bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized phase II trial of abiraterone +/- dasatinib for patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Dorff Tanya B. , Quinn David I. , Pinski Jacek K. , Goldkorn Amir , Sadeghi Sarmad , Tsao-Wei Denice , Groshen Susan G. , Kuhn Peter , Gross Mitchell E.
Published: March 2017

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Background: Signaling via Src pathway is thought to be a mediator of resistance to androgen targeted therapy in mCRPC. We sought to determine whether adding the Src inhibitor dasatinib (Das) to abiraterone (Abi) would prolong progression free survival (PFS). Methods: Eligible patients had mCRPC which had progressed on androgen targeted therapies but no prior chemotherapy. Abi was prescribed at 1000 mg daily with prednisone 5 mg BID (both arms) and Das 100 mg daily added for Arm B. Primary endpoint was PFS at 24 weeks. Interim analysis planned after 48 subjects randomized but study terminated early due to lack of funding. PFS was evaluated using logrank testing and responses were compared using Fisher’s exact test. Circulating tumor cells (CTC) were evaluated with EPIC platform. Results: 26 men were randomized, 14 to Abi+Das and 12 to Abi. Median age was 67 (56-85), baseline PSA 19.8 (0.84-1387). Only 1 patient had received ketoconazole, none had received enzalutamide. With 30 months median follow-up, median PFS was 15.7 (95% CI:8.2, 31.1+) months for Abi+Das and 9 (95% CI: 4.4, 45.6+) months for Abi (p = 0.30). 86% were progression free at 24 weeks with Abi+Das compared to 75% on Abi. RECIST responses were seen in 5/14 (35%, 95% CI: 17%, 66%) with 2 CR on Abi+Das and 1/12 (8%, 95% CI (0%, 37%) on Abi (p = 0.16). With a specificity of 83%, the probability that the true rate of CR in intervention arm is higher or doubled (ex: 35% vs 17%) is 71%. Grade > 3 toxicities more common on Das arm included hypertension (43% vs 8% Abi), pleural effusion/dyspnea (14% vs 0 Abi), and gastrointestinal (25% vs 8%). CTC were detected at baseline in 8/17 evaluable patients (3/8 Abi, 5/9 Abi+Das), median 2.7 CTC/mL blood (range 0.5-59.7) At week 4, CTC increased in 1/8 (12.5%) on Abi vs 4/9 (44.4%) on Abi+Das but by week 12 CTC increases persisted in 2/8 (25%) on Abi and 1/9 (11%) on Abi+Das. Conclusions: Das did not significantly prolong PFS in combination with Abi although power was limited due to incomplete study cohort. Abi+Das was associated with robust objective responses including RECIST CR. Clinical trial information: NCT01685125.
A novel small molecule inhibitor of p300/CBP for the treatment of castration-resistant prostate cancer: Preclinical evaluation.
Authors: Brooks Nigel , Pegg Neil , Worthington Jenny , Young Barbara , Prosser Amy , Lane Jordan , Taddei David , Schiewer Matthew Joseph , Gordon Nicolas , Knudsen Karen E.
Published: March 2017

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Background: Targeted degradation of androgen receptor (AR) and androgen receptor variants (ARV) remains an attractive therapeutic opportunity for patients with castrate resistant prostate cancer (CRPC). E1A binding protein (p300) and CREB binding protein (CBP) are two closely related histone acetyl transferase proteins that act as transcriptional activators of AR. We have developed potent, selective and orally active small molecule inhibitors of the bromodomain of p300/CBP and investigated their role in regulating the expression and function of AR and ARV. Methods: Binding affinity to p300, CBP and BRD4 was measured in a surface plasmon resonance (SPR) assay and potency and functional activity was demonstrated in a panel of prostate cells lines representing hormone responsive (LNCaP), hormone independent (DU145, PC3) and castrate resistant disease (22Rv1, C4-2, VCaP, LNCaP-AR). Effects of p300/CBP inhibitors (and the BET inhibitor, JQ1), on AR, AR-V7 splice variant and c-Myc protein, as well as c-Myc, KLK3 and TMPRSS2 gene expression, were assessed in 22Rv1 cells in vitro. In vivoeffects on biomarkers were measured in a 22Rv1 xenograft model. Results: CCS1357, an in vitro probe compound, binds to p300 and CBP with high affinity (Kd=4nM) and selectivity (Kd=245nM; BRD4) and is a potent inhibitor of cell proliferation in castrate resistant cell lines (IC50=100nM in LnCaP-AR; 350nM in 22Rv1) with minimal effects in hormone independent lines. CCS1357 significantly down-regulated AR-FL, AR-V7 and c-Myc protein by Western, an effect not seen with JQ1 at equivalent proliferation IC50s. CCS1357 effects were reversed by the proteasome inhibitor, MG132. CCS1357 also caused a profound inhibition of c-Myc, KLK3 and TMPRSS2 genes measured by qPCR in 22Rv1 cells in vitro. A preclinical candidate (CCS1477) given as a single oral dose (30mg/kg) inhibited plasma PSA and tumour AR and AR-V7 in a 22Rv1 xenograft model. Conclusions: Small molecule inhibition of the bromodomain of p300/CBP, leads to down-regulation of AR, ARV and c-Myc as well as inhibition of key downstream PD biomarkers including PSA and TMPRSS2 and represents a promising new approach for the treatment of CRPC.
Impact of the primary information source used for decision making and implications for treatment regret in prostate cancer.
Authors: Shaverdian Narek , Kishan Amar Upadhyaya , Veruttipong Darlene , Jeffrey Demanes D. , Kupelian Patrick , McCloskey Susan Ann , Steinberg Michael L. , King Christopher R.
Published: March 2017

17

Background: Patients with localized prostate cancer (PCa) assimilate information from varying sources to inform their treatment decision. We assessed the impact of the primary information source used to select a modern radiation treatment on patient perceptions of their treatment experience and on treatment regret. Methods: Patients with favorable-risk PCa treated with SBRT, IMRT or HDR brachytherapy and at least one year of follow-up were surveyed. The questionnaire explored the decision-making experience, expected treatment experience vs. the reality, and treatment regret via a validated tool. Multivariate logistic regression adjusted for demographics, disease characteristics, treatment modality, time since treatment and current bowel, urinary and sexual function. Results: 322 consecutive patients were surveyed with an 86% (n = 276) response rate. 48% (n = 132) selected their radiation oncologist as the primary information source, 23% (n = 62) selected their urologist, 16% (n = 44) selected the internet, 6% (n = 17) selected other patients and 8% (n = 21) selected other. Overall, 13% (n = 36) endorsed treatment regret. 39% of patients who selected the internet as their primary information source reported their actual treatment experience to be worse than expected vs. 13% of respondents who selected their urologist, 12% who selected other patients, 2% who selected their radiation oncologist and 9% who selected other ( p< 0.01). Similarly, 43% who selected the internet as their primary information source endorsed treatment regret vs. 10% who selected their urologist, 7% who selected their radiation oncologist, 6% who selected other patients and 6% who selected other ( p< 0.01). On multivariate logistic regression, only patients who selected the internet as their primary information source were more likely to endorse treatment regret (OR = 46.5, p< 0.01) and were more likely to choose a treatment they thought ‘had the least side effects’ (OR = 2.1, p= 0.016). Conclusions: Patients who used the internet as their primary source of information had a worse perception of their treatment experience and had more treatment regret, highlighting the need for physicians to proactively counsel patients.
Relationship between quality of life and overall survival in metastatic castration-resistant prostate cancer (mCRPC) patients in ALSYMPCA.
Authors: Nilsson Sten , Sartor A. Oliver , Vogelzang Nicholas J. , Coleman Robert E. , O'Sullivan Joe M. , Shore Neal D. , Heinrich Daniel , Bottomley David , Hoskin Peter , Franzen Lars , Solberg Arne , Reuning-Scherer Jonathan D. , Zhan Lin , Parker Chris
Published: March 2017

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Background: Radium-223 improved overall survival (OS) with meaningful improvements vs placebo in health-related quality of life (HRQoL) in phase 3 ALSYMPCA (Parker NEJM 2013; Nilsson Ann Oncol 2016). We examined the relationship of OS to HRQoL scores at baseline or change from baseline. Methods: HRQoL in ALSYMPCA was assessed by FACT-P questionnaire at baseline, during treatment (wk 16, 24), and follow-up. Cox proportional hazards model for OS was fitted using HRQoL baseline scores and included previously identified covariates: treatment (radium-223 vs placebo); log10 baseline LDH, ALP, and PSA; age; baseline ECOG-PS; and albumin. A time-dependent model also included change from baseline HRQoL scores. Results: Analysis includedbetween 810-836 patients with baseline HRQoL scores for various FACT-P metrics. Significant associations were seen between OS and FACT-P total score at baseline or change from baseline. Every 10-point increase in FACT-P total score (ie, improvement) was associated with 7% decreased risk of death (Table). Results for FACT-P subscales were similar, except social well-being. Conclusions: This analysis of ALSYMPCA data shows that baseline HRQoL and changes in HRQoL are prognostic of OS in mCRPC. Clinical trial information: NCT00699751. [Table: see text]
Association of PET index quantifying skeletal uptake in NaF PET/CT images with overall survival in prostate cancer patients.
Authors: Lindgren Belal Sarah , Sadik May , Kaboteh Reza , Hasani Nezar , Enqvist Olof , Svärm Linus , Kahl Fredrik , Simonsen Jane , Poulsen Mads Hvid , Ohlsson Mattias , Høilund-Carlsen Poul Flemming , Edenbrandt Lars , Tragardh Elin
Published: March 2017

178

Background: Bone Scan Index (BSI) derived from 2D whole-body bone scans is considered an imaging biomarker of bone metastases burden carrying prognostic information. Sodium fluoride (NaF) PET/CT is more sensitive than bone scan in detecting bone changes due to metastases. We aimed to develop a semi-quantitative PET index similar to the BSI for NaF PET/CT imaging and to study its relationship to BSI and overall survival in patients with prostate cancer. Methods: NaF PET/CT and bone scans were analyzed in 48 patients (aged 53-92 years) with prostate cancer. Thoracic and lumbar spines, sacrum, pelvis, ribs, scapulae, clavicles, and sternum were automatically segmented from the CT images, representing approximately 1/3 of the total skeletal volume. Hotspots in the PET images, within the segmented parts in the CT images, were visually classified and hotspots interpreted as metastases were included in the analysis. The PET index was defined as the quotient obtained as the hotspot volume from the PET images divided by the segmented bone tissue volume from the CT images. BSI was automatically calculated using EXINIboneBSI. Results: The correlation between the PET index and BSI was r2= 0.54. The median BSI was 0.39 (IQR 0.08-2.05). The patients with a BSI ≥ 0.39 had a significantly shorter median survival time than patients with a BSI < 0.39 (2.3 years vs. not reached after 5 years). BSI was significantly associated with overall survival (HR 1.13, 95% CI 1.13 to 1.41; p < 0.001), and the C-index was 0.68. The median PET index was 0.53 (IQR 0.02-2.62). The patients with a PET index ≥ 0.53 had a significantly shorter median survival time than patients with a PET index < 0.53 (2.5 years vs. not reached after 5 years). The PET index was significantly associated with overall survival (HR 1.18, 95% CI 1.01 to 1.30; p < 0.001) and C-index was 0.68. Conclusions: PET index based on NaF PET/CT images was correlated to BSI and significantly associated with overall survival in patients with prostate cancer. Further studies are needed to evaluate the clinical value of this novel 3D PET index as a possible future imaging biomarker.
A phase II study of enzalutamide (Enz) with dutasteride (Dut) or finasteride (Fin) in men ≥ 65 years with hormone-naive systemic prostate cancer (HNSPCa).
Authors: Kilari Deepak , Guancial Elizabeth A. , Sahasrabudhe Deepak M. , Bylow Kathryn A. , Burfeind John D. , Musto Kaylinn , Feng Changyong , Messing Edward M. , Mohile Supriya Gupta , Fung Chunkit
Published: March 2017

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Background: Older men are at a high risk for adverse events (AEs) from androgen deprivation therapy (ADT). In prior studies, peripheral androgen blockade with bicalutamide and Fin was better tolerated but less efficacious than ADT in HNSPCa. The potential syngerism of Enz (a potent antiandrogen) and Dut/Fin (5-a reductase inhibitors for conversion of testosterone [T] to dihydrotestosterone [DHT]) provided the rationale for this Phase II study that examined the clinical efficacy and safety of Enz with Dut/Fin in men > 65 years with HNSPCa. Methods: Eligible patients were > 65 years (y) ; at a high risk of AE from ADT by comprehensive geriatric assessment or treating physicians; had metastatic (M1) or biochemical recurrent (M0) HNSPCa with a PSA doubling time < 9 months; and had T > 50ng/dl. They received Enz (160mg daily) and Dut (0.5mg daily) or Fin (5mg daily) until disease progression according to the Prostate Cancer Working Group 2 guidelines. The primary study endpoint is time to PSA progression. The secondary endpoints are time to PSA nadir and treatment-related AEs. Results: As of July 31, 2016, 24 patients were screened (3 ineligible) and 21 were enrolled with a median follow-up of 31 weeks (7-79). Median age at enrollment was 79.5 y (66-94) and 14 %, 72% and 14% had ECOG performance status of 0, 1, and 2, respectively. 57% (n = 12) had M0 and 43% (n = 9) had M1 HNSPCa, with 18%, 62%, 5%, and 10% having Gleason 6, 7, 8, and 9 disease, respectively (5% with unkown Gleason sum). The median PSA at enrollment was 12 ng/ml (2-102). The median time to 90% PSA decline after treatment initiation was 7 weeks (7-20) and 92% achieved 80% DHT decline in 9 months. At the time of analysis, all patients had ongoing PSA decline of > 90% without radiographic evidence of disease progression. Common Grade 1 AEs included gynecomastia (28%), fatigue (28%), hot flashes (19%) and paresthesias (15%). One patient withdrew from the study due to Grade 2 paresthesia. None had Grade 3 or 4 treatment-related AEs. One patient died due to colitis unrelated to study treatments. Conclusions: Enz with Dut/Fin appears to have clinical activity for older patients with M0 and M1 HNSPCa with acceptable side effects. Clinical trial information: NCT02213107.
Clinical utility of CLIA-grade AR-V7 testing in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Markowski Mark Christopher , Silberstein John , Eshleman James R. , Luo Jun , Antonarakis Emmanuel S.
Published: March 2017

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Background: The AR-V7 splice variant may confer resistance to AR-targeted therapies but not taxane chemotherapies. Since August 2015, a clinical-grade assay to detect AR-V7 mRNA expression in circulating tumors cells (CTC) has been available through a CLIA-certified lab at Johns Hopkins. In the first 12 months after launch, 195 AR-V7 tests were ordered for clinical purposes. We contacted the ordering providers of the first 100 tests using a questionnaire-based survey to determine how (and if) the results of AR-V7 testing were used in clinical practice. Methods: We identified 100 consecutive mCRPC pts who underwent AR-V7 testing in our CLIA lab. Ordering providers received a questionnaire for each test ordered, asking how (and if) the results of the assay affected their clinical decision-making, and whether a PSA50 response was obtained on next-line therapy after AR-V7 testing was performed. Results: 80 of 100 questionnaires were completed by 26 providers from 17 sites across 14 states. AR-V7 assay results were reported either as CTC negative (21/80: 26%), CTC+ AR-V7 negative (26/80: 33%), or CTC+ AR-V7 positive (33/80: 41%). Prevalence of AR-V7 detection increased with prior exposure to AR targeted drugs (Abi/Enza-naive 29%, post-Abi or Enza 39%, post-Abi and Enza 62%). Overall, management was impacted by AR-V7 testing in 54% of cases (43/80), and even more so with AR-V7+ results (see Table). AR-V7+ pts were commonly switched from AR targeted therapies to a taxane (10/19: 53%) or were offered a clinical trial (8/19: 42%). Pts who had a change in management based on AR-V7 testing were more likely to achieve a PSA50 response on next-line therapy than those not changing treatment (18/36: 50% vs 10/30: 33%). Conclusions: Providers used AR-V7 testing to influence clinical practice more often than not. AR-V7+ pts were most often treated with taxane-based therapy or offered a clinical trial, which may have improved outcomes. Clinical qualification of AR-V7 is ongoing. [Table: see text]
Genomic diversity between primary tumor tissue and tumor circulating cell-free DNA (cfDNA) in patients (pts) with metastatic prostate cancer.
Authors: Carroll Emma , Gill David Michael , Poole Austin , Hahn Andrew W. , Bailey Erin B. , Streeter Jessica , Batten Julia A. , Gupta Sumati , Agarwal Neeraj , Maughan Benjamin Louis
Published: March 2017

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Background: Tumor tissue and tumor cfDNA next-generation sequencing (NGS) tests are obtained in pts with metastatic prostate cancer and have demonstrated a diverse genomic landscape. High-level evidence does not exist for utilizing these tests to guide treatment selection in these pts. Targeted therapies are available for metastatic prostate cancer treatment and clinical trials are investigating drugs targeting specific molecular pathways. The objective of this study was to assess type and number of genomic aberrations between tumor tissue and cfDNA. Methods: Pts with metastatic prostate cancer who had both tissue and cfDNA results were selected and genomic profiles were compared between these two technologies. The mean number of tissue mutations was compared to cfDNA mutations for all pts using the t-test. The mutations for both tests were then categorized into five pathways: DNA repair, cell cycle regulation, PI3K, epigenetics, and androgen receptor (AR). For each pathway, the total number of patients with a mutation was compared between tissue and cfDNA using the Mann-Whitney test. Results: Nineteen pts were identified with both tissue and cfDNA results. The mean number of mutations identified was significantly less with cfDNA (95% CI, 2.7-5.3) compared to tissue (95% CI, 7.0-9.7; P < 0.0001). There were significantly more patients with PI3K pathway mutations identified in the tissue compared to cfDNA (73.7% vs 21.1% P = 0.0018), as well as epigenetic mutations (47.4% vs 0.0% P = 0.0012). There was no difference in the number of patients identified to have DNA repair, cell cycle regulation, and AR variances between the two tests. Conclusions: The lower number of aberrations detected by the cfDNA test may have occurred due to lower sensitivity of cfDNA compared to tissue based NGS. Discordance in the type of genomic variances between the two tests suggests intra-individual genetic diversity, and these results may have implications in treatment selection of pts with metastatic prostate cancer. Data are hypothesis generating and need further investigation in a larger cohort.
AR-V7 detection by a novel junction-specific RNA in situ hybridization (RISH) test.
Authors: Zhu Yezi , Sharp Adam , Anderson Courtney M , Silberstein John , Taylor Maritza N. , Demarzo Angelo , Antonarakis Emmanuel S. , Wang Mindy , Luo Yuling , Su Nan , Figueiredo Ines , Nava Rodrigues Daniel , Park Emily , Ma Xiao-Jun , Coleman Ilsa , Morrissey Colm , Plymate Stephen R , Nelson Peter , De Bono Johann S. , Luo Jun
Published: March 2017

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Background: Previous studies have reported an association between blood-based detection of androgen receptor splice variant-7 (AR-V7) and resistance to abiraterone/enzalutamide in men with metastatic castration-resistant prostate cancer (mCRPC). Further characterization of AR-V7 and its clinical correlates are necessary but depend on the development of methods that allow for reliable and specific measurement of AR-V7. In this study, we developed and evaluated a novel junction-specific AR-V7 RNA in situ hybridization (RISH) test. Methods: We developed a novel RISH assay targeting single exon-exon junction, allowing for highly-specific detection of mature cytoplasmic AR-FL and AR-V7 mRNA in native cell and tissue environment. We compared quantitative RISH AR-V7 results generated from an automated scoring system with AR-V7 levels quantified by RT-PCR in a panel of cell lines. Using the validated assay, we quantified AR-V7 signals in 58 prostate tumor biopsies. We conducted preliminary evaluation of the clinical correlates of AR-V7 detected. Results: The novel AR-V7 RISH test specifically detected mature cytoplasmic AR-V7 mRNA and did not detect nuclear pre-mRNA. AR-V7 RISH results were highly concordant with RT-PCR results. We generated quantitative AR-FL and AR-V7 data from 93.1% of the clinical specimens examined (54 of 58). Positive AR-V7 signals were detected in 23 specimens, all of which also co-expressed AR-FL. The median AR-V7/AR-FL ratio was 4.6%. Positive detection of AR-V7 was significantly correlated with prior treatment with second-line AR targeting agents and serum PSA ( p <0.05), but not with any other baseline clinical variables. Notably, all castration-sensitive prostate cancer specimens (CSPC) (n = 9) were AR-V7 negative by this method. Association between AR-V7 and treatment outcome has yet to be fully evaluated. Conclusions: We demonstrate for the first time a highly specific and quantifiable AR-V7 RISH test for detection of clinically significant levels of AR-V7 mRNA in prostate tissue specimens. This test may be applied to liquid biopsy specimens to expand the utility. Prospective studies can be designed to evaluate the potential utility of this novel test in drug development and patient management.
Glucocorticoid receptor (GR) expression in circulating tumor cells (CTCs) to prognosticate overall survival (OS) for metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with androgen receptor signaling inhibitors (ARSi).
Authors: Wise David , Kelvin James , Graf Ryon , Schreiber Nicole A. , McLaughlin Brigit , Fernandez Luisa , Rivera Normy , Petines Bianca , Harvey Melissa , Nguyen Linda , Oh Aaron , Horiuchi Lee , Dittamore Ryan Vance , Scher Howard I.
Published: March 2017

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Background: Upregulation of GR protein expression in metastatic biopsies from pts with CRPC has previously been shown to correlate with resistance to enzalutamide and has been validated as a therapeutic target in pre-clinical studies. We sought to determine whether upregulated GR protein expression in CTCs from pts with progressing mCRPC predicted clinical outcomes following treatment with enzalutamide (E) or abiraterone (A). Methods: Pre-therapy blood samples from 54 pts with progressing mCRPC were subjected to CTC analysis using the Epic Sciences platform. Samples were examined to identify CK+ (CK+, CD45- cells, with intact nuclei, morph distinct) CTCs for GR protein expression. GR+ CTCs were defined as having expression greater than the 95th percentile of GR expression in the GR negative LNCAP cell line. Kaplan-Meier analysis was used to test the impact of GR+ CTCs on OS following treatment with A or E. A Cox proportional hazards model with CTC number and GR positivity was used in a multivariate analysis. Results: 37 out of 54 pts (69%) had detectable and viable CK+ CTCs. 28 out of 37 pts (76%) had CTCs with upregulated GR staining with a median of 6 GR+/CK+ cells/ml per patient (range 0.7 – 244 cells/ml). The OS of patients with GR+ CTCs treated with ARSi was significantly worse than that of patients without detectable GR+ CTCs (11.4 mo. vs NA, p < 0.01), an effect independent and additive to the presence of viable CTCs, a previously described prognostic biomarker (see Table). Conclusions: GR protein upregulation in CTCs can be detected in a significant percentage of pts with progressing mCRPC and the presence of GR+ CTCs predicts worse OS in response to ARSi. The data supports previously reported pre-clinical data proposing a pathogenic role for GR in mediating resistance to ARSi therapy. Detection of GR in patient CTCs may be a useful predictive biomarker to guide GR-directed therapies. [Table: see text]
Boosting long-term immune responses to sipuleucel-T (sip-T) by retreatment of patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Beer Tomasz M. , Corman John , Lance Raymond S. , Campogan Dwayne , Vu Tuyen , Haynes Heather , Chang Nancy N. , Sheikh Nadeem Anwar , Curti Brendan D.
Published: March 2017

196

Background: Sip-T, an autologous cellular immunotherapy for asymptomatic/minimally symptomatic mCRPC, induces immune responses to target antigens prostatic acid phosphatase (PAP) and PA2024, a recombinant protein of PAP and granulocyte macrophage colony-stimulating factor. Immune responses with sip-T correlate with overall survival. PROTECT (phase 3 NCT00779402) assessed sip-T in biochemically recurrent androgen-dependent PC. PROTECT pts developing mCRPC were eligible for P10-1 (phase 2 NCT01338012). Methods: PROTECT pts (sip-T arm) were retreated with sip-T in mCRPC. Antigen presenting cell (APC) activation (CD54 molecule ratio after and before culture with PA2024), cellular (PA2024/PAP ELISPOT; T cell proliferation) and humoral responses were assessed and compared with treatment-naïve mCRPC pts (IMPACT NCT00065442; STAMP NCT01487863; STRIDE NCT01981122). Results: Caucasian men (n=8), median follow-up 9.2 y and age 74 y, had an ECOG PS of 0 (75%) or 1. Median APC activation with sip-T infusion 1 was ~3-fold higher in P10-1 (20; n=7) vs treatment-naïve mCRPC pts (7; n=447). In P10-1, high magnitude cellular and humoral responses were seen at baseline (BL) (Table). Immune memory was heterogeneous, strong BL humoral and/or robust cellular memory was observed. Sip-T boosted PA2024/PAP cellular and humoral responses (Table). Immune responses were maintained up to wk 52, and were higher over time vs 1st time treated mCRPC pts. Conclusions: Sip-T in an earlier disease setting generated sustained antigen-specific immune memory lasting up to 10 y. Consistent with vaccine-induced immune responses, sip-T retreatment rapidly boosted both cellular and humoral antigen-specific responses in mCRPC pts. Clinical trial information: NCT01338012. [Table: see text]
The Prostate Cancer Project (PC Project): Translational genomics through direct patient engagement.
Authors: Mullane Stephanie Anne , Painter Corrie , Dunphy Michael , Anastasio Elana , Simoncelli Tania , Zarrelli Kristen , Philippakis Anthony , McKay Rana R. , Choueiri Toni K. , Golub Todd , Lander Eric , Wagle Nikhil , Van Allen Eliezer Mendel
Published: March 2017

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Background: While there has been substantial advancement in the genomic understanding of prostate cancer (PCa), there is still much to be discovered. Additional progress is dependent upon obtaining a large amount of clinically annotated genomic data. As PCa is often treated in a community setting, where research samples are not collected, we are starting a direct-to-patient nationwide research initiative where patients can donate their medical records and biospecimens to accelerate research. Previously, we launched the metastatic breast cancer project (MBCproject; mbcproject.org) that leverages social media to engage the MBC community. Based on the initial success with this approach, we now aim to build out the PCproject. Methods: In collaboration with patients, we are developing a website to enable participation in the PCproject. Enrolled patients will be sent a saliva kit, used for germline DNA. We will also obtain medical records. Metastatic patients will also be sent a blood draw kit for circulating tumor DNA (ctDNA). Whole exome sequencing of the ctDNA will be performed. We will use the recruitment infrastructure, clinical record abstraction, and biospecimen processing developed for the MBC project. The data will be shared widely with the research community. Aggregate study results will be reported to patients. Results: In the first year of the MBCproject, 2912 MBC patients from all 50 states enrolled. 2766 (95.0%) completed the 16-question survey about their cancer, treatments, and demographic information. 1716 (58.9%) completed the online consent form permitting acquisition and analysis of medical records, tumor tissue, and saliva samples. 936 (68.8% success rate) saliva samples have been received. To date, we have obtained medical records from 155 patients (72.1% success rate) and tumor samples from 60 patients (72.3% success rate). Based on initial recruitment and surveys among PCa patients, we estimate that 500 patients will enroll in 2017. Conclusions: Based on experience from the MBC project, we will partner directly with patients to recruit and drive the PCproject forward. Remote acquisition of medical records, saliva samples, and tumor tissue for patients located throughout the US is feasible.
Genomic analysis of untreated prostate adenocarcinoma, treatment-emergent neuroendocrine carcinoma, and circulating tumor cells.
Authors: VanderWeele David James , Lack Justin , Gillard Marc , Cam Maggie , Paner Gladell
Published: March 2017

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Background: The prostate cancer genome evolves in response to therapeutic pressure, requiring repeated evaluation as the disease progresses. Biopsies of metastatic sites are invasive and often low yield. Circulating tumor cells (CTCs) offer an alternative source, but few studies have evaluated their genomic relationship with untreated and contemporaneous disease. Methods: We performed exome sequencing of untreated tumor tissue, a late stage liver biopsy, and the amplified genome of EpCAM+ CTCs in a patient with therapy-emergent neuroendocrine carcinoma. Results: Exome sequencing of CTCs captured 71% of the founder mutations shared between the two tissue samples. The allele fraction of founder mutations in the CTCs was 47.8%, indicating a nearly pure population of CTCs from a single clonal disease. Other mutations were at lower allele frequency, suggesting genomic heterogeneity among pooled CTCs. CTCs demonstrated late divergence from the contemporaneous neuroendocrine carcinoma liver biopsy, with 62% of mutations also found in this tissue. An acquired premature stop codon mutation in the Retinoblastoma (RB1) gene, which is associated with progression to small cell cancer, was identified in neuroendocrine and CTC samples, but not untreated tissue. Conclusions: These data support the clonal relationship of untreated adenocarcinoma and treatment-emergent neuroendocrine carcinoma. They also support the use of pooled EpCAM+ CTCs to facilitate the genetic analysis of late stage prostate cancer, including neuroendocrine carcinoma.
Studies of a novel modified E2F-targeted peptide with activity against castration-resistant prostate cancer.
Authors: Bertino Joseph R. , Szekely Zoltan , Scotto Kathleen W
Published: March 2017

205

Background: The E2F family of genes encodes transcription factors that are key to the regulation of a number of target genes, including those encoding cyclins , CDKs , checkpoints regulators, and DNA repair and replication proteins. One of the primary functions of the E2Fs is to control the cell cycle, playing a major role in regulating the G1/S transition. One of the primary regulators of E2F expression is the retinoblastoma gene, RB, a chromatin associated protein that, in its unphosphorylated state, binds to and negatively regulates E2F; hyperphosphorylation of RB releases E2F, allowing cell cycle progression. Many tumor cells have mutant or dysfunctional RB, allowing the aberrant overexpression of the E2Fs and tumor cell proliferation; this aberrant overexpression is better tolerated when p53 is mutated, suppressing subsequent apoptosis. Overexpression of E2F, particularly E2F1, has thus been an attractive target for therapeutic intervention. However, this approach has not yet been successful, most likely due to the redundancy of the E2Fs and the lack of biomarkers for sensitivity. Methods: Using phage display, we have previously identified a novel peptide that, when coupled with penetratin (PEP) to enhance uptake), targets the E2F consensus site in E2F1,2 and 3a, leading to the downregulation of the activating E2Fs and their downstream targets. We have recently enhanced the stability and potency of this peptide by substituting L-Arg within the peptide with D-Arg. Results: Castrate resistant prostate cancer (CRPC) cells, DU-145, lack functional RB, have mutant p53, and are more sensitive to the D-Arg PEP than LnCap or PC-3 cells, with functional RB. Xenograft studies in mice show that the PEP, when encapsulated in PEGylated liposomes (PL-D-Arg PEP) , regresses DU-145 tumors without toxicity. Current studies are examining the combination of the (PL-D-Arg PEP) with taxotere, cisplatin and irradiation in prostate cancer xenografts and organoids from patients. Conclusions: A peptide that inhibits transcription of the activating E2Fs has promise to treat CRPC.
Racial and age specific differences in localized and metastatic prostate cancer incidence: 1988-2013.
Authors: Dall'Era Marc , deVere White Ralph , Rodgriguez Danielle , Cress Rosemary Donaldson
Published: March 2017

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Background: The United States Preventive Services Task Force (USPSTF) recommended against routine PSA based prostate cancer screening in all men in 2012. This led to dramatic reductions in screening and rates of localized disease across all clinical risk groups. We sought to study the impact of this on rates of metastatic disease, specifically by patient race and age. Methods: We analyzed new prostate cancer incidence by stage at diagnosis between 1988-2013 within the Cancer Registry of Greater California. We further stratified cases by four major race/ethnicity groups (non-Hispanic white (NHW), non-Hispanic black (NHB), Hispanic and non-Hispanic Asian/PI (API)) and age. Incidence rates were calculated and compared per 100,000 and age-adjusted to the 2000 US Standard Population. Joinpoint regression was used to detect changes in incidence and to calculate the average percent change (APC). Results: Adjusted rates of remote prostate cancer incidence for NHW men increased slightly in the most recent decade (+0.28%) after steady declines in previous years with the inflection point occurring in 2002, however this was not statistically significant. In contrast, incidence of remote prostate cancer continued to decline for NHB (-2.73%), Hispanic (-2.04%), and API (-1.45%) men. The greatest increase of +1.1% a year since 2002 was observed for NHW men under age 65. The incidence of localized prostate cancer declined for all race/ethnicity groups over the most recent time period and also declined in all age groups. After remaining relatively flat since 1992, incidence of localized prostate cancer among NHW men declined by over 8% per year starting in 2007 compared with a more gradual decline of -3.52% a year since 2000 for NHB, and more recent declines of -14.41% and -16.64% for Hispanic and API men, respectively. Incidence of regional stage cancer also declined in all groups, but less dramatically. Conclusions: Incidence rates of newly metastatic prostate cancer have not significantly changed since PSA screening declined in the US although we noted a slight upward trend primarily for younger, white men since 2002.
Real-world outcomes in first-line treatment of metastatic castration-resistant prostate cancer (mCRPC): The prostate cancer registry.
Authors: Chowdhury Simon , Birtle Alison J. , Bjartell Anders , Costa Luis , Feyerabend Susan , Galli Luca , Kalinka-Warzocha Ewa , Kramer Gero , Lumen Nicolaas , Maroto Pablo , Matveev Vsevolod B. , Paiss Thomas , Pisconti Salvatore , Spaeth Dominique , Antoni Laurent , Klumper Edwin , Wapenaar Robert , Van Den Berg Erik , Lee Emma
Published: March 2017

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Background: The Prostate Cancer Registry is the first prospective, international observational study in mCRPC documenting characteristics and management in routine clinical practice, independent of treatment used. The study began in June 2013 enrolling > 3000 mCRPC patients (pts) followed for ≤ 3 years. Methods: Source-verified data were collected from men with documented mCRPC initiating a new mCRPC treatment or in surveillance. A history of disease progression despite surgical or chemical ADT was confirmed in all pts. This interim analysis reports baseline characteristics, treatments and outcomes in pts with no prior mCRPC treatment. To evaluate comparative effectiveness between treatments, propensity scoring (PS) methods were used to reduce effects of confounding. Results: Of 1906 evaluable pts with ≥ 12-month follow-up, the most commonly initiated first-line mCPRC treatments (n ≥ 50) were abiraterone acetate + prednisone (AA, n = 472), enzalutamide (ENZ, n = 98) or docetaxel (DOC, n = 382). Baseline characteristics, time to progression (TTP) and prostate-specific antigen (PSA) response ( ≥ 50% decrease within 6 months) are shown in the table below. Conclusions: In this real-world study, pts receiving DOC as their first mCRPC treatment had more severe disease at entry and a trend for shorter TTP vs androgen inhibitors. TTP results are consistent with those in randomised clinical trials for AA and ENZ. Clinical trial information: NCT02236637. [Table: see text]
Evaluation of treatment patterns and costs for patients with prostate cancer and bone metastases.
Authors: Valdarrama Adriana , Yao Jianying , Wen Lonnie Kent
Published: March 2017

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Background: To describe treatment patterns and costs of care associated with the use of FDA-approved agents for metastatic castrate-resistant prostate cancer (mCRPC). Methods: Two large integrated claims databases (MarketScan, PharMetrics) were used to identify males ≥ 18 years old diagnosed and treated for prostate cancer (ICD9 = 185.xx or 233.4) with bone metastases (ICD9 = 198.5) from 06/2013 to 09/2014. Patients were required to be continuously enrolled ≥ 6 months pre- and post-initiation of treatment with abiraterone, cabazitaxel, docetaxel, enzalutamide, mitoxantrone, radium-223, or sipuleucel-T. Results: There were 953 and 565 patients meeting all inclusion criteria in each database, with a median follow-up time of 18 and 14 months, respectively. Mean age was 69 to 71 years. Prior to mCRPC treatment initiation, 14.0% to 18.2% of patients received radiation therapy, 36.1% to 40.0% denosumab, 16.5% to 16.8% zoledronic acid, and 0.2% to 0.8% pamidronate. Across both databases, abiraterone was most commonly received agent across all lines of therapy, except fourth line (Table 1). The median cost per patient per month during the post-index period was $10,292 to $10,916 in the each database, respectively, compared to $2,643 to $2,742 per patient per month during the 6-month pre-index period. Conclusions: Patients were treated mainly with abiraterone across most lines of care, with bone-targeted therapy being used in < 3% of patients. Median costs per patient per month increased approximately ~$8,000 over this period. [Table: see text]
Relationship between smoking, prognostic factors, and outcomes in patient (pts) with metastatic castration-resistant prostate cancer (mCRPC) receiving sipuleucel-T (sip-T): Preliminary analysis of the PROCEED registry.
Authors: Armstrong Andrew J. , Higano Celestia S. , Sartor Oliver , Penson David F. , Vogelzang Nicholas J. , Dakhil Shaker R. , Pieczonka Christopher Michael , Vacirca Jeffrey L. , Tutrone Ronald F. , Nordquist Luke T. , Chang Nancy N. , Cooperberg Matthew R.
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Background: Smoking is associated with poor treatment outcomes after definitive therapy for PC (Steinberger 2015 BJU Int; Joshu 2011 JNCI). However, there is a paucity of data on the effects of active smoking on pts with mCRPC. The PROCEED registry provides an opportunity to evaluate differences in disease characteristics and outcomes by smoking status in men receiving sip-T, an FDA-approved, autologous cellular immunotherapy for asymptomatic or minimally symptomatic mCRPC. Methods: Enrolled pts with mCRPC who never smoked (NS) or were current smokers (CS) were evaluated.Pt characteristics, time to first anticancer intervention (tACI; measured from last sip-T infusion to first ACI; agents: abiraterone, enzalutamide, docetaxel, cabazitaxel, radium-223), PC-specific survival, and OS were assessed. Results: Of 1956 enrolled pts with known smoking status, 904 were NS, 179 were CS; 873 were former smokers and not included in this analysis. Compared with NS, CS were younger, had lower BMI (p < 0.001), higher hemoglobin (Hgb; p < 0.001), lower lactate dehydrogenase (LDH; p = 0.05), and shorter time between PC diagnosis and first sip-T infusion (p = 0.01). Fewer CS pts had Gleason score < 8 (p = 0.2) and prior radical prostatectomy (p = 0.07). CS and NS did not differ in pattern or extent of metastatic disease spread. CS was associated with shorter OS, PC-specific survival, and tACI (Table). Conclusions: CS were younger at enrollment and had shorter OS, PC-specific survival, and tACI. Higher Hgb in CS likely reflects reduced plasma volume and/or increased red cell production. A multivariate analysis of prognostic factors for survival outcomes including smoking status in mCRPC is planned. However, active smoking represents a possible modifiable risk factor in the mCRPC setting. Clinical trial information: NCT01306890. [Table: see text]
Patient expectations from systemic treatment of metastatic prostate cancer (mPC).
Authors: Moses Kelvin A. , Penson David F. , Du Liping , Ahmed Ivy , Morgans Alicia Katherine
Published: March 2017

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Background: Multiple systemic therapies prolong the survival of men with mPC, but the disease remains incurable. High-quality treatment decisions require an informed understanding of the purpose of treatment and expected risks and benefits, particularly because cancer patients may accept otherwise unacceptable treatment if they believe there is a ≥ 1% chance of cure. Reconciling patient expectations with expected outcomes of providers is necessary to prevent treatment with toxic therapies that patients would refuse if cure were not possible. We assessed patient expectations from treatment among men receiving systemic therapy for mPC. Methods: Between 6/1/15 and 9/29/16, men with mPC completed surveys defining expectations of cure from their current mPC treatment. We used frequencies and relative frequencies to describe expectations, and proportional odds models with robust standard errors to assess the association between expectations, optimism, clinical characteristics, and sociodemographic factors. Results: Among 96 men completing surveys, 32 (33%) reported that cure was at least a little likely (8% very likely, 14% somewhat likely, and 11% a little likely). Higher optimism scores were associated with higher expectations of cure (adjusted OR 2.5, 95% CI 1.3-4.8 for most versus least optimistic), and non-white race was associated with lower expectations of cure as compared with white patients (adjusted OR 0.08, 95% CI 0.02 – 0.3). Report of excellent or good overall health was associated with greater odds of expecting cure than report of fair or poor health (adjusted OR 13, 95% CI 1.3 – 125). Marital status and age were not associated with expectations. Conclusions: Up to 1/3 of men with mPC receive treatment with an expectation that it may cure their cancer. Men with greater optimism and better reported health status have greater odds of expecting cure. Actions to align patient and physician expectations are necessary to adequately counsel patients and avoid overtreatment with toxic therapies.
Exploring optimal sequence of abiraterone and enzalutamide in patients with castration-resistant prostate cancer: The Kyoto-Baltimore collaboration.
Authors: Terada Naoki , Maughan Benjamin Louis , Akamatsu Shusuke , Kobayashi Takashi , Yamasaki Toshinari , Inoue Takahiro , Kamba Tomomi , Ogawa Osamu , Antonarakis Emmanuel S.
Published: March 2017

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Background: Abiraterone (ABI) and enzalutamide (ENZA) are novel hormonal treatments for castration-resistant prostate cancer (CRPC) used before and after docetaxel (DTX) chemotherapy. We aimed to evaluate and compare the efficacy of sequential treatment with ABI followed by ENZA or vice versa in patients with CRPC, using combined data from two institutions. Methods: We retrospectively evaluated data on 352 consecutive patients who had received both ABI and ENZA for CRPC at Kyoto University Hospital and at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. Using Kaplan-Meier analysis and log-rank tests, we compared PSA progression-free survival (PSA-PFS) and overall survival (OS) in patients treated with sequential ABI-to-ENZA versus ENZA-to-ABI without intervening therapies. Results: The number of patients receiving ABI-to-ENZA and ENZA-to-ABI were 163 (pre-DTX: 116, post-DTX: 47) and 189 (pre-DTX: 85, post-DTX: 104), respectively. The > 50% PSA response rates to ABI and ENZA were 47% and 52% in the first-line CRPC setting, and were 9% and 29% in the second-line setting. In the pre-DTX population, median PSA-PFS was not significantly different between ABI (median: 194 days) and ENZA (median: 126 days) in the first-line setting (p = 0.411), but there was an advantage favoring ENZA (median: 91 days) compared to ABI (median: 55 days) in the second-line setting (p = 0.008). Furthermore, the combined PSA-PFS was significantly longer in the ABI-to-ENZA sequence (median: 455 days) than in the ENZA-to-ABI sequence (median: 296 days) (p < 0.001). There was no statistical difference in OS between the two sequences (p = 0.598). Conclusions: The ABI-to-ENZA sequence may have more favorable efficacy in terms of combined PSA-PFS than the ENZA-to-ABI sequence, although no differences in OS were observed. This may possibly be attributable to higher PSA response rates and longer PSA-PFS to second-line ENZA compared to ABI (i.e., ENZA retains activity after ABI but not vice versa).
Accuracy of 68Ga-PSMA-PET/CT for patient selection for lymphadenectomy in addition to salvage radical prostatectomy in locally recurrent prostate cancer after primary radiotherapy.
Authors: Pfister David , Heidegger Isabel , Verburg Frederik , Porres-Knoblauch Daniel , Heidenreich Axel
Published: March 2017

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Background: Salvage radical prostatectomy, sRPE, is an option for patients in locally recurrent prostate cancer with curative intent. Patients with low PSA at time of salvage treatment and initially low-risk disease have a favourable outcome whereas locally advanced and lymph node positive patients do not. Imaging studies could be beneficial for patient selection of lymph node dissection in addition to sRPE. Here we show first results of the diagnostic accuracy of PSMA-PET/CT in this setting. Methods: We reviewed 87 patients with sRPE and PSMA-PET/CT prior to surgery. In all patients an extended sRPE with an extended lymphnode dissection including the internal, external iliac artery, fossa obturatoria as well as the A iliaca communis to the ureteral crossing, was performed. For diagnostic accuracy Sensitivity, Specifity, pos. and neg. predictive value was calculated per person and per lymph node. Results: 11 patients had a PSMA PET/CT prior to surgery. All scans showed positive results in the prostate but only one showed a positive lymph node. A total of 141 lymph nodes were dissected (median 13,5; 8-29 per patient). Pathological analysis showed 6 lymph nodes with a metastasis in 4 patients. No positive lymph node was identified correctly by PSMA PET/CT. Specificity and negative predictive value per patient / per lymph node were high with 85% / 99% and 60% / 95.7%, respectively. As no patient or lesion was identified correctly sensitivity and pos. predictive value could not be calculated. Accuracy was 55% / 95.7%. Conclusions: In this small patient group PSMA PET/CT has an insufficient per-patient accuracy for patient selection of lymph node dissection in addition to sRPE. For patient selection clinical data including primary risk profile and PSA kinetics prior to surgery are still more useful for this purpose.