0.001), and acute CV events (HR = 1.62; p for trend < 0.001). Also, patients in the high-CS-use cohort were more likely to develop endocrine disorder (HR = 1.61; p for trend < 0.001), peptic ulcer (HR = 1.91; p for trend < 0.001), or mental health condition (HR = 1.28; p for trend = 0.014) in comparison with patients in the no-use cohort. Conclusions: Cumulative CS exposure was associated with a greater risk of clinical events such as infection, fracture, and acute CV events among men with CRPC. The risk was more pronounced with higher cumulative CS doses of > 2.0 g. The study provides important data on the impacts of cumulative CS use on the risk of clinical events among CRPC patients who tend to be older and more prone to these events.
Cell plasticity associated to taxane-resistance in preclinical cell models and in circulating tumor cells from metastatic castration-resistant prostate cancer patients.
Authors: Montalbo Ruth , Jiménez Natalia , Mila Maria , Reig Òscar , Victoria Iván , Prat Aleix , Marin Mercedes , Mellado Begona
Published: March 2019

238

Background: Treatment resistance is associated with tumor cells molecular plasticity. In metastatic castration resistant prostate cancer (mCRPC), alterations in androgen receptor (AR) have been described as predictors of shorter response to hormonal treatments. Previously, we associated epithelial to mesenchymal transition (EMT) phenotype with chemotherapy resistance. However, other molecular changes responsible of such resistance should be elucidated. Here, we investigate the effect of taxanes on cell plasticity through in vitro models and in circulating tumor cells (CTCs) from mCRPC patients. Methods: Molecular differences due to taxane-exposure were evaluated in cell models of mCRPC (PC-3 and DU-145 resistant to taxanes). Global gene expression (GE) analysis was performed using Affimetrix GeneChip Human Gene 2.0 arrays. GE related with AR axis, EMT and neuroendocrine (NE) phenotypes was validated by quantitative (qRT-PCR). Clinical validation was performed in CTCs from 24 mCRPC patients collected prior and post taxane-treatment. CTCs enrichment was achieved by Isoflux technology through a personalized combination of EpCAM, CDH2 and PSCA antibodies. Results: GE analysis revealed a different deregulation pattern related to the EMT, NE and AR-related phenotypes in resistant CRPC-cells compared to parental cells. Docetaxel resistance was more associated to an EMT phenotype while cabazitaxel resistance to NE patterns. GE patterns in CTCs at post taxane-treatment showed a common upregulation of AR-related genes compared to pre-treatment collected samples. Moreover, most patients experienced upregulation of EMT and NE markers after treatment, which was more pronounced after docetaxel than cabazitaxel therapy. Conclusions: GE changes related to taxane-resistance observed in pre-clinical models also occur in CTCs. This supports the great value of CTCs to evaluate cell plasticity due to taxanes treatment. Further investigation is ongoing to better characterize cellular plasticity and to improve personalized therapeutic strategies that would enhance better clinical outcomes in mCRPC.
Risk of subsequent dementia from androgen deprivation therapy (ADT) versus orchiectomy among men with prostate cancer.
Authors: Parikh Ravi Bharat , Chhatre Sumedha , Malkowicz S. Bruce , Li Bingnan , Jayadevappa Ravishankar
Published: March 2019

239

Background: Retrospective studies have suggested an association between ADT and cognitive dysfunction among men with prostate cancer. This association may be mediated directly by ADT or indirectly by long-term decreased androgen levels. We hypothesized that there would be no difference in rates of subsequent dementia among elderly men who received ADT vs orchiectomy for treatment of prostate cancer. Methods: We conducted a retrospective cohort study using the SEER-Medicare database of men ≥66 years old diagnosed with localized or advanced prostate cancer between 1996 and 2003 who were treated with ADT (n = 60146) or orchiectomy (n = 1760), either alone or as part of combined therapy. We used propensity score-adjusted regression to study the association between ADT or orchiectomy and subsequent risk of Alzheimer’s disease or dementia. We excluded patients diagnosed with dementia before or within 2 years of therapy. Results: Men receiving ADT were younger and less likely to be married than men receiving orchiectomy (Table). There was no difference in ethnicity, comorbidity index, or socioeconomic status (SES) between the two groups. ADT did not carry a higher risk of subsequent Alzheimer’s (HR 1.10, 95% CI 0.95-1.28) or dementia (HR 0.93, 95% CI 0.83-1.05) compared to orchiectomy. Conclusions: Among a large cohort of elderly men with prostate cancer, ADT and orchiectomy carried similar long-term risks of subsequent dementia. [Table: see text]
Percent genome alteration and outcomes after radical prostatectomy in African American men.
Authors: Faisal Farzana A , Tomlins Scott A. , Schaeffer Edward M. , Lotan Tamara L.
Published: March 2019

24

Background: African American (AA) men have a higher incidence of and mortality from prostate cancer (PCa) than European American (EA) men. The potential biological determinants of these racial disparities are unknown. Cancer genome evaluations with available clinical outcome data have been limited to EA cohorts. Here we characterize PCa genomes from a large cohort of AA men and identify the associations between genomic alterations and clinical outcomes. Methods: Cancer genomes from 205 AA men treated with radical prostatectomy (RP) were profiled for known somatic mutations and percent genome alteration (PGA; defined as percentage of tumor genome with copy number variation). Logistic regression and Cox proportional hazard analyses assessed the association of genomic alterations with clinical outcomes in multivariate models. PGA was dichotomized by quartiles in analytical models (≤75th percentile vs. >75th percentile). Results: The median PGA was 3.7% and increased with pathologic grade (p<0.001) and stage (p=0.02). Median follow-up was 5 years. AA men with the highest quartile of PGA had significantly worse biochemical recurrence (BCR)-free survival (10 year: 33.5% vs. 50.2%; p=0.006) and metastasis-free survival (10 year: 47.9% vs. 89.0%; p<0.001) than men with lower quartiles of PGA. PGAwas associated with increased risks of higher grade (OR 2.0, 95% CI 1.1-3.7, p=0.03), higher stage (OR 2.0, 95% CI 1.1-3.8, p=0.03), BCR (univariate: HR 1.9, 95% CI 1.2-3.2, p=0.01), and metastasis (HR 9.6, 95% CI 2.9-31.3, p<0.001). The most common somatic mutations were SPOP (12.5%, 123/184), FOXA1 (9.2%, 17/184), and TP53 (4.4%, 8/184). Only TP53 was associated with increased risks of adverse outcomes: higher stage (OR 5.3, 95% CI 1.5-19.4, p=0.01), BCR (univariate: HR 2.4, 95% CI 1.0-5.9, p=0.06), and metastasis (HR 9.5, 95% CI 2.2-40.6, p=0.002). Conclusions: In AA men, PCa genome profiles reveal unique genomic alterations. Notably, PGA in AA men predicts adverse pathologic and oncologic outcomes after RP and can potentially be considered a prognostic biomarker in this racial group. This research highlights the importance of racial ancestry in cancer genomics studies and precision medicine strategies.
Modeling time from bone metastasis to death in a racially diverse cohort of military health care beneficiaries.
Authors: Cullen Jennifer , Chen Yongmei , Kuo Huai-Ching , Rice Kevin R. , Rosner Inger L. , Forsberg Jonathan
Published: March 2019

246

Background: Development of prostate cancer (PCa) metastasis, while uncommonly observed in US men, typically occurs to bone and ultimately leads to disease-specific death. The goal of this study was to estimate OS in a racially diverse cohort of military health care beneficiaries diagnosed with metastatic PCa to bone, to enhance understanding of factors such as patient race and receipt of palliative treatment, that potentially affect OS in advanced PCa patients. Methods: A retrospective cohort study was conducted, examining men consented to participate in the CPDR multi-center national database who underwent biopsy for suspicion of prostate cancer between 1989-2017 and subsequently diagnosed with bone metastasis, confirmed by bone scan, bone biopsy and/or MRI. Multivariable Cox proportional hazards (PH) analysis was used to model OS as a function of race and palliative treatment, controlling for clinical covariates. Hazard ratios (HR) and 95% Confidence intervals (CI) are reported. Results: Among 17,356 patients diagnosed with prostate cancer (PCa) between 1989 and 2017, 869 (5.0%) developed bone metastasis. Median patient age was 67 years; median follow-up time following diagnosis with bone metastasis was 2.4 years. Over one-fifth of patients (22.5%) self-reported as African American. Only 11.5% of all patients with metastasis received palliative treatment (radiation (RT) only, RT+ hormone therapy (HT), RT+HT, or RT+HT+chemotherapy). While race did not predict OS, receipt of palliative treatment was strongly predictive of better OS (p<0.0005). Conclusions: Patient race did not predict OS among those with distant metastatic PCa but receipt of palliative care and slower PSADT were critical factors in lengthening OS. This work is being extended to examine the combinations and sequencing of palliative care on OS, to provide improved patient-tailored prediction tools for men with advanced prostate cancer. [Table: see text]
Pembrolizumab (pembro) in heavily pretreated metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Moses Marcus Marie , Ledet Elisa , Manogue Charlotte , Lewis Brian E. , Barata Pedro C. , Sartor A. Oliver , Layton Jodi Lyn
Published: March 2019

255

Background: KEYNOTE-199 has shown PSA responses of 11% to pembro in mCRPC. This study aims to further evaluate pembro in heavily pre-treated mCRPC patients (pts) correlating clinical outcomes with somatic and germline mutational burden. Methods: Single-institution retrospective analysis of mCRPC pts treated with pembro with germline panel testing and baseline ctDNA analysis using Guardant360 (Redwood City, CA). Baseline clinical annotation was collected and correlated with ctDNA data and clinical outcomes; ctDNA annotations included amplification (amp) and somatic mutation (mut; allele fraction ≥0.3%). Clinical outcomes were assessed after 3 cycles defined as: PSA≥50% PSA decline) or PSA≥30 response. Results: 27 mCRPC pts were treated with pembro between Oct 2016 and June 2018, median age 69 (56-82), 70% Caucasian, 26% African-American, and 4% Other, 70% Gleason 8-10, 59% bone-only, 22% bone+tissue, and 19% bone+LN metastases, were included. Pembro was given after a median 5 CRPC therapies with a median initial PSA of 76.1 ng/mL (4.85-1160), median treatment duration of 1.4 months (0-24.3). Prior treatments include abiraterone (n = 27), enzalutamide (n = 17), docetaxel (n = 19), and provenge (n = 16). 18 pts had ctDNA testing both pre- and post-pembro with a median time from testing to pembro of 0.9 months (0-3.9) and a median time from pembro to NGS testing of 0.7 months (0-2.6). Pre-pembro NGS had the following cfDNA alterations: 74% AR (mut = 8, amp = 8, both = 4), 55% TP53, and 0% DNA repair. ctDNA allelic fraction decrease occurred in 50% (6/12) of pts with AR mutations. 55% (15/27) of pts completed ≥3 cycles of pembro with the following responses: PSA≥50 13% and PSA≥30 20%. Two PSA complete responders (CR) (PSA < 0.01) had germline pathogenic alterations (BLM or MSH2). One of these pts was bone only; the other had radiographic CR. The MSH2 germline tumor was MSI-H and lacked MSH2/MSH6 on immunohistochemistry. The other PSA CR was not assessed given limited tissue. Conclusions: 33% of pts evaluated, achieved a PSA decline of ≥30% al response or greater signifying there is a subset of mCRPC pts that can benefit from pembro. Further evaluation is necessary to determine predictive biomarkers for this patient population.
Germline DNA repair mutations in men with prostate cancer are less frequent in African Americans as compared with Caucasians.
Authors: Nicolosi Piper L.W. , Ledet Elisa , Yang Shan , Michalski Scott T. , Vu James , Sartor A. Oliver
Published: March 2019

258

Background: Pathogenic DNA repair defects are well described in Caucasian (C) men with prostate cancer (PCa) but comparative data on African-American (AA) men are sparse. Methods: Germline testing for DNA repair defects were assayed by Invitae (Invitae.com). Pathogenic variants in 14 genes were compared between AA and C men with PCa; these particular genes were also assessed by Pritchard et al NEJM 375:443, 2016. Identical gene panels were not used in all men, thus variations in assay numbers from gene to gene are noted. Chi square was used to compare proportions. Results: In the 14 genes, there were 16/214 (7.5%) AA men and 347/2488 (13.9%) C men with pathogenic findings (p=0.008). As shown in the Table, the most common pathogenic variants in AA men were BRCA2 (6/214, 2.8%), BRCA1 (3/213, 1.4%), PALB2 (2/182, 1.1%), ATM (2/206, 1.0%), RAD51C (1/148, 0.68%), CHEK2 (1/207, 0.48%), and PMS2 (1/212, 0.47%). In contrast to C men in this series, no AA men had pathogenic mutations in BARD1, BRIP1, MLH1, MSH2, MSH6, NBN, or RAD51D. Pathogenic CHEK2 was less commonly detected in AA as compared to C (p=0.03) in this dataset. Comparing our C men revealed no differences in the proportion of men with pathogenic findings compared to Pritchard et al (13.9% here vs 11.8%, P=0.15). Conclusions: AA men with PCa are less likely to have pathogenic DNA repair mutations among these 14 assayed DNA repair genes compared to C men. Limitations regarding lack of stage, Gleason scores, and FH are notable. Details on gene assays and comparison to Pritchard et al NEJM 375:443, 2016 [Table: see text]
ctDNA and copy-number variant quantification in mCRPC at the time of progression.
Authors: Cotogno Patrick , Moses Marcus Marie , Ranasinghe Lahiru , Christensen Bryce Raymon , Steinwald Peter , Chapman Lynne , Manogue Charlotte , Lewis Brian E. , Layton Jodi Lyn , Sartor A. Oliver , Ledet Elisa
Published: March 2019

265

Background: Tumor burden is a prognostic biomarker in cancer; however, in metastatic castration resistant prostate cancer (mCRPC), quantification of tumor burden markers is difficult. Circulating ctDNA is an accessible biomarker which can be used to characterize somatic DNA. The goal of this study was to evaluate the utility of ctDNA quantification and characterization at time of disease progression in mCRPC. Methods: From 2015 to 2018, 221 mCRPC patients underwent ctDNA screening with Guardant 360 (Guardant Health, Inc. Redwood City, CA) at times of disease progression. This analysis consisted of exonic coverage of 70 genes as well as amplifications in 18 genes, with pathogenic mutations categorized by effect and mutant fraction ctDNA. Clinical annotation including lines of life-extending therapies (LET) before and after testing were collected. Statistical analyses included repeated measure ANOVA, logistic regression, and parameter estimations. Results: An increasing number of LETs resulted in a clinically significant increase in mutant ctDNA fraction (P < 0.001). Subjects that received ≥ 5 or 3-4 LETs had significantly higher total mutant ctDNA fraction compared to subjects exposed with either 0 (p = 0.0007 and 0.0196, respectively) or 1-2 LETs (p = 0.0013 and 0.0432, respectively). 1-2 LETs did not demonstrate a significantly different total mutant ctDNA compared to subjects with 0 LETs (p = 0.4578). The estimated mean total mutant ctDNA fraction demonstrated a positive trend with an increasing number of LETs, including 2.08% (95% CI 1.24-3.49) without a LET, 2.62% (95% CI 1.71–4.01%) with 1-2 LETs, 4.58% (95% CI 2.92–7.17) with 3–4 LETs, and 7.79% (95% CI 4.51-13.48) for subjects with ≥5 LETs. The presence of copy number gain variations (CNVs) demonstrated an increased frequency with exposure to more LETs (p = 0.0005). Subjects with ≥5 or 3-4 LETs were 5.192 (p = 0. 0.0011, 95% CI 1.934-13.942) and 4.808 (p = 0.0019, 1.780-12.983) times more likely to have CNVs present compared to those without LETs. Conclusions: As mCRPC patients progress through lines of therapy, both the mutant ctDNA fraction and frequency of copy number gain variations increase.
Assessing the real-world (RW) efficacy and toxicity of docetaxel (D) for the treatment of metastatic castrate sensitive prostate cancer (mCSPC): A single institution experience.
Authors: Delos Santos Seanthel , Phillips Cameron , Emmenegger Urban
Published: March 2019

270

Background: While D has been shown to prolong survival and improve quality of life in men with mCSPC in clinical trial settings, less is known about its effectiveness in the RW setting. Furthermore, it is uncertain whether the timing of D affects toxicity and outcome. We aimed to identify effectiveness and toxicity outcomes as well as patient (pt) characteristics and prescribing patterns at our institution. Methods: In this retrospective chart analysis, we identified 70 pts with mCSPC who were treated with D between June 2014 and September 2018 at an academic cancer centre in Toronto. The main outcomes studied included time to castrate resistance (TCR), change in PSA, number of cycles completed, and rates of febrile neutropenia (FN). We also analyzed pt subgroups including pts starting D <50 days after the start of androgen deprivation therapy (ADT) versus those starting >50 days after ADT initiation. Results: The median age of our pts was 69 (IQR: 64-74). The median follow-up time was 598 days. 79% of pts had high volume disease per CHAARTED criteria, 73% had de novo metastatic disease and 85% had bone-only disease. The median TCR from the start of ADT was 12.3 months. The median change in PSA from pre-ADT to post-D nadir was 99%. The mean D dose intensity was 86% of the ideal dose and 91% of pts completed all 6 cycles of D. 11% of pts were diagnosed with FN during treatment. 6% of pts required treatment delays and 19% required toxicity-related dose reductions. Subgroup analysis showed that patients (n=41) who received D >50 days from the start of ADT did not have significant differences in TCR, rates of FN, need for a decrease in dose intensity or treatment delays compared to those starting <50 days after ADT (n=29). Conclusions: D can be delivered safely in RW pts, with low rates of FN, however, there is evidence of an efficacy-effectiveness gap with a shorter TCR compared to that observed in CTs. The timing of D (<50 days vs. >50 days) does not appear to have an impact on outcome or toxicity.
Clinical and molecular analysis of patients treated with prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy.
Authors: Conteduca Vincenza , Oromendia Clara , Vlachostergios Panagiotis J. , Hackett Amy , Thomas Charlene , Case Aidan , Manohar Jyothi , Eng Kenneth , Sboner Andrea , Ballman Karla V. , Elemento Olivier , Nanus David M. , Beltran Himisha , Tagawa Scott T.
Published: March 2019

272

Background: PSMA targeted therapy has recently emerged as a promising approach for patients with advanced prostate cancer. However, there is still a need for reliable biomarkers that provide information about clinically meaningful outcomes and treatment responses. Methods: Baseline, treatment and outcomes data along with tumor whole-exome sequencing (WES) data were retrospectively evaluated in anti-PSMA-treated patients (pts). Statistical comparisons utilized Cox regression analysis and Kaplan-Meier method for association with overall/progression-free/survival (OS/PFS) and PSA response. Results: We analyzed 25 pts treated with PSMA targeted radionuclide therapies refractory to standard therapy. 15 received 177Lu-J591, 8 received 177Lu-PSMA-617, 1 received both, and 1 225Ac-J591. WES data (n=28) showed an incidence of AR, BRCA1, BRCA2, ATM alterations (copy number variations and point somatic mutations) in 71.4% (n=20), 11.1% (n=3), 29.6% (n=8), and 14.3% (n=4), respectively. Variables found with backward selection with AIC criterion for PFS and OS suggest significant clinical and molecular predictors of PFS/OS (Table). Conclusions: Knowledge of prognostic factors such as baseline narcotic use and ALP, and BRCA1/BRCA2 and TP53 alterations may have potential clinical utility in patients being considered for anti-PSMA targeted radionuclide therapies. Validation of these findings in larger prospective trials is warranted.[Table: see text]
Survival outcomes for adjuvant or salvage radiation in men with pN+M0 prostate cancer.
Authors: Tward Jonathan David , O'Neil Brock , Stephenson Robert A , Agarwal Neeraj , Farr Tyler , Petragallo Rachel , Lowrance William Thomas
Published: March 2019

276

Background: The benefit of adjuvant or salvage radiation in pN+ men following radical prostatectomy (RP) is debated. Prior outcome studies are hampered either by missing prognostic variables or poor statistical analysis. We performed a rigorous outcome analysis in completely pathologically staged pN+ men treated with radical prostatectomy at the Univ. of Utah between the years 1998 and 2018. Methods: Men who were cN0M0 prior to surgery found with pN+ disease after RP were identified in our combined prospectively and retrospectively gathered institutional database. Those with metastasis found within 3 months of RP were excluded. The pathologic T and N stage, margin status, # of nodes resected, # of nodes positive, age, and NCI comorbidity scores were known for all subjects. Propensity weighted adjustment for the aforementioned covariates was performed to balance prognostic covariates in those who received EBRT + ADT (RT) versus those who didn’t (No-RT). Cox proportional hazards and KM analysis in the propensity-adjusted and original populations were used to evaluate metastasis free and overall survival. Results: Median follow-up time was 3.7 years. There were 129 men in the No-RT cohort and 72 in the RT cohort. Those in the No-RT group were twice as likely to develop metastasis (p < 0.05 in all statistical models) and 2-3 times as likely to die of any cause (p 0.03 to 0.12 depending on model) than those receiving RT at any time after surgery. The median time to metastasis in the No RT cohort was 7.3 years and was not-reached in the RT cohort. The median time to death was 11.9 years in the No-RT cohort and was not reached in the RT cohort. Conclusions: The addition of adjuvant or salvage pelvic nodal radiation with limited duration ADT results in clinically and statistically significant reduction in metastasis and death following RP. A nomogram has been created which can be used to predict metastasis and mortality for individual subjects based on pathologic findings after RP.
Abi1 loss drives prostate tumorigenesis through activation of EMT and noncanonical WNT signaling.
Authors: Nath Disharee , Li Xiang , Mondragon Claudia , Post Dawn , Chen Ming , Hryniewicz-Jankowska Anita , Caza Tiffany , White Julie , Kuznetsov Vladimir , Hehnly Heidi , Khanna Rakesh , Gleicher Stephanie , Jamaspishvili Tamara , Berman David Monty , Zhang Fan , Kung Sonia H.Y. , Fazli Ladan , Bratslavsky Gennady , Pandolfi Pier Paolo , Kotula Leszek
Published: March 2019

280

Background: Prostate cancer is characterized by heterogeneity of mechanisms which are poorly understood but pointing to epithelial plasticity as the key mechanism in progression to metastatic disease. ABI1, a member of WAVE complex and actin cytoskeleton regulator and adaptor protein, is proposed to act as tumor suppressor in prostate cancer, but the mechanism of tumor progression due to Abi1 loss is not clear. Methods: To address Abi1’s role in prostate cancer we used CRISPR-based gene editing and retroviral expression to manipulate Abi1 levels in prostate cancer cell lines. Levels of Abi1 expression in prostate organoid tumor cell lines were evaluated by Western blotting and/or RNA sequencing. Association of Abi1 loss with tumor grade was evaluated by immunohistochemistry. Results: Abi1 expression is downregulated in tumor organoid cell lines from metastatic bone and lymph node biopsies. Moreover, low Abi1 expression is associated with high-grade prostate tumors (GG3 or higher, p < 0.001). Disruption of Abi1 gene in a benign prostate epithelial cell line RWPE-1 resulted in a gain of invasive phenotype, which is characterized by loss of cell-cell adhesion markers and increased migratory ability of RWPE-1 Abi1 KO spheroids. Through RNA sequencing and protein expression analysis we discovered that Abi1 loss leads to activation of non-canonical WNT signaling and EMT pathways, which are rescued by re-expression of Abi1. Furthermore, increase in STAT3 phosphorylation upon Abi1 inactivation and evidence for high affinity interaction of FYN-SH2 domain with Abi1 pY421 support the model that Abi1 acts as a gatekeeper of the non-canonical WNT-EMT pathway activation downstream from FZD2 receptor. The gene expression profile of Abi1-EMT-WNT pathway overlaps with the reported gene signature of high-risk prostate tumors. Conclusions: Abi1 contributes to prostate cancer progression and epithelial plasticity through regulation of EMT-WNT pathways. Understanding of Abi1’s role may provide more mechanistic understanding of prostate cancer tumor progression.
Somatic alterations in a seven-gene DDR gene panel predicts platinum sensitivity in advanced prostate cancer patients.
Authors: Vlachostergios Panagiotis J. , Manohar Jyothi , Niaz Muhammad Junaid , Lee Aileen , Hackett Amy , Molina Ana M. , Nanus David M. , Beltran Himisha , Tagawa Scott T.
Published: March 2019

283

Background: Genomic alterations in the DNA damage response and repair (DDR) pathways are common in advanced PC. Platinum compounds are active in CRPC pts. DDR-defective PC tumors have increased sensitivity to PARP inhibitors (PARPi); the mechanisms involved in sensitivity to platinum and PARPi may be similar but not identical. This study aimed to assess the impact of somatic DDR alterations on clinical outcome of platinum-treated patients with advanced PC. Methods: We reviewed records of advanced PC patients, who received platinum-based chemotherapy with available tumor tissue specimens. We used next generation sequencing (whole exome or targeted) to assess for mutations and copy number alterations in a selected panel of DDR genes, including BRCA1, BRCA2, ATM, ERCC3, ERCC5, TP53 and RB1. We used Kaplan Meier curves to predict PFS and OS after initiation of platinum chemotherapy. Results: Our cohort included 50 men, median age 69.5 years (45-91), median PSA 0.81 (0.008-2291.25), median LDH 264 (109-6714). 39 had visceral metastases (38 liver, 15 lung, 2 adrenal, 2 peritoneal, 1 brain). The majority or pts (33/50) received carboplatin, 17 received cisplatin (2 subsequently also received carbo with initial platinum used for data analysis). Most pts received chemotherapy doublets, and platinum was most frequently combined with etoposide (N=27) and paclitaxel (N=9). 39 pts had tumors harboring at least one DDR alteration. Somatic deletions in BRCA2 gene (N=18) were associated with a significantly longer PFS compared to men with wild-type BRCA2 (median PFS: 6 versus 3 months, P=0.019). No significant associations were identified between somatic DDR alterations and OS. Presence of ≥2 concomitant DDR somatic alterations predicted a favorable PFS compared to single-gene alterations or lack thereof (6 vs 3 months, P=0.006). Conclusions: Our study suggests that presence of ≥2 concomitant DDR somatic alterations from a 7-gene DDR panel, including BRCA1, BRCA2, ATM, ERCC3, ERCC5, TP53, and RB1, may predict longer PFS in pts with advanced PC treated with platinum-based chemotherapy. Further studies are needed to clinically qualify multiplex predictive biomarkers of DDR-defective PCs.
Concomitant characterization of androgen receptor (AC) and immune checkpoints (ICs) in cell-free (cf) DNA and RNA from patients with metastatic castration resistant prostate cancer (mCRPC).
Authors: Pal Sumanta K. , Szeto Christopher , Reddy Sandeep K. , Nussenzveig Roberto , Lam Richard Y. , Scholz Mark C. , Agarwal Neeraj
Published: March 2019

286

Background: Immunotherapy (IO) appears to benefit a subset of patients (pt) with mCPRC, with recent data showing disease control > 6 mo in 11% of patients (De Bono et al ASCO 2018). We interrogate cfDNA/cfRNA from pt with mCRPC to ascertain relationships between AR and IC markers, and offer preliminary correlation with response to IC inhibitors (ICIs). Methods: Pt in this series were on active therapy for mCRPC and received cfDNA/cfRNA assessment for 26 analytes using the CLIA-certified NantHealth LiquidGPS platform during the course of routine clinical care. For this assay, 10 mL of blood were separately collected in DNA and RNA stabilizing solutions, respectively. DNA was amplified via mutant allele-specific blocker or allele-specific PCR assays. Wild type (WT) DNA was PCR amplified in an area where mutations had not been detected, and allele fractions were determined by the ratio of mutant to WT alleles. RNA was reverse transcribed to cDNA using random hexamer primers and amplified via gene specific assays relative to a stably expressed housekeeping gene, beta actin. Results: 103 pt were tested, median age 74y (range, 51-95). Expression was elevated for AR in 41%, and for AR-V7 in 3% pt. cfRNA detected expression for PD-L1, CTLA4, LAG-3 and TIM-3 in 60%, 52%, 72%, and 81% pt respectively. There was no strong association between AR and PD-L1 expression (Rho = 0.03, P = 0.77), or coincidence of detectable levels (OR = 1.4, p = 0.43). AR expression weakly inversely correlated with expression of CTLA4, LAG-3 and TIM-3. In 2 pts responding to ICI therapy, markedly increased PD-L1 and CTLA4 expression was noted. Multiple additional pts are receiving ICIs and correlation between expression of AR/IC markers and response will be presented. Conclusions: Unlike within the tumor microenvironment,expression ofcirculating AR and IC markers are independent biomarkers offering potentially more specific insights into combination versus sequential strategies for AR-directed tx and IO. Our preliminary observation of elevated circulating IC makers in the context of ICI response in mCRPC will be assessed in a larger series.
Phase II trial enzalutamide and androgen deprivation therapy (ADT) with salvage radiation in men with high-risk PSA recurrent prostate cancer (PC): The STREAM trial.
Authors: Armstrong Andrew J. , Bitting Rhonda L. , Healy Patrick , George Daniel J. , Kim Sung , Mayer Tina M. , Winters Carolyn , Riggan Colleen , Rasmussen Julia , Wilder Rhonda , Anand Monika , Stein Mark N. , Frizzell Bart , Harrison Michael Roger , Zhang Tian , Lee W. Robert , Wu Yuan , Koontz Bridget F.
Published: March 2019

29

Background: Salvage external beam radiotherapy (RT) and hormonal therapy improves survival over RT alone in men with non-metastatic hormone naïve PC and PSA recurrence after radical prostatectomy (RP). We investigated the safety/efficacy of enzalutamide with salvage RT and ADT in this setting. Methods: This was a 3 center prospective phase 2 single arm clinical trial in the Dept of Defense Prostate Cancer Clinical Trials Consortium. Eligibility: Gleason 7-10 PC and PSA recurrence within 4 years (yrs) of RP, PSA 0.2-4.0, no prior hormonal therapy, and no metastases on CT/Bone Scan imaging. Men received 6 months (mos) of ADT with 160 mg/d enzalutamide and 66 Gy RT to the prostate bed. Primary endpoint was 2 yr PFS with testosterone (T) recovery to >100 ng/dl. Secondary objectives included PSA nadir, 3 yr PFS, safety and patient reported quality-of-life over time. This trial was designed with 84% power to detect a 20% improvement in 2 yr PFS vs historic data and a 1-sided alpha of 0.05. Results: We enrolled 38 men (90% white, 8% black, 2% Asian); 37 (97%) completed therapy and were evaluable with T recovery at 2 yrs. Median age was 64 yrs; 47% Gleason 8-10, 79% T3/T4 disease, 21% had resected N+ PC; median PSA was 0.4 (0.19-4.19). Median follow-up is 29.5 mo. Treatment was well tolerated with 11 patients (29%) experiencing G3 toxicities (including 4 HTN, 2 urinary retention, 2 CV events); no G4-5 or unexpected toxicities were observed. T recovery occurred in 35 (95%) at 12 mos. The primary endpoint of 2 yr PFS was 65% (95% CI: 47%-78% vs. historic controls with 51% 2 yr PFS rate) among the 37 patients with T recovery. PSA remained at undetectable levels in 69% at 2 yrs. The 3 yr PFS was 53% (95% CI: 36%, 68%). QOL data over time suggest short term reductions in urinary and sexual function with recovery by 12-24 mo in most men. Conclusions: Salvage enzalutamide and ADT for 6 months with RT following RP for men with PSA recurrent high risk PC is safe, and demonstrates encouraging efficacy at 2 and 3 years. Most men have testosterone recovery at 1 year. These data warrant prospective controlled phase 3 trials to assess the impact of potent AR inhibition in this curative intent setting. Clinical trial information: NCT02057939.
Drug-drug interaction (DDI) of darolutamide with cytochrome P450 (CYP) and P-glycoprotein (P-gp) substrates: Results from clinical and in vitro studies.
Authors: Zurth Christian , Graudenz Kristina , Denner Karsten , Korjamo Timo , Fricke Robert , Wilkinson Gary , Seitz Friedeborg , Prien Olaf
Published: March 2019

297

Background: Maintaining quality of survival, by delaying disease progression and minimizing therapy burden, is critical for patients and has been evaluated in the pivotal phase III ARAMIS study in patients with non-metastatic castration-resistant prostate cancer. Due to comorbidity, elderly men often receive multiple comedications, including CYP and P-gp substrates, eg, simvastatin and digoxin. Enzalutamide and apalutamide, approved androgen receptor (AR) inhibitors, are strong CYP3A4 inducers and thus have potential for CYP-mediated DDIs. The effect of darolutamide, a structurally unique AR antagonist, on CYP activity ( in vitro and in vivo) and P-gp activity ( in vivo) was assessed. Methods: Inhibition of CYP isoforms by Daro was investigated in human liver microsomes using standard substrates. In addition, CYP and P-gp activity during darolutamide treatment was studied in a phase I trial of 15 healthy men who received 75 mg dabigatran etexilate (DABE, P-gp substrate) + 1 mg midazolam (MDZ, CYP3A4 substrate) once followed by 600 mg darolutamide (two 300 mg tablets) twice daily (BID) given with food for 9 days. On day 9, darolutamide was concomitantly administered with a single dose of 75 mg DABE + 1 mg MDZ. Results: Based on in vitro data, no clinically relevant inhibition of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 by darolutamide is expected. In 13 evaluable subjects in the phase I study, concomitant darolutamide reduced MDZ Cmax by ~32% and AUC by ~29% vs MDZ alone. Concomitant darolutamide reduced non-conjugated dabigatran Cmax by 16% and AUC by 9% vs DABE alone. The observed treatment-emergent adverse events were consistent with the known safety profile of darolutamide. No new safety risks were revealed by co-administration of darolutamide and DABE or MDZ. Safety data for patients in ARAMIS who received darolutamide, including those with concomitant CYP or P-gp substrates, will be presented. Conclusions: Darolutamide showed only weak effects or none on P-gp, CYP3A4, or any other relevant CYP enzyme. Thus, darolutamide is not expected to cause any clinically relevant DDI with CYP or P-gp substrates, minimizing complications of polypharmacy. Clinical trial information: NCT03237416.
Timing of docetaxel chemotherapy and impact on outcomes in metastatic castrate-resistant prostate cancer (MCRPC).
Authors: Thomson Alastair , Pollard Adam , Mark Frances May
Published: March 2019

298

Background: Docetaxel use has led to a significant prolongation in overall survival (OS) in metastatic prostate cancer after castrate resistance, with a more substantial OS gain when used in combination with initial androgen deprivation therapy (ADT). There is however limited information on outcomes in patients who initially do not receive chemotherapy, perhaps through patient choice or impaired performance status, who become suitable for docetaxel, comparing earlier with later docetaxel treatment. Methods: We retrospectively reviewed patients’ electronic clinical and prescribing records diagnosed with MCRPC and treated with docetaxel from 01/01/2006 to 24/11/2016 in a single centre in the UK. Data was reviewed for number of individual treatments received pre and post chemotherapy, including initial ADT, enzalutamide, abiraterone, docetaxel, cabazitaxel, mitoxantrone, radium 223, single agent steroids and diethylstilboestrol. Prostate specific antigen (PSA) response, number of cycles and dosing of docetaxel and OS were also reviewed. Results: 168 consecutive patients with MCRPC receiving docetaxel were reviewed. Median Gleason grade across the three groups was 8. 48 patients (29%) received docetaxel after 1 or 2 previous treatments, 105 (63%) after 3 or 4 previous treatments and 15 (9%) after 5 or 6. PSA response rates were superior in the earlier treated group (61%, p=0.003), compared with 30% and 31% respectively in the later groups. Median number of cycles was 5.5 overall, with a mean weighted dose received of 396mg/m2, 373mg/m2 and 301mg/m2 in the after 1 or 2 treatments, after 3 or 4 treatments and after 5 or 6 treatment groups. Median OS from castrate resistance for the earlier group was 29 months, not significantly less (p=0.1) than the 35 months for an intermediate number of prior treatments and 42 months for the later treated group. Conclusions: In this group of patients in routine clinical practice who do not receive docetaxel with initial ADT, PSA response rates are significantly improved and overall dose received is higher with subsequent earlier use. However, overall survival is not significantly different between the early and later docetaxel treated patients.
SABR in high-risk prostate cancer: Outcomes from two prospective clinical trials with and without elective nodal irradiation.
Authors: Alayed Yasir , Cheung Patrick , Vesprini Danny , Liu Stanley K. , Chu William , Chung Hans T. , Musunuru Hima Bindu , Davidson Melanie , Ravi Ananth , Ho Ling , Deabreu Andrea , D'alimonte Laura , Bhounr Zeeba , Zhang Liying , Commisso Kristina , Loblaw Andrew
Published: March 2019

3

Background: There is limited data on SABR in high-risk prostate cancer (PCa) especially regarding the role of elective nodal irradiation (ENI). This study compares two prospective phase II trials using SABR in high-risk prostate cancer, with and without ENI. Methods: Both trials enrolled patients with high-risk PCa only. Trial1 (pHART8) patients received 40Gy/5 to the prostate and 30Gy/5 to the seminal vesicles. Trial2 (SATURN) patients received 40Gy/5 to the prostate and 25Gy/5 to the pelvis and seminal vesicles. CTCAE and RTOG toxicities were collected. Biochemical failure (BF) was defined as nadir+2 and 4-year PSA response rate (4yPSARR) was < 0.4 ng/ml. Results: 60 patients were included (pHART8, n=30; SATURN, n=30). Median follow-up was 5.6y and 4.0y. Median nPSA was 0.02ng/ml for both. Six patients had BF, all from pHART8; four were managed with ADT and two are being observed. The BF rate was 14.6% at 5y in pHART8 and 0% in SATURN. All six biochemical failures were associated with a PSA of ≥ 0.4 ng/ml at 4y. 63% of patients in pHART8 and 93% in SATURN had a 4yPSARR. BF probability at 5y was 0% for those achieving a 4yPSARR, and 35.1% if not (p = p < 0.0001). Two patients died in pHART8, one from metastatic disease. One patient in SATURN died from other causes. No other patients developed metastatic disease, and one patient in pHART8 had CRPC. OS at 5y was 93.2% and 96.7% (p=0.86). There was significantly worse late GI and sexual toxicity in pHART8, but no difference in late GU toxicity between the two trials. Conclusions: SABR in high-risk prostate cancer yields biochemical control rates that are comparable to other radiotherapy modalities. ENI using SABR is feasible and led to a significant improvement in biochemical control as well as in 4yPSARR which proved to be a predictor of biochemical control, without an increase in late GI or GU toxicity. Longer follow-up would provide a better assessment of biochemical control. Clinical trial information: NCT01505075 and NCT01953055.
Abiraterone acetate plus prednisone/prednisolone compared with enzalutamide in metastatic castration resistant prostate cancer before or after chemotherapy: A retrospective study of real-world data (ACES).
Authors: Das Prantik , Price James , Jones Michael , Martin-Fernandez Cristina , Ali Akram , Mugunthan Thangrarajh , Mallick Chandrani
Published: March 2019

303

Background: Abiraterone acetate (a prodrug of abiraterone, which is a selective inhibitor of androgen biosynthesis) combined with prednisone/prednisolone (AA+P) and enzalutamide (ENZ) (an androgen-receptor–signalling inhibitor) have proven survival benefit in men with metastatic castration resistant prostate cancer (mCRPC) in chemo naïve and prior chemo patients. There have been no studies directly comparing the effectiveness of ENZ to AA+P in mCRPC patients. Methods: A retrospective, survival analysis study of 143 real world mCRPC patients (90 in AA+P and 53 in ENZ group) was conducted. Patients who started their treatment between 1st February 2012 and 31st May 2016 were included. The primary endpoint was biochemical progression free survival (PFS). Secondary end points were radiographic progression free survival (rPFS) and overall survival (OS). Data was analysed using Cox proportional hazards models, adjusting for covariates: prior radical or palliative treatment; Gleason score; baseline PSA; age; and chemo naïve or not. Results: After median follow up of 15 months (IQR 7 to 23) 112 events of biochemical progression were observed (71 in AA+P and 41 in ENZ). 41%in AA+P group and 30% patients in ENZ group received prior chemo. The chance of biochemical progression was significantly lower among ENZ patients than AA+P patients, when adjusting for all covariates in the Cox PH model (Hazard Ratio 0.54, 95% CI 0.35 to 0.82, p=0.004. There was a trend implying the chance of rPFS could be higher among ENZ patients than AA+P patients (HR 1.24, 95% CI 0.76 to 2.02, p=0.4). OS is lower among ENZ patients than AA+P patients, when adjusting for all covariates in the Cox PH model (HR 0.91, 95% CI 0.59 to 1.41, p=0.7). 38% of ENZ patients reported fatigue compared to 16% of AA+P patients while hypertension was reported slightly more in AA+P patients than in ENZ patients. Conclusions: This study showed a statistically significant difference in biochemical progression-free survival, favouring ENZ, but no significant difference in radiographic progression-free survival or overall survival.
Intermittent bicalutamide in recurrent non-metastatic castrate sensitive prostate cancer: A single institution experience.
Authors: Prentice Mark , Davda Reena , Durno Kimberley , Payne Heather Ann
Published: March 2019

307

Background: Despite radical treatment, a proportion of men with prostate cancer will develop localized recurrence. Intermittent LHRH analogue (LHRHa) therapy has shown equivalence to long-term hormone manipulation with reduced toxicity. The non-steroidal competitive androgen receptor antagonist, bicalutamide, offers disease control with a further reduced toxicity profile. We report our institution’s experience of intermittent bicalutamide therapy (IBT) in recurrent non-metastatic castrate sensitive disease. Methods: Patients with biochemical recurrence and non-metastatic status on conventional imaging treated with IBT April 2016-November 2017 are reported. Previous LHRHa in the radical setting was allowed if testosterone recovery had occurred. For inclusion, one full course of IBT therapy had to be completed and treatment break commenced. Dose was 150mg with all other treatment decisions were at clinician discretion. Results: 103 men were identified with 4 were excluded due to insufficient data or failure to start treatment break. Mean age at initial diagnosis was 64.5yrs and, at commencement of IBT, 71.7. Mean overall time on IBT was 47months (20 and 27 months on and off treatment respectively). The longest recorded time on IBT was 153 months. 1 patient completed 8cycles of IBT. Mean number of cycles was 2.8 (range 1-8). Mean length of treatment break reduced with successive cycles of therapy measuring less than time on treatment after cycle 4. Of 39 patients with follow up therapies recorded, 77% received continuous bicalutamide as second line therapy. Conclusions: IBT offers a valid alternative to intermittent LHRHa therapy in recurrent non-metastatic castrate sensitive prostate cancer with the advantage of an improved toxicity profile benefiting patients. Further work to assess long-term outcomes in this patient population is warranted.[Table: see text]