bluuebunny/crossref_metadata_2025 huggingface dataset:
Prostate cancer meta-analysis from more than 145,000 men to identify 65 novel prostate cancer susceptibility loci.
Authors: Eeles Rosalind , Al Olama Ali Amin , Berndt Sonja , Wiklund Fredrik , Conti David V , Ahmed Mahbubl , Benlloch Sara , Easton Douglas , Kraft Peter , Chanock Stephen J. , Kote-Jarai Zsofia , Haiman Christopher , Schumacher Fredrick R
Published: March 2017

1

Background: Currently genome-wide association studies (GWAS) have identified over 100 prostate cancer (PrCa) susceptibility loci, capturing 33% of the PrCa familial relative risk (FRR) in Europeans. To identify further susceptibility variants, we conducted a PrCa GWAS, larger than previous studies, comprising ~49,000 cases and ~29,000 controls among individuals of European and Asian descent using the OncoArray, a platform consisting of a 260K GWAS backbone and 310K custom content selected from previous GWAS and fine-mapping studies of multiple cancers ( http://epi.grants.cancer.gov/oncoarray/ ). Methods: Genotypes from the OncoArray were used to impute genotypes from ~70M variants using the October 2014 release of the 1000 genomes project as a reference, and then combined with several previous PrCa GWAS of European ancestry: UK stage 1 (1,906 cases/1,934 controls) and stage 2 (3,888 cases/3,956 controls); CaPS 1 (498 cases/502 controls) and CaPS 2 (1,483 cases/519 controls); BPC3 (2,137 cases/3,101 controls); NCI PEGASUS (4,622 cases/2,954 controls); and iCOGS (21,209 cases/ 20,440 controls). Risk analyses for overall PrCa risk, aggressive PrCa (several definitions defined by PrCa clinical characteristics), and Gleason score were performed. Logistic and linear regression summary statistics were meta-analysed using an inverse variance fixed effect approach. Results: We identified novel loci significantly associated ( P < 5.0x10-8) with overall PrCa (N = 65). Our novel findings are comprised of several missense variants, including a SNP in the ATM gene - a key member of the DNA repair pathway. When combined multiplicatively, the 65 novel PrCa loci identified here increases the captured heritability of PrCa, explaining 38.5% of the FRR when combining novel and previously identified PrCa loci. Conclusions: In risk stratification, men in the top 1% of the genetic risk score group have a relative risk of 5.6 fold for developing PrCa compared with the median risk group. These results will improve the utility of genetic risk scores for targeted screening and prevention for prostate cancer.
Baseline differences in characteristics of a racially diverse group of men electing active surveillance.
Authors: Feibus Allison H. , Haney Nora M. , Liu James , Chiang Jason H , Ledet Elisa M. , Boxberger John , Levy Justin , Moparty Krishnarao , Lewis Brian E. , Thomas Raju , Sartor Oliver , Silberstein Jonathan L.
Published: March 2017

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Background: To date, large populations of men from European ancestry have been prospectively evaluated on Active Surveillance (AS), a strategy reserved for low risk prostate cancer (PCa). African Americans (AA) deemed to be candidates for AS have yet to be fully characterized. We sought to determine the similarities and differences of our AS cohort stratified by race. Methods: We identified 308 men from our multi-institutional, prospective AS database were analyzed. Inclusion criteria was PSA < 20ng/mL, Gleason score ≤ 7, and clinical stage ≤ T2a. Men who sought treatment for their PCa or refused subsequent imaging and biopsy were excluded. Univariate analysis was done to analyze racial differences in demographic, clinical and pathologic variables. Results: We identified 308 men, 131 (43%) AA and 177 nonAA (57%). The groups were not significantly different with respect to age; 65 years, BMI 28.4, family history of PCa (22%), prior negative biopsy (21%) and clinical staging (87% T1c). Median follow-up is 25 months (IQR 12-44). Significant differences between the AA and nonAA cohorts did exist at baseline with respect to overall health, suggesting AA having worse overall health. More AA had diabetes (29 vs 14%; p = .03), were smokers (55 vs 29%; p < .01), cardiovascular disease (21 vs 9%) and erectile dysfunction (43 vs 18%; p < .01). Social characteristics also differed within the groups, with AA less likely to be married (47 vs 51%; p = .01). Despite a lack of difference with respect to biopsy Gleason score, AA had higher PSA (5.7 vs 5.0 ng/mL; p = 0.02), lower testosterone levels (250 vs 334 ng/dL; p = 0.05), greater PSA density (0.15 vs 0.12; p < 0.01), and greater linear length of cancer per biopsy core (16 vs 13mm; p < 0.01) at time of diagnosis and initiation of AS. Conclusions: Within our AS cohort, AA have worse overall health and more aggressive PCa features despite meeting inclusion criteria and selecting AS. Further prospective study is needed to determine how these competing factors may impact long term outcomes.
Application of stable isotopic tracing in an ex-vivo system to reveal heterogeneous patterns of androgen metabolism in localized, hormone-naïve prostate cancer.
Authors: Dai Charles , Sharifi Nima , Chung Yoon-Mi , Klein Eric A.
Published: March 2017

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Background: The 5α-androstanedione (5α-dione) pathway is the demonstrated route through which adrenal precursor steroids bypass testosterone (T) to form dihydrotestosterone (DHT) in metastatic castration-resistant prostate cancer (mCRPC). However, accessible pathways of DHT synthesis are less clear in localized, hormone-naïve prostate cancer (HNPCa), where steroidogenic enzyme expression may differ and circulating T and adrenal steroids could act as competing substrates for 5α-reductase. We employed a dual substrate, ex-vivo system with selective stable isotopic labeling of DHT precursors to better understand alterations in androgen synthesis that occur in the transition of HNPCa to mCRPC. Methods: Under IRB approval and patient consent, tumor and adjacent benign prostate tissues were procured from radical prostatectomy specimens of men with HNPCa (n = 16). Tissues were grossly homogenized and incubated ex-vivo in serum-free media spiked with 1 µM of 13C3-AD +/- equimolar unlabeled T. Media was collected over 48 hours and subjected to liquid-liquid extraction to capture free and glucuronidated steroid metabolites for analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Both AD and T were readily 5α-reduced in treated prostate tissues. 13C labeling revealed DHT originating from metabolism of AD. Co-incubation with T did not dramatically alter the efficiency of AD metabolism. Minimal differences were found in metabolism between PZ and TZ tissue. No glucuronidated steroid was detected in media, in contrast to in prostate cancer cell lines and xenograft tumor tissue. Considerable heterogeneity was observed in measurements of reaction efficiency across different patients. Conclusions: AD is an active substrate for 5α-reductase comparable to T in HNPCa. Adrenal steroids may therefore contribute to DHT in HNPCa via the 5α-dione pathway. Metabolic heterogeneity may reflect currently unappreciated genotypic differences in patient tumors.
Characterization of circulating tumor cells in patients with localized high risk prostate cancer, post-prostatectomy.
Authors: Friedlander Terence W. , Anantharaman Archana , Welty Christopher , Zejnullahu Kreshnik , Hough Jeffrey , Edwards Matthew , Jendrisak Adam , Lee Jerry , Greene Stephanie , Ontiveros Priscilla , Graf Ryon , Rodriguez Angel , Suraneni Mahipal , Wang Yipeng , Landers Mark Andrew , Cooperberg Matthew R. , Carroll Peter , Dittamore Ryan Vance , Paris Pamela
Published: March 2017

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Background: Approximately 15% of men with newly diagnosed prostate cancer (PCa) have high-risk features, many of these patients will recur despite definitive therapy. Better predictive biomarkers could allow for earlier detection of recurrence and change surveillance paradigms. The role of circulating tumor cells (CTCs) as biomarkers in this context is not well defined. Here, we evaluate the ability to detect CTCs from men with high risk, localized PCa after radical prostatectomy (RP) and correlate their presence with prospective clinical data. Methods: Blood samples from 31 patients with high risk, localized PCa were obtained 2-4 months post RP and sent to Epic Sciences on an IRB approved protocol. Nucleated cells were subjected to immunofluorescent (IF) staining for cytokeratin (CK), CD45, and AR N-terminus. CTCs were identified by fluorescent scanners using algorithmic analysis. Cytokeratin expressing (CK+) CTCs were enumerated and subsequently analyzed for AR expression and individually sequenced for copy number variation (CNV) and large scale transitions (LST, a surrogate of genomic instability). Patients were followed prospectively for biochemical recurrence, defined as detectable PSA. Progression free survival (PFS) was calculated using Kaplan-Meier and Cox proportional hazards. Results: CTCs were detected in 87.1% (27/31) samples with an average of 5.6 CTCs/ml (range: 0 – 22.87) detected per patient. AR expression was detected in 12.9% (4/31) of patients. Ninety-nine CTCs from 14 patients were amenable to LST and CNV analyses. 10.1% (10/99) CTCs from 7 patients exhibited higher ( > = 6) LSTs than control WBCs (95% WBCs had LST < 6). Copy number alterations were detected in CTCs in commonly mutated genes in PCa, including AR, MYC, and TP53 amplification and deletions in PTEN and RB1. Patients with higher CTC burdens exhibited a trend toward shorter PFS (hazard ratio: 1.65; 95% confidence interval: 0.7-3.86; p: 0.13). Conclusions: There was a high incidence of CTC detection after RP in this population using a novel platform. We observed a trend toward shorter PFS in those with higher CTC burden. Genomic alterations were detectable in CTCs and consistent with established CNAs in PCa.
Racial variation in the reliability of prostate cancer indicators in men undergoing subsequent prostate biopsy.
Authors: Libby Robert Scott , Nguyen Hoang MT , Kramer Jordan J. , Feibus Allison H. , Thomas Raju , Silberstein Jonathan L.
Published: March 2017

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Background: Many men with an initial negative prostate biopsy have a persistently elevated prostate specific antigen (PSA) prompting physicians to perform repeat biopsies. African American men (AA) are at particular risk as they have a greater prostate cancer (PCa) incidence and mortality, yet traditional PSA testing may be less reliable in this cohort. We sought to determine the predictors of PCa and PCa severity in a racially diverse population on subsequent biopsy following an initial benign biopsy. Methods: Upon receiving Institutional Review Board approval, a retrospective analysis was performed on men with repeat prostate biopsies at Tulane Medical Center and Southeast Louisiana Veterans Health Care Services in New Orleans, Louisiana from 2003-2015. Inclusion criteria included patients with a benign initial prostate biopsy and underwent subsequent repeat prostate biopsy within 5 years. Race, age, serum PSA, PSA density (PSAD), and prostate volume by transrectal ultrasound (TRUS) were evaluated to determine if they correlate with the presence and severity of PCa. Aggressive PCa was defined as Gleason score >6. Results: A total of 209 men were included; 127 (61%) were AA, and 82 (39%) were Caucasian American men (CA). The two groups were similar with respect to PSA, PSAD, and TRUS. More AA (25.2% vs. 17.1%) had a repeat biopsy showing any PCa. Of those with PCa, 28.1% of AA and 28.6% of CA had aggressive PCa. PSAD positively correlated with any PCa (p=.015). TRUS negatively correlated with any PCa (p=.008). PSA levels (p<.001) and PSAD (p<.001) positively correlated with aggressive PCa in CA but not in AA. Conclusions: The goal of prostate biopsy particularly for those with a prior negative biopsy is to detect aggressive PCa. PSA and PSAD positively correlated with finding any PCa in both AA and CA but not with aggressive PCa in AA. PSA and PSAD are less accurate predictors of aggressive PCa in AA, and novel biomarkers are needed. [Table: see text]
Predicting late fecal incontinence risk after RT for prostate cancer: External independent validation.
Authors: Cicchetti Alessandro , Avuzzi Barbara , Palorini Federica , Rancati Tiziana , Stucchi Claudio , Fellin Giovanni , Gabriele Pietro , Vavassori Vittorio , Degli Esposti Claudio , Cozzarini Cesare , Fiorino Claudio , Valdagni Riccardo
Published: March 2017

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Background: To validating a predictive model for late fecal incontinence (FI) on a recent population (pop) of prostate cancer patients (pts) treated with radical radiotherapy. NTCP model was derived from literature. Methods: Pop included 267 pts treated with IMRT in 2010-2014. Prescribed dose was between 68 and 80 Gy with conventional and hypo-fractionated (HF, from 2.2 to 2.8 Gy) treatment. Rectal toxicity was scored using the LENT/SOMA. Follow-up (FU) was considered up to 2 years. We chose to validate a model for prediction of chronic FI through multiple measures during FU. Mean FI was defined as the average score during the FU period after RT (Mean incontinence > 1). Literature based multivariate model included: mean rectal dose (Dmean), previous diseases of colon (COLO) and previous abdominal surgery (SURG). Dose distributions were corrected EQD in 2 Gy fractions. Results: 186 pts were available. Mean grade > 1 FI was scored in 18 patients (〜10%). Univariate logistic analysis confirmed the risk factors reported in literature. Similar Odds Ratios (OR) were found for Dmean (1.04vs1.05) and SURG (1.90vs1.50). COLO was not a risk factor for this pop. As consequence, NTCP models including Dmean and Dmean+SURG were evaluated through calibration plot. The models showed a clear trend (increasing observed toxicity rates with predicted risk), but the observed toxicity rates were underestimated (slope〜3, R2〜0.7). Including HF (OR = 2.20, 8.6% vs 17.6%) as a variable into the previous model the calibrations improved significantly (slope〜1, R2〜0.9). Conclusions: The study confirms formerly published results on effect of abdominal surgery and dose to large rectal volumes as potential risk factors for late FI. The overfitting in calibrations could be due to an effect of HF, not included in previous models developed on normofractionated treatments. This effect goes beyond the applied standard correction using LQ model for late effects and also beyond the time recovery correction (slope〜2, R^2〜0.8). Probably we should found a more suitable alpha/beta value for the longitudinal definition (toxicity starting in acute phase and persisting during follow-up) instead of using the assumption settled on incidence of late peak events.
The impact of pretreatment MRI on genitourinary and gastrointestinal toxicity after radiation therapy in patients with localized prostate cancer.
Authors: Kilinski Kyle , Naghavi Arash , Abuodeh Yazan Asad , Echevarria Michelle , Yamoah Kosj
Published: March 2017

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Background: MRI has several advantages relative to other imaging modalities in evaluating, diagnosing, and planning treatment for prostate cancer yet it is rarely ordered for localized disease. While the diagnostic abilities have been studied, little has been done to associate clinical outcomes with prostate cancer patients who received MRI. We evaluated the effect of pre-treatment MRI on genitourinary (GU) and gastrointestinal (GI) toxicity in prostate cancer patients who received definitive radiation treatment. Methods: We retrospectively analyzed prostate cancer patients who underwent definitive radiation treatment at our facility between January 01, 1999 and July 31, 2014. All patients who underwent MRI of the pelvis or prostate within 5 years prior to treatment were included in the MRI cohort. The American Urological Symptom Score (AUA) and Rectal Assessment Scale (RAS) were used to measure GU and GI toxicity, respectively. We compared the toxicity profile of patients in our MRI cohort to a comparable cohort of patients who did not receive pre-treatment MRI. Results: 1085 patients (211 with MRI) were analyzed. Median follow-up was 30 months. Mean increase from baseline in AUA scores at 6 months was 3.58 for the MRI cohort and 5.04 for the comparison cohort (p = 0.017). RAS scores were not significantly different between the MRI and comparison cohorts at 6 months (mean increase: 0.62 vs. 0.77, p = 0.662). AUA scores returned to baseline after 6 months in the MRI cohort and after 12 months in the comparison cohort. RAS scores returned to baseline after 12 months in the MRI cohort but never returned to baseline in the comparison cohort. Biochemical failure rates were not significantly different between the MRI cohort and comparison cohort (86.3% vs. 91.1%, p = 0.083). Conclusions: Pre-treatment MRI was associated with significantly less GU and GI toxicity. These results may be influenced by more advanced disease and higher use of hormonal therapy in the MRI cohort. Future prospective studies in a risk-matched cohort are required to validate these findings.
Results from a phase II trial (NTC01902680) of ultrafocal brachytherapy for low/intermediate risk prostate cancer.
Authors: Graff-Cailleaud Pierre , Malavaud Bernard , Portalez Daniel , Brun Thomas , Aziza Richard , Lusque Amellie , Khalifa Jonathan , Filleron Thomas , Bachaud Jean-Marc
Published: March 2017

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Background: Biology suggests that the most significant focus drives the natural history of prostate cancer. We assessed the feasibility of ultrafocal brachytherapy (BT) of the index tumor. Methods: In a 2-step Simon’s design (&=0.1, ß=0.1), 17 patients were needed to assess that 100% of clinical target volume (CTV) - gross tumor volume on T2-MRI plus 2mm margin - received ≥95% of the prescribed dose (primary objective: D100≥152Gy). Pre-inclusion:EAU guidelines for Surveillance [PSA <10ng/mL, cT1c-cT2a, Gleason sum on referring biopsies ≤6(3+3), ≤3 positive biopsies, ≤50% of cancer] and for BT [IPSS <10, no TURP, prostate <60mL, >10yr life expectancy]. Inclusion:when mpMRI detected a PIRADS≥3 focal lesion, confirmed as Gleason sum ≤7a (3+4) cancer on elastic fusion registration (EFR) biopsies (Koelis). Procedure:EFR was used to insert trans-rectally a US-visible marker (Bard SourceLink) within CTV before biplanar TRUS for BT. Dose distribution was optimized by inverse planning (Variseed v7.2) before ultrafocal implantation of I-125 seeds (Bard Pro-Link). 1ary objective:Doses delivered within the first 30d to CTV were assessed by Variseed rigid registration between pre-implant MRI and d30 CT-Scan. 2ary objectives: GI, GU CTCAE toxicity & QoL (IPSS, IIEF5, QLQc30) were prospectively accrued. Protocol biopsies of GTV and rest of the gland were obtained by EFR 1yr post-implantation. Results: 27 patients failed confirmatory biopsies (multifocal n=10; aggressive 11; no cancer 6). Of 17 included (10/2013-8/2016), only 3 did not meet the primary objective (D100: 76, 105, 132 Gy) and the trial was deemed successful. Mean CTV was 0.74±0.31mL that is 1.9±1.1% of the gland. Prescribed dose was delivered to 14.5±6.4% of the gland, in line with the ultrafocal nature of the treatment. To date 11 patients, including the previous 3, received 1yr biopsies. No in-field recurrences (GTV) were observed, 5 non-clinically significant cancers were found in the contralateral lobe. No grade>2 toxicity was observed. QoL evaluation is in process. Conclusions: As shown by optimal dosimetry in 14/17(82.4%), minimal toxicity in all, and no in-field recurrences (0/11), ultrafocal BT is a promising avenue in focal treatment. Clinical trial information: NCT01902680.
The long tail of significantly mutated genes in prostate cancer.
Authors: Armenia Joshua , Mullane Stephanie Anne , Gao JianJiong , Chakravarty Debyani , Kundra Ritika , Huang Franklin W. , Han G. Celine , Robinson Dan , Garraway Levi A. , Nelson Peter , Rubin Mark A. , Taplin Mary-Ellen , Abida Wassim , Sawyers Charles L. , Chinnaiyan Arul M. , Kantoff Philip W. , De Bono Johann S. , Schultz Nikolaus , Van Allen Eliezer Mendel
Published: March 2017

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Background: The mutational landscapes of primary and metastatic PCa have been robustly analyzed in multiple whole exome sequencing (WES) studies. We hypothesized that an aggregate, uniform analysis of all data generated to date would enable discovery of new significantly mutated genes and pathways not previously associated with PCa, and shed more light onto the genetic differences between primary and metastatic PCa. Methods: We assembled and uniformly analyzed a cohort of 1,021 tumor and matched germline primary and metastatic PCa whole exomes (686 primary, 335 metastatic), and performed mutational significance analysis using statistical and biological approaches to determine which genes and pathways are recurrently altered. Results: We identified 117 significantly mutated genes (Mutsig q<0.1) in PCa, which included many novel genes and pathways. These include epigenetic modifiers [KMT2C (6%), KMT2D (6%), and KDM6A (2.7%)], regulators of the SWI/SNF complex [SMARCA1 (1.1%), ARID1A (1.5%), ARID1B (1.3%), ARID2 (1.3%), and PBRM1 (0.7%)], and the splicing pathway [SF3B1 (1.1%) and U2AF1 (0.5%)]. In addition, we identified mutations in FUBP1 (0.4%), a splicing regulator involved in the regulation of MDM2 splicing. We also found truncating mutations in SPEN, a hormone inducible transcriptional repressor, in 2.8% of samples, similar to the frequency observed in breast tumors. Finally, a comparison of primary and metastatic samples enabled discovery of a genetic profile associated with metastatic disease, including AR amplifications and mutations, and loss of TP53, PTEN, and RB1. At lower frequency, metastatic tumors showed enrichment in mutations in MLLs (KMT2C/D), APC, CDK12, BRCA2, CTNNB1, and amplifications of MYC and CCND1. Conclusions: Through aggregation and uniform genomic analysis, we refined the map of somatic mutations in PCa and identified cancer genes and pathways not previously associated with this disease. Our findings may inform patient stratification and translational investigation.
A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 in patients with mCRPC.
Authors: Kolinsky Michael Paul , Rescigno Pasquale , Bianchini Diletta , Zafeiriou Zafeiris , Mehra Niven , Mateo Joaquin , Riisnaes Ruth , Crespo Mateus , Figueiredo Ines , Flohr Penelope , Tunariu Nina , Banerji Udai , Raynaud Florence I. , Swales Karen E , Tovey Holly , Porta Nuria , Slade Rachel , Leonard Lorna , Hall Emma , De Bono Johann S.
Published: March 2017

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Background: Activation of the PI3K/AKT/mTOR pathway may contribute to resistance to androgen receptor targeted therapies in metastatic CRPC (mCRPC). The phase I/II RE-AKT trial (NCT02525068) investigates the safety and activity of enzalutamide (enza) in combination with the AKT inhibitor, AZD5363, in patients (pts) with mCRPC. Results of the phase I run-in are reported. Methods: mCRPC pts progressing after 1-2 lines of taxane chemotherapy and at least 12 weeks (wks) of abiraterone or enza were treated with enza (160mg od) and AZD5363 bid 4-days on, 3-days off, in a 3+3 dose escalation design. Co-primary endpoints were to assess toxicity (CTCAE), and identify the recommended phase II dose (RP2D) of AZD5363; antitumour activity and pharmacokinetics (PK) were secondary endpoints. Response was assessed by PSA, RECIST v1.1 and circulating tumor cell (CTC) conversion. Pts were considered evaluable for response if they completed 12 wks of treatment. Results: 16 pts were enrolled between 12/2014 & 04/2016 with 15 receiving treatment. At the AZD5363 320mg dose 3 pts were treated with no dose limiting toxicity (DLT). At the AZD5363 480mg dose, 5 pts were treated with 2 DLTs of grade (G) 3 maculopapular rash (MPR) related to AZD5363. An intermediate dose level of AZD5363 400mg was selected with 7 pts treated. 1 pt withdrew consent prior to completing the DLT window. 1 DLT of G3 MPR occurred and this dose was selected as the RP2D. Non-DLT treatment related (TR) G3/4 adverse events (AEs) were hyperglycaemia (n = 4, 26.7%), neutropenia (n = 1, 6.7%) & diarrhea (n = 1, 6.7%). All other TR AEs were G1 or G2, with diarrhea (n = 9, 60%), anorexia (n = 8, 53.3%) & nausea (n = 7, 46.7%) being most common. Of the 10 pts who completed 12 wks of treatment, 3 met at least one of the criteria for response. 1 pt (AZD5363 320mg) who had previously progressed on enza exhibited RECIST v1.1 partial response, > 50% PSA response, and CTC conversion by wk 13. Enza decreased AZD5363 PK exposure; robust modulation of pS6, pGSK3b and pPRAS40 was demonstrated. Conclusions: AZD5363 at the RP2D of 400mg bid 4 days on, 3 days off combined with enza 160mg od is safe and tolerable. Antitumor activity is reported, suggesting that AZD5363 may be able to overcome resistance to enza. Clinical trial information: NCT02525068.
Development and validation of a prognostic model for overall survival in chemotherapy-naïve men with metastatic castration-resistant prostate cancer (mCRPC) from the phase III PREVAIL clinical trial.
Authors: Armstrong Andrew J. , Lin Ping , Higano Celestia S. , Sternberg Cora N. , Sonpavde Guru , Tombal Bertrand F. , Templeton Arnoud J. , Fizazi Karim , Phung De , Wong Elaine Karol , Krivoshik Andrew , Beer Tomasz M.
Published: March 2017

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Background: Prognostic models require updating to reflect contemporary medical practice. In a post hoc analysis of the phase 3 PREVAIL trial (enzalutamide vs placebo), we identified prognostic factors for overall survival (OS) in chemotherapy-naïve men with mCRPC. Methods: Patients were randomly divided 2:1 into training (n = 1159) and testing (n = 550) sets. Using the training set, 23 predefined candidate prognostic factors (including treatment) were analyzed in a multivariable Cox model with stepwise procedures and in a penalized Cox proportional hazards model using the adaptive least absolute shrinkage and selection operator (LASSO) penalty (data cutoff June 1, 2014). A multivariable model predicting OS was developed using the training set; the predictive accuracy was assessed in the testing set using time-dependent area under the curve (tAUC). The testing set was stratified based on risk score tertiles (low, intermediate, high), and OS was analyzed using Kaplan-Meier methodology. Results: Demographics, disease characteristics, and OS were balanced between the training and testing sets; median OS was 32.7 months for both datasets. There were no enzalutamide treatment-prognostic factor interactions (predictors). The final multivariable model included 11 prognostic factors: prostate-specific antigen, treatment, hemoglobin, neutrophil-lymphocyte ratio, liver metastases, time from diagnosis to randomization, lactate dehydrogenase, ≥ 10 bone metastases, pain, albumin, and alkaline phosphatase. The tAUC was 0.74 in the testing set. Median (95% confidence interval [CI]) OS for the low-, intermediate-, and high-risk groups (testing set) were not yet reached (NYR) (NYR–NYR), 34.2 months (31.5–NYR), and 21.1 months (17.5–25.0). The hazard ratios (95% CI) for OS in the low- and intermediate-risk groups vs the high-risk group were 0.20 (0.14–0.29) and 0.40 (0.30–0.53), respectively. Conclusions: Our validated prognostic model incorporates factors routinely collected in chemotherapy-naïve men with mCRPC treated with enzalutamide and identifies subsets of men with widely differing survival times.
Antigen spread (AgS) after sipuleucel-T (sip-T): A cross-trial comparison of 4 sip-T clinical trials of patients (pts) with prostate cancer (PC).
Authors: Fong Lawrence , Small Eric Jay , Petrylak Daniel Peter , Quinn David I. , Antonarakis Emmanuel S. , Kibel Adam S. , Chang Nancy N. , Kandadi Harini , Sheikh Nadeem Anwar , Drake Charles G.
Published: March 2017

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Background: Sip-T, an FDA-approved autologous immunotherapy for pts with asymptomatic or minimally symptomatic metastatic castration-resistant PC (mCRPC), is manufactured from peripheral blood mononuclear cells cultured with PA2024, a fusion antigen of prostatic acid phosphatase (PAP) conjugated to granulocyte macrophage colony-stimulating factor. In sip-T–treated pts, antibody responses to PA2024/PAP (target antigens) and AgS (antibody responses to secondary [2°] antigens) correlate with improved OS (Sheikh 2013; GuhaThakurta 2015). We assessed if a greater magnitude of AgS would be observed in an earlier PC disease stage when the immune system is more intact. Methods: Pt serum was from 1 non-metastatic, androgen-dependent PC (ADPC) sip-T trial (STAND, sip-T + androgen deprivation, NCT01431391) and 3 mCRPC sip-T trials (IMPACT, sip-T vs control, NCT00065442; STAMP, sip-T + abiraterone acetate, NCT01487863; STRIDE, sip-T + enzalutamide, NCT01981122). Using a Luminex assay, mean fold-change in IgG responses to target and 2° cancer-related antigens (PSA, LGALS3, LGALS8, ERAS, KRAS, KLK2) was evaluated from baseline to wk 6. Results: AgS was evaluated in 308 pts. The mean fold-change in IgG responses to target antigens was greater for ADPC vs mCRPC pts (p < 0.01). Moreover, the magnitude of IgG responses was greater for most 2° antigens in ADPC vs mCRPC pts (p < 0.05; Table), except for PSA and KLK2 in ADPC vs STRIDE pts. Conclusions: The magnitude ofantibody responses to target and 2° antigens was greater earlier in the PC disease course, consistent with increased antigen-presenting cell activation in ADPC vs mCRPC pts. Increased AgS likely reflects stronger sip-T–induced immune responses, previously associated with extended OS in mCRPC (Sheikh 2013; GuhaThakurta 2015). Future research is warranted on the clinical benefit of sip-T earlier in the PC disease course and the potential impact of androgen suppression on the magnitude of AgS and outcomes. Clinical trial information: NCT01431391; NCT00065442; NCT01487863; NCT01981122. [Table: see text]
PACIFIC trial: A randomized phase II study of apatorsen and abiraterone in patients (Pts) with metastatic castration-resistant prostate cancer (mCRPC) who have had PSA progression while receiving abiraterone (ABI).
Authors: Chi Kim N. , Fleming Mark T. , Sunderland Katherine , Albany Costantine , Gingerich Joel , Saad Fred , North Scott A. , Starodub Alexander , Lauer Richard C. , Ruether Joseph D. , Sgroi Madelaine Miranda , Scholz Mark C. , Sweeney Christopher
Published: March 2017

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Background: Heat Shock Protein 27 (Hsp27) is a multi-functional chaperone that regulates cell signaling and survival pathways implicated in cancer progression. In prostate cancer models, Hsp27 chaperones androgen receptor (AR) and enhances transactivation of AR-regulated genes. Apatorsen is a 2nd generation antisense that inhibits Hsp27 expression with clinical activity demonstrated in pts with mCRPC. Methods: mCRPC patients with PSA-only progression on ABI + prednisone (P) 10-20 mg daily were randomized to continuing ABI + P (Control Arm) or ABI + P with Apatorsen 600 mg IV x 3 loading doses then 800 mg IV weekly (Study Arm). Control Arm pts could cross over to receive apatorsen at time of progression. Primary endpoint was the proportion of pts progression free (PSA, clinical and radiologic) at day 60. Assuming a 25% increase in proportion of pts progression free and a null hypothesis of 5%, the planned sample size was 74 patients (type I error 20%, type II error 10%). Results: 72 pts were randomized: 36 to Control Arm, 36 to Study Arm. Baseline characteristics were similar in both arms: median age was 72 years (53-89); ECOG PS 0/1 in 44/56% of pts; median PSA of 29.4 (2.5-470.0); metastases to bone/lymph nodes/liver or lung occurred in 63/27/10%; elevated LDH and alkaline phosphatase in 26% and 26% ; 47% had ≥ 5 CTC/7.5 mL. Adverse events (AEs) were mainly grade 1-2 infusion reactions. 18 pts had grade 3/4 adverse events considered apatorsen related including: dyspnea (14%), fatigue (14%), increased ALT (9%), increased AST (9%), and thrombocytopenia (9%). Primary and secondary outcomes are summarized in the Table. Conclusions: Apatorsen may have activity when added to abiraterone for mCRPC patients progressing on abiraterone. Establishing predictors of response should be a priority for future studies. Clinical trial information: NCT01681433. [Table: see text]
Feasibility of cotargeting cell cycle and androgen signaling in metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Palmbos Phillip Lee , Tomlins Scott A. , Agarwal Neeraj , Twardowski Przemyslaw , Morgans Alicia Katherine , Kelly William Kevin , Arora Vivek , Antonarakis Emmanuel S. , Siddiqui Javed , Daignault Stephanie , Knudsen Karen E. , Feng Felix Yi-Chung , Hussain Maha
Published: March 2017

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Background: Most patients (pts) with mHSPC treated with androgen deprivation therapy (ADT) will progress to castration resistance. Androgens drive PC cell proliferation via upregulation of cyclin D which complexes with the cyclin-dependent protein kinases 4/6 (CDK4/6) resulting in phosphorylation of retinoblastoma (Rb) tumor suppressor protein and G1/S progression. Alterations in this pathway contribute to progression to castration-resistance (CR). In preclinical PC models, palbociclib, a novel specific CDK4/ 6 inhibitor, blocked proliferation and promoted G1 arrest in an Rb and Cyclin D dependent manner. Rb is lost in <10% of localized PC, but >30% of CR disease. Rb loss in mHSPC is estimated to be 10-20%. Based on this preclinical data, we designed a randomized phase II clinical trial (NCT02059213) to test the hypothesis that palbociclib + ADT in newly metastatic Rb-positive PC pts will significantly increase ADT efficacy. Methods: mHSPC pts with Rb intact tumors based on metastatic biopsy are stratified by disease extent and randomized (1:2) to ADT or ADT+ palbociclib. Primary endpoint is confirmed prostate specific antigen (PSA) response (≤ 4 ng/mL) after 28 weeks of therapy. With 20 patients randomized to ADT and 40 to ADT + palbociclib there will be a 64.2% power to detect a 20% difference in proportions with a one-sided type I error of 0.10 using the mid p-value method of the Fisher’s exact test. Secondary endpoints: safety and tolerability, rate of undetectable PSA (≤ 0.2ng/mL), biochemical and clinical PFS, overall PSA and radiographic RR, therapeutic biomarkers (circulating DNA and tumor cells, tumor protein and transcriptome) and to establish a repository of mHSPC samples. Results: Since July 2014, 68 patients have been registered and underwent tumor metastatic disease biopsy (36 soft tissue, 32 bone). 60/68 (88%) had adequate tissue for Rb assessment. 58/60 (97%) tumors were Rb positive (IHC). To date, 58/60 patients have been randomized to ADT (19 patients) or ADT + palbociclib (39 patients). Conclusions: Biopsy driven studies are feasible in the mHSPC population. Rb expression was present in 58/60 (97%) patients. This study is ongoing. Support: Movember-PCF Challenge Award, Pfizer. Clinical trial information: NCT02059213.
Safety and efficacy of 177lu-PSMA-617 radioligand therapy in patients with mCRPC: A multicenter study.
Authors: Rahbar Kambiz , Ahmadzadehfar Hojjat , Kratochwil Clemens , Baum Richard P. , Schmidt Matthias , Pfestroff Andreas , Prasad Vikas , Heinzel Aelxander , Ruf Juri , Eveslage Maria , Boegemann Martin , Fendler Wolfgang , Krause Bernd J
Published: March 2017

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Background: Prostate specific membrane antigen (PSMA) is a promising target for imaging and therapy of prostate cancer. Small cohorts trials have shown promising results for response and tolerability of 177Lu-PSMA-617 radioligand therapy (RLT) in patients with metastatic castration-resistant disease. The aim of this multicenter study was to investigate safety and efficacy of this new therapy in a large, multicenter cohort. Methods: Data of 145 patients with metastatic castration resistant prostate cancer treated with at least a single dose of 177Lu-PSMA-617 at 12 therapy centers in Germany (median age 73 years, range 43-88) were collected. Up to 4 therapy cycles (range of administered activity 2 – 8 GBq) were given. Toxicity was categorized by the common toxicity criteria for adverse events based on serial blood tests and the physician’s report. Biochemical response was defined by a PSA decline ≥ 50% from baseline. Results: 248 therapy cycles were performed. Data for biochemical response were available in 99 patients and data for physician-reported and lab-based toxicity in 145 and 121 patients. The median follow-up was 16 weeks (range 2-30 weeks). Nineteen patients died during the observation period. Grade 3 to 4 hematotoxicity occurred in 18 patients: 10%, 4% and 3% of the patients experienced anemia, thrombocytopenia and leukopenia, respectively. Xerostomia occurred in 8%. Overall biochemical response rate was 45% following all therapy cycles. Elevated alkaline phosphatase and presence of visceral metastases were negatively correlated and the total number of therapy cycles correlated positively with biochemical response. 22 of 31 patients with no PSA decline > 50% after the first cycle did not respond to the second therapy cycle. Conclusions: Radioligand therapy with 177Lu-PSMA-617 shows promising response rates and a low toxicity in extensively pretreated patients with prostate cancer. Future prospective trials have to evaluate the effect of RLT on survival and potentially be considered in earlier stages of prostate cancer.
Aberrant tumor metabolism to enable glucocorticoid receptor takeover in enzalutamide-resistant prostate cancer.
Authors: Sharifi Nima , Li Jianneng , Alyamani Mohammad , Zhang Ao , Chang Kai-Hsiung , Berk Mike , Li Zhenfei , Zhu Ziqi , Petro Marianne , Taplin Mary-Ellen , Garcia Jorge A. , Courtney Kevin Dale , Klein Eric A.
Published: March 2017

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Background: Prostate cancer is driven by androgen stimulation of the androgen receptor (AR). The next-generation AR antagonist, enzalutamide, prolongs progression-free and overall survival, but resistance and lethal disease eventually prevail. Emerging data suggest that the glucocorticoid receptor (GR) is upregulated in this context, stimulating expression of approximately 50% of genes normally stimulated by AR, thereby permitting continued growth despite AR blockade. However, countering this mechanism by administration of GR antagonists is problematic because GR is essential for life. Methods: We assessed the effects of enzalutamide on metabolism of cortisol to cortisone in the LAPC4 and VCaP models of prostate cancer using [3H]-cortisol and high performance liquid chromatography. Expression of 11β-hydroxysteroid dehydrogenase-2, encoding the enzyme 11βHSD2, which converts cortisol to cortisone, was assessed by immunoblot, in models of prostate cancer, tissues from patients treated with enzalutamide and prostate tissues treated exogenously with enzalutamide. The effect of shRNA knockdown of the AMFR ubiquitin E3-ligase on 11βHSD2 protein expression and enzyme activity was assessed. Finally, the potential therapeutic effects of 11βHSD2 re-expression on enzalutamide resistance was assessed in xenograft models. Results: Enzalutamide impedes inactivation of cortisol to cortisone, thereby sustaining tumor cortisol concentrations, permitting GR stimulation and enzalutamide resistance. Impeded cortisol inactivation by enzalutamide occurs by way of 11β-HSD2 expression loss in models of prostate cancer, prostate tissues from enzalutamide-treated patients and fresh prostatic tissues treated exogenously with enzalutamide. AMFR mediates loss of 11β-HSD2, which otherwise inactivates cortisol. Remarkably, reinstatement of 11β-HSD2 expression, or AMFR loss, reverses enzalutamide resistance in mouse xenograft tumors. Conclusions: Together, these findings reveal a surprising metabolic mechanism of enzalutamide resistance that may be targeted with a strategy that circumvents a requirement for systemic GR ablation.
Avelumab in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Fakhrejahani Farhad , Madan Ravi Amrit , Dahut William L. , Karzai Fatima , Cordes Lisa M , Schlom Jeffrey , Gulley James L.
Published: March 2017

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Background: Despite recent progress, mCRPC remains a lethal disease. While programmed cell death 1 (PD-1) and PD-1 ligand (PD-L1) inhibitors have shown activity in variety of malignancies, to this point there is minimal evidence of activity in mCRPC. This is a report of avelumab, anti-PDL1 in mCRPC patients (pts). Methods: This is an expansion cohort of the first in human, phase I trial (JAVELIN Solid Tumor; EMR100070-001) that evaluated 10 mg/kg of avelumab in pts with mCRPC who had progressive disease (PD) on previous treatment. Pts who had PD on an androgen receptor antagonist (ARA) could enroll on trial and continue their ARA. Avelumab was administered as a 1-hour intravenous infusion every 2 weeks (w) with restaging scans every 6 w. Prostate cancer working group 2 criteria were used to determine PD. Results: 18 patients were enrolled on this cohort; the median age of pts was 67 years. Median on study PSA was 11ng/mL. 11 pts had Gleason score (GS) ≥ 8 and 7 had GS of 7. 3 pts had previous chemotherapy with docetaxel, 8 pts received previous vaccine treatment including 4 pts with sipuleucel-T and 4 pts with Prostvac. Overall avelumab treatment was safe and tolerable. 15 pts experienced grade ≤ 2 treatment related adverse events (TRAEs), fatigue being the most common one. 4 pts developed treatment related hypothyroidism, 3 with grade 2 and 1 with grade 1. In addition, 2 pts had grade 3 asymptomatic TRAEs (amylase & lipase elevations). 7 pts had stable disease (SD) > 24 w post treatment, 6 pts had PD after first restaging scans at 6 w which was reconfirmed in 2nd restaging scan at 12 w. PSA doubling time (PSADT) prior to avelumab was compared with PSADT after 3 months (m) of treatment. Among 17 pts with available data, 3 pts had a prolonged PSADT which was defined at 3 m (twice as high as on-study PSADT), 7 pts had stable PSADT and 7 had decreased PSADT. 5 of 18 pts enrolled while on enzalutamide with a rising PSA. Among these pts 1 had prolonged PSADT, 2 had a stable PSADT and 2 with decreased PSADT after 3 m of follow up. 3 of 5 pts had SD > 24 m, 1 had SD for 13 w and 1 had PD at first restaging scans. Conclusions: These data provide safety data of avelumab on a population of pts with mCRPC. Immune analysis is under way to determine correlation with immune responses in the pts on this trial that had prolonged SD. Clinical trial information: NCT01772004.
A phase II study of the anti-programmed death ligand-1 antibody durvalumab (D; MEDI4736) in combination with PARP inhibitor, olaparib (O), in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Karzai Fatima , Madan Ravi Amrit , Owens Helen , Hankin Amy , Couvillon Anna , Houston Nicole D. , Fakhrejahani Farhad , Bilusic Marijo , Theoret Marc Robert , Cordes Lisa M , Trepel Jane B. , Edelman Daniel C. , Meltzer Paul S. , Gulley James L. , Dahut William L. , Lee Jung-min
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Background: Recent data suggests 25-30% of sporadic mCRPC has defects in DNA repair pathways which may confer sensitivity to PARP inhibition. Immune checkpoint blockade is a promising avenue in mCRPC treatment. We hypothesize that increased DNA damage by O will complement anti-tumor activity of immune checkpoint inhibitor, D, in mCRPC (NCT02484404). Methods: Eligible pts have mCRPC with adequate end organ function and biopsiable disease (bone or soft tissue). Prior treatment with enzalutamide and/or abiraterone is required. D is administered at 1500 mg iv q28 days with O at 300 mg po q12 h. Primary endpoint is PFS. Secondary endpoints include PSA responses, safety and ORR. Single arm pilot study with a total accrual of 25 pts. On-study core biopsies undergo mutational analysis. Results: 6 pts have enrolled (median age 67 yr [range 60-79], median ECOG PS 1 [1-2]). Median baseline PSA: 258.1 (54.1-809.9 ng/mL). 4 pts have Gleason score (GS) > 8 and 2 pts have GS of 7. Grade 3/4 adverse events include anemia 2/6 (33%), thrombocytopenia, lymphopenia, nausea, febrile neutropenia, aspiration pneumonia [1 each, (17%)]. Conclusions: Exploiting synergy of D+O is a treatment option for heavily pre-treated pts. Preliminary data shows D+O is tolerable and active in mCRPC pts without germline BRCA mutation. Paired tumor biopsies and blood samples including ctDNA are being collected. Accrual is ongoing. Clinical trial information: NCT02484404. [Table: see text]
Efficacy and safety of enzalutamide (ENZA) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with abiraterone acetate (Abi): A multicenter, single-arm, open-label study.
Authors: De Bono Johann S. , Chowdhury Simon , Feyerabend Susan , Elliott Tony , Grande Enrique , Melhem-Bertrandt Amal , Baron Benoit , Hirmand Mohammad , Werbrouck Patrick , Fizazi Karim
Published: March 2017

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Background: This phase 4, multicenter, single-arm, open-label study evaluated the efficacy and safety of ENZA in patients (pts) with progressing mCRPC previously treated with Abi. Methods: All pts maintained castration therapy with luteinizing hormone-releasing hormone for the duration of the trial or had a bilateral orchiectomy. Pts were required to have progressive disease at study entry and ≥ 24 weeks of Abi treatment prior to receiving 160 mg/day ENZA. Prior chemotherapy was allowed. The primary end point was radiographic progression-free survival (rPFS). The secondary end points were overall survival (OS), prostate-specific antigen (PSA) response, and time to PSA progression. Safety was also assessed. Results: A total of215 pts were enrolled; 214 were treated with ENZA (median age, 73 years). The analysis was performed on data up to 48 weeks after the last pt started ENZA treatment. Median duration of prior Abi therapy was 54 weeks. The median duration of ENZA treatment was 5.7 months: 12 months in PSA responders and 4.6 months in non-PSA responders. 16% of pts received treatment for ≥ 1 year. The most common reason for treatment discontinuation was disease progression (65%). Median rPFS was 8.1 months (95% CI 6.1, 8.3). Median OS was not reached in the overall population and 75% of pts were alive 1 year after treatment initiation. PSA response (confirmed or unconfirmed) rate was 26.5% (48/181). The median time to PSA progression was 5.7 months (95% CI 5.6, 5.8). The overall objective response rate in pts with measurable disease at study entry was 12%. The most common treatment emergent adverse events (TEAEs) were fatigue (32%), decreased appetite (25%), asthenia (18%), back pain (17%), and arthralgia (16%). ENZA was primarily discontinued due to TEAEs in 8% of pts. No seizures were reported. Conclusions: In this study, ENZA remained active in pts with mCRPC previously treated with Abi. Median rPFS in pts with prior chemotherapy was consistent with previously reported data of ENZA in pts with mCRPC and prior chemotherapy/Abi therapy.Reported TEAEs were consistent with the known safety profile of ENZA. Clinical trial information: NCT02116582.