bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study of the safety and pharmacokinetics of DSTP3086S, an anti-STEAP1 antibody-drug conjugate (ADC), in patients (pts) with metastatic castration-resistant prostate cancer (CRPC).
Authors: Danila Daniel Costin , Szmulewitz Russell Zelig , Higano Celestia S. , Gilbert Houston , Kahn Robert S. , Wood Katie , Agarwal Priya , Lin Kedan , Kabbarah Omar , Fine Bernard M. , Maslyar Daniel J. , Vaishampayan Ulka N. 
Published: March 2020

5020 Background: Six-transmembrane epithelial antigen of the prostate-1 (STEAP1) protein is a cell-surface antigen overexpressed in human epithelial prostate cancers. The ADC DSTP3086S contains the humanized IgG1 anti-STEAP1 monoclonal antibody linked to the potent anti-mitotic agent MMAE. Methods: This study evaluated safety, pharmacokinetics, and pharmacodynamic activity of intravenous DSTP3086S (0.3-2.8 mg/kg) given every 3 weeks (q3w) to pts with CRPC. A traditional 3+3 design was used to determine maximum-tolerated dose, followed by cohort expansion at the recommended Phase II dose (RP2D). Clinical activity was evaluated per PCWG criteria. Dose escalation results are presented. Results: Twenty-eight pts were enrolled with a median age of 67 (43-76), all ECOG PS 0-1, and with a median of 7 prior systemic regimens (including a median of 4 hormonal and 3 non-hormonal regimens). Pts received a median of 3 doses (range 1-10) of DSTP3086S. Reversible Grade 3 transaminitis DLTs occurred in one pt each in the 2.25 mg/kg and 2.8 mg/kg cohorts. Serious AEs (SAE) related to study drug (3 total) included one DVT (Grade 3) in the 1.5 mg/kg cohort, as well as one GI hemorrhage (Grade 3) and one sepsis event (Grade 5) in the 2.25 mg/kg cohort. The most common related AEs across all doses were fatigue (36%), nausea (32%), constipation (25%), decreased appetite and diarrhea (each 21%), and musculoskeletal pain and vomiting (each 18%). Exposure for total antibody, free MMAE, and conjugated MMAE was dose proportional. Approximately 60% of the tumor samples assessed showed high STEAP1 expression. CTC reductions were most robust at 2.8 mg/kg; 4/4 patients with unfavorable CTCs at baseline (median of 99, range: 21-205) exhibited CTC conversions from unfavorable to favorable (<5) after a single dose of DSTP3086S. CTC conversions were also observed at lower doses. PSA decreases of ≥ 50% were observed in 1 pt at 2.25 mg/kg, and 2 pts at 2.8 mg/kg who also had PCWG2 radiologic responses. Conclusions: DSTP3086S at the RP2D of 2.8 mg/kg q3w has a tolerable safety profile and shows evidence of anti-tumor activity. Enrollment in the expansion cohort is ongoing.
Automated quantum dots ISH assay for detection of ERG rearrangement and PTEN deletion in prostate cancer.
Authors: Tang Lei , Zhang Wenjun , Hubbard Antony , Brunhoeber Patrick S , Wang Yixin 
Published: March 2020

5045 Background: ERG rearrangement and PTEN deletion are the two most common genomic events in prostate cancer. Overexpression of the ERG protein caused by rearrangement of the ERG gene has been frequently associated with more aggressive prostate cancers and a poor prognosis. PTEN genomic deletion and absence of PTEN expression are associated with unfavorable clinical outcome. To detect ERG rearrangement and PTEN deletion simultaneously, we developed a four-color multiplex ISH assay using non-organic quantum dots (QD). The photo-stability and narrow emission spectra of QDs makes them desirable for ultrasensitive and multiplexing ISH applications. The automated QD ISH assay allows adequate delivery of QDs to nuclear targets and reproducible detection of ERG and PTEN gene targets. Methods: DNA probes specific for ERG 5’, ERG 3’, PTEN and CEN 10 were labeled with different haptens, digoxigenin (DIG), dinitrophenyl (DNP), thiazole sulfonamide (TS), or nitropyrazole (NP). QDs with 565, 655, 605 and 525nm wavelengths were conjugated to the anti- DIG, DNP, TS or NP antibodies, respectively. The multiplex QD ISH assay was fully automated on the VENTANA BenchMark ULTRA. FFPE prostate tissue slides were hybridized with the labeled probes. The probes were then detected by the QD-conjugated antibodies and visualized under fluorescent microscope. Results: We performed the multiplex QD ISH assay on 386 slides with tissue sections from 10 prostate specimens on 13 BenchMark ULTRA instruments. The 10 cases consisted of either benign prostate tissues or prostate cancer, positive or negative for ERG rearrangement and/or PTEN deletion. 350 (91%) of the slides were successfully stained for all 4 molecular targets. The expected ERG and PTEN status were detected with high reproducibility. Conclusions: We developed an automated QD based multiplex ISH assay to simultaneously detect ERG rearrangement and PTEN deletion in prostate cancer. The assay is highly sensitive and reproducible. It enables investigation of potential clinical use of ERG and PTEN as predictive or prognostic markers. In addition, the same technology is expected to enable multiplex in situ detection of other molecular biomarkers using standard clinical specimens.
Profile study: Genetic prostate cancer risk stratification for targeted screening.
Authors: Castro Elena , Bancroft Elizabeth , Taylor Natalie , Dadaev Tokhir , Page Elizabeth , Keating Diana , Borley Nigel , DeSouza Nandita , Saunders Ed , Lee Andrew , Neal David , Antoniou Antonis C. , Kote-Jarai Zsofia , Eeles Ros A. 
Published: March 2020

5054 Background: Prostate cancer (PC) screening is controversial and better approaches are needed, including a better assessment of individualized PC risk. Several studies have identified a number of common single nucleotide polymorphisms (SNPs) that confer a cumulative risk of PC. We have explored the potential role of genetic markers in identifying men who should be selectively targeted for screening in a population with increased risk of PC due to family history (FH) of the disease. Methods: PROFILE has been developed as a pilot study. The primary aim is to determine the feasibility of targeted PC screening using prostatic biopsy (PB) and its association with specific genetic profiles in men with FH. Secondary aims are to evaluate the role of PSA and Diffusion Weighted MRI (DW-MRI) as screening tools in this population. From December 2010 men aged 40-69 with FH of PC were invited into the study until 100 men were enrolled. Blood samples were provided for PSA and DNA extraction. The cumulative SNP risk scores for each patient were calculated by summing 59 risk alleles for each locus using the weighted effect as estimated in previous studies (log-additive model). DW-MRI was performed in 50 patients. All participants were asked to undergo a 10 core PB regardless of baseline PSA. Those who declined PB have been excluded from this analysis. Data on side effects and cancer worry were also collected. Results: 35% of invited men entered the study. Median age was 53 yrs (40-69) and median PSA was 1.15. Ninety men accepted to undergo a PB as primary PC screening. Twenty-two tumours were found and 45% of them were clinically significant [Median age 64yrs (47-69), median PSA 5.4 (0.91-9.3)]. The predictive performance of DW-MRI, PSA, genetic model and genetic model plus PSA measured by AUC were: 0.85, 0.73, 0.57 and 0.74, respectively. The genetic model performed better in men with PSA<3(AUC 0.63). No severe side effect or adverse psychosocial variables were noted. Conclusions: Our results indicate that PB is acceptable as a means of PC screening in men with FH of PC. Overall, DW-MRI and PSA were more predictive of PC than the genetic risk score. As more SNPs are found, a larger study is warranted to evaluate their role in the PC screening algorithm.
A pilot phase II study of digoxin in patients with recurrent prostate cancer as evident by a rising PSA.
Authors: Lin Jianqing , Hoffman-Censits Jean H. , Duffy Danielle , Chervoneva Inna , Kilpatrick Deborah , Kennedy Brooke , Trabulsi Edouard John , Lallas Costas D. , Gomella Leonard G. , Force Thomas , Kelly William Kevin 
Published: March 2020

5061 Background: Hypoxia-inducible factor 1α (HIF-1α) is a novel cancer drug target and inhibitors of hypoxia-response pathway are being developed. Digoxin and other cardiac glycosides were found to inhibit prostate cancer (PCa) growth via the inhibition of HIF-1α synthesis in mouse model. Epidemiologic data showed that use of digoxin in men was associated with a significant lower risk of development of PCa. We hypothesized that therapeutic dose of digoxin could inhibit human PCa growth and disease progression. Methods: Open label, non-placebo pilot study. Non-metastatic, biochemically relapsed PCa patients (pts) with prostate specific antigen doubling time (PSADT) of 3 -24 months and no hormonal therapy within the past 6 months were enrolled. All pts had testosterone > 50 ng/dL at baseline. Digoxin was taken daily with dose titration to therapeutic level (0.8 – 2 mg/dl) and pts had routine follow-up that include cardiac monitoring with EKG. The primary endpoint was to evaluate the proportion of patients at 6 month post-treatment that had a PSADT > 200% from the baseline. Results: Fifteen pts were enrolled into the study with 13 pts finishing the planned 6 months of treatment. Twenty percent (3/15) of the pts had PSA decrease >25% from baseline. At 6 months, 7 of 15 (47%) pts had PSADT > 200% of the baseline PSADT and were continued on study for an additional 24 weeks of treatment. Mean duration of digoxin treatment was 34.5 weeks. Digoxin was well tolerated with possible relation of one grade 3 back pain and one grade 2 hyperglycemia. No pts came off study due to cardiac reasons. Pre-and post-treatment PSA kinetics, vascular endothelial growth factors and other cytokines levels are being determined. Conclusions: Digoxin was well tolerated and showed a prolongation in the PSDAT in 47% of the patients. Digoxin may have biologic activity in men with androgen-dependent PCa but further controlled studies are required to confirm the results. Clinical trial information: NCT01162135.
Use of [-2]proPSA and prostate health index (phi) to improve the diagnostic accuracy of prostate cancer compared to t-PSA and %f-PSA in young men (≤ 65 years old).
Authors: Boegemann Martin , Vincendeau Sebastien , Stephan Carsten , Houlgatte Alain , Krabbe Laura-Maria , Semjonow Axel , Blanchet Jean-Sebastien 
Published: March 2020

5074 Background: Although prostate-specific antigen (tPSA) screening reduced prostate cancer (PCa) mortality recent recommendations do not endorse PSA-screening due to overdiagnosis and overtreatment and the resulting harm afflicted to patients. Screening studies showed the maximum benefit in young men < 65 years of age. tPSA and percent free PSA (%fPSA) lack specifity in the diagnosis of PCa. [-2]proPSA and the prostate health index (phi) improved this diagnostic specifity. Markers to diagnose clinicaly relevant cancers in young men are needed. Methods: The clinical performance of [-2]proPSA and phi was evaluated in a multicenter study. A total of 1362 patients scheduled for initial or repeated prostate biopsy (668 with, 694 without PCa, each ≥ 10 core biopsies) were recruited in 4 different sites based on PSA level 1.6 – 8.0 ng/mL WHO-calibrated (2-10 ng/mL classically calibrated). Serum samples taken prior to digital rectal examination (DRE) were measured for the concentration of tPSA, fPSA and [-2]proPSA with Beckman Coulter immunoassays on Access 2 or DxI800 instruments. Phi was calculated as [-2]proPSA/fPSA*√tPSA. Results: In univariate analysis [-2]proPSA/fPSA (%[-2]proPSA) and phi were the best predictors of PCa detection in patients at initial biopsy (AUC: 0,72 and 0,73) and repeated biopsy (AUC: 0,74 and 0,74). Analysis of the data for men ≤ 65 years of age (n=593) showed that %[-2]proPSA and phi significantly improved PCa dectection (AUC: 0,72 and 0,73) as compared with tPSA (AUC: 0,54) or %fPSA (AUC: 0,62). In the detection of significant PCa (based on PRIAS criteria) %[-2]proPSA and phi demonstrated the best performance in the whole cohort and in young men (≤ 65) years as well (AUC 0,68 and 0,73). Conclusions: This multicenter study showed that [-2]proPSA and phi have a superior clinical performance in detecting PCa in the PSA range of 2-10 ng/mL compared with tPSA and %fPSA at initial and repeated biopsies. This superiority is maintained for the detection of PCa in young men (≤ 65 years of age).
Safety, efficacy, and health-related quality of life (HRQoL) of the investigational single agent orteronel (ortl) in nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Hussain Maha , Corn Paul Gettys , Michaelson M Dror , Hammers Hans J. , Alumkal Joshi J. , Ryan Charles J. , Bruce Justine Yang , Moran Susan , MacLean David , Lee Shih-Yuan , Lin H. Mark , Zhu Yanyan , Shi Hongliang , Mortimer Peter , George Daniel J. 
Published: March 2020

5076 Background: Ortl is a selective, non-steroidal, oral 17,20-lyase inhibitor. Due to its lower inhibition of 17α-hydroxylase vs 17,20-lyase, ortl may allow steroid-free dosing. Ortl 300 mg BID was studied in nmCRPC patients (pts). Methods: Pts with nmCRPC, PSA ≥2 ng/mL (PSA ≥8 ng/mL if doubling time >8 mo), and testosterone (T) <50 ng/dL received ortl 300 mg BID until PSA progression, development of metastases (mets), or unacceptable toxicity. Primary endpoint: the percentage of pts with PSA ≤0.2 ng/mL at 3 mo. Secondary endpoints included safety, PSA kinetics, time to mets, and PFS (PSA progression, mets, or death), endocrine and bone markers, bone mineral density (BMD), HRQoL, cardiac and lipid assessments. Results: 38 pts enrolled: median PSA 11.7 ng/mL (range 2.6–67.8), T 8.5 ng/dL (1.4–17.3), and ACTH 20 ng/L (n=32; 0–47). Median therapy duration was 12.4 mo (0.7–27.8); 55% of pts were treated >12 mo. 6 had dose reduction, 12 discontinued due to adverse events (AEs), including 2 for possible adrenal insufficiency. Gr 3 hypertension occurred in 7 pts (18%); various ≥Gr 3 AEs occurred in another 14 pts; 10 pts (26%) had serious AEs. At 3 mo, median T declined 89% to 0.78 ng/dL; median ACTH increased 171%; median cortisol declined 21%, but remained within normal range. 97% of pts had PSA declines; median PSA declined 83%. 18% had PSA ≤0.2ng/mL at 3 mo; 32% achieved PSA ≤0.2ng/mL as best response. Median time to PSA progression was 13.8 mo. Median PFS was 13.8 mo. Kaplan-Meier estimates of 1 and 2 y mets-free rates were 94% and 69%, respectively; 8 pts developed mets on study. The patient-reported Aging Male Symptoms Scale showed no decrease in overall scores, psychological, somatic, or sexual domains in 37, 34, 25, and 19 pts assessed at visits 2, 4, 7, and 13, respectively. Serum lipids, cardiac assessments, HbA1C, or bone-specific enzymes (N-telopeptide, or BMD) were not adversely affected. Conclusions: In pts with nmCRPC, long-term steroid-free ortl was feasible, with clinical activity as reflected by sustained marked declines in PSA and T, and had manageable toxicities, with no adverse effects on HRQoL, cardiac, bone or lipid profiles. Clinical trial information: NCT01046916.
Evaluating the hypothalamic-pituitary-adrenal axis (HPAA) in men receiving ketoconazole for castrate resistant prostate cancer (CRPC).
Authors: Aggarwal Rahul Raj , Weinberg Vivian K. , Sosa Eduardo V. , Lin Amy M. , Harzstark Andrea Lynne , Small Eric Jay , Fong Lawrence , Hsieh Andrew Caleb , Formaker Carl , Koepfgen Kathryn M. , Hang Evelyn , Friedlander Terence W. , Ryan Charles J. 
Published: March 2020

5077 Background: Serum adrenal androgen (AA) levels may be prognostic for survival in men with CRPC treated with androgen synthesis inhibitors (ASIs) including ketoconazole (keto) and abiraterone. We hypothesize that up-regulation of the HPAA and adrenocorticotropic hormone (ACTH) may contribute to therapeutic resistance on ASIs. The current study explores the relationship between ACTH, AA, testosterone (T) and estradiol (E) among CRPC patients (pts) treated with ASI + corticosteroids. Methods: Phase II study of keto (400 mg TID) + hydrocortisone (HC) (30 mg/day) in pts with CRPC. Pts who achieved ≥ 30% PSA decline from baseline at week 12 continued keto/HC until progression, at which point HC was replaced by dexamethasone (dex). Serum hormone (H) levels were measured (in AM) at baseline and every 4 weeks using standard assays. Statistical tests include Spearman’s rank test for correlation between baseline H levels; Wilcoxon matched pairs for baseline vs. week 4 distribution; and Fisher’s exact test for associations between H levels (dichotomized at median) with PSA decline. Results: Of 30 pts enrolled and 24 evaluable for PSA response, 13 pts (54%) achieved ≥ 30% PSA decline at 12 weeks. Baseline ACTH was positively correlated with DHEA (r = 0.40; p = 0.04) and cortisol (r = 0.52; p = 0.007). Change from baseline to week 4 in H levels is shown in table. There was a significant increase in pts achieving a PSA decline of > 30% if there was a decrease in E at week 4 vs. no decrease (83% vs. 18%; p = 0.003). Baseline and changes in other H levels were not associated with PSA outcome at week 12. Conclusions: ACTH is positively correlated with DHEA and cortisol in CRPC pts. Declines in E may serve as an additional predictive marker of benefit for ASI therapy. These observations require prospective validation. Analyses exploring changes in ACTH at disease progression and impact of substituting dex for HC are ongoing. Clinical trial information: NCT01036594. [Table: see text]
Ejaculation frequency and prostate cancer: A large, prospective study with 16 years of follow-up.
Authors: Rider Jennifer R , Wilson Kathryn M , Kantoff Philip W. , Giovannucci Edward L. , Mucci Lorelei A. 
Published: March 2020

5078 Background: A prospective study in the Health Professionals Follow-up Study (HPFS) cohort published in 2001 found significantly lower risks of prostate cancer (PCa) among men with more frequent ejaculation. Because associations were stronger among men at older ages, which could be indicative of reverse causation (i.e., men ejaculating less because of symptoms associated with PCa) and few advanced cases were included, we conducted an updated study with an additional 8 years of follow up. Methods: We included 31,929 men aged 46-81 years from the HPFS who answered ejaculation frequency questions on the 1992 questionnaire. We assessed average frequency per month at three time points: age 20-29, age 40-49, and in 1991 (the year prior to the questionnaire). These data were also combined to estimate average lifetime frequency. Using follow up through January 31, 2008, we used Cox proportional hazards models to estimate relative risks (RR) and 95% confidence intervals (95% CI) for total PCa risk, as well as risk of advanced, lethal, and high-grade (Gleason 8-10) disease. As sensitivity analyses, we also examined associations within a subgroup of highly screened men and a subgroup of men without erectile dysfunction at baseline. Results: During 16 years of follow up, 3403 men were diagnosed with PCa; 455 were advanced, 360 were high grade, and 304 were lethal. Three percent of men reported a lifetime average frequency of >21 times per month while 34% reported 4-7 times per month. Compared to a frequency of 4-7 times per month, multivariate RRs for total PCa for men with >21 ejaculations per month were 0.81 (95% CI: 0.71-0.91) for ages 20-29; 0.76 (95% CI: 0.66-0.88) for ages 40-49; 0.68 (95% CI: 0.53-0.86) in 1991; and 0.57 (95% CI: 0.43-0.75) for lifetime average frequency. RRs for advanced PCa were of similar magnitudes at ages 20-29 years and 40-49 years but not statistically significant. Results were similar when we included only highly screened men or men without a history of erectile dysfunction. Conclusions: With extended follow up, ejaculation frequency continues to be strongly inversely associated with risk of total PCa. These findings are unlikely to be attributable to underlying disease or screening frequency.
Correlation between baseline variables and survival in the radium-223 dichloride (Ra-223) phase III ALSYMPCA trial with attention to total ALP changes.
Authors: Sartor A. Oliver , Amariglio Roy , Wilhelm Scott , Garcia-Vargas Jose E. , O'Bryan-Tear C. Gillies , Shan Minghua , Fang Fang , Parker Chris 
Published: March 2020

5080 Background: In patients (pts) with castration-resistant prostate cancer and bone metastases (mCRPC), total ALP (tALP) has been shown to be a prognostic marker for overall survival (OS) (Cook 2006). Here the prognostic value of tALP and other baseline clinical variables in Ra-223 pts is presented, along with the initial results of an exploratory analysis of changes in tALP seen with Ra-223. Methods: Study population included 921 pts (intent-to-treat population) from the ALSYMPCA trial. The Cox proportional hazards model was used to evaluate the prognostic potential of tALP and other baseline variables (albumin, Hb, LDH, ECOG performance status, PSA, and age). Log transformation was done for baseline variables (tALP, PSA, and LDH) with heavily skewed distributions. Baseline variables were assessed for interaction with treatment. To determine changes in tALP from baseline at 12 wk, 708 pts who had tALP measurements at both baseline and 12 wk were included. Results: The baseline variables in the Table were significantly associated with OS. Hb was not a significant factor when adjusting for all other covariates and was therefore removed from the final Cox regression model. No significant treatment-by-covariate interactions were detected. After controlling for other variables, higher baseline tALP was significantly associated with an increased risk of death (p < 0.0001). At 12 wk, a decline in tALP relative to baseline was seen in 87% (433/497) of Ra-223 pts, compared to 23% (49/211) of placebo pts. The mean percentage change from baseline in tALP at 12 wk was a 32% decline for Ra-223 pts, in contrast to a 37% increase for placebo pts (p< 0.001). Conclusions: In mCRPC pts, higher baseline levels of tALP were associated with an increased risk of death. With the majority of Ra-223 pts experiencing a decline in tALP at 12 wk, and the marked mean percentage tALP decline in these pts, further analysis to determine a correlation between tALP dynamics and survival is warranted. Clinical trial information: NCT00699751. [Table: see text]