bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term follow-up from STAMP, a phase II trial, evaluating sipuleucel-T and concurrent (CON) vs sequential (SEQ) abiraterone acetate + prednisone in metastatic castration-resistant prostate cancer patients (pts).
Authors: Small Eric Jay , Lance Raymond S. , Redfern Charles H. , Millard Frederick E. , Gardner Thomas A. , Dawson Nancy Ann , Fong Lawrence , Karsh Lawrence Ivan , Corman John M. , Nordquist Luke T. , Murdock Myron I , Curti Brendan D. , Chang Nancy N. , Shore Neal D. 
Published: March 2017

190 Background: The optimal sequence and combination of life-extending anticancer therapies in mCRPC pts remains unknown. Sipuleucel-T (sip-T), an autologous cellular immunotherapy approved for the therapy of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC) pts, was evaluated in combination with abiraterone acetate and prednisone (abi) in the phase II STAMP trial (NCT01487863), with pts randomly assigned to receive CON sip-T + abi or SEQ sip-T followed by abi. The combination was well-tolerated and did not alter the immune response parameters that correlate with overall survival (OS) (Small Clin Can Res 2015). Here, we present long-term follow-up of clinical outcomes, including OS. Methods: mCRPC pts were randomized 1:1 to CON or SEQ therapy with sip-T and abi. Abi began 1 day after (CON) or at wk 10 (SEQ) after the first sip-T infusion and continued for 26 wk of therapy, after which continued abi therapy was permitted. Long-term clinical outcomes included OS, disease-specific death (DSS), progressive disease (PD), time to first anticancer intervention (tACI), and safety. Results: 69 pts were enrolled (35 CON; 34 SEQ). Median OS was 34.0 mo (95% CI, 24.4-not estimable [NE]; 30.0 mo CON; 34.2 mo SEQ; p = 0.921), and median time to DSS was not reached (CON vs SEQ; p = 0.733). Median time to PD was 17.3 mo (95% CI, 9.7–NE; 17.7 mo CON vs 13.9 mo SEQ; p = 0.914; consistent with higher rates of abi discontinuation due to PD in SEQ [26.5% vs 14.3% in CON]). tACI was similar between arms at 15.4 mo (95% CI, 11.0–19.9). No new safety signals were observed with the combination, and no discernable difference in clinical outcomes was observed with CON or SEQ treatments. Conclusions: Long-term follow-up data confirm that sip-T + CON or SEQ abi is well-tolerated, with no new safety signals. No clear differences were observed in clinical outcomes between arms, although the study was not powered to detect these differences. Future and more appropriately powered studies on the effect of sip-T + continuous abi for responding pts may provide further insights on the benefit of combination therapy. Clinical trial information: NCT01487863.
Adjuvant androgen deprivation (ADT) versus mitoxantrone plus prednisone (MP) plus ADT in high-risk prostate cancer (PCa) patients following radical prostatectomy: A phase III intergroup trial (SWOG S9921) NCT00004124.
Authors: Glode L. Michael , Tangen Catherine M. , Hussain Maha , Swanson Gregory P. , Wood David Peter , Sakr Wael , Dawson Nancy Ann , Haas Naomi B. , Flaig Thomas W. , Dorff Tanya B. , Lin Daniel W. , Crawford E. David , Quinn David I. , Vogelzang Nicholas J. , Thompson Ian Murchie 
Published: March 2017

2 Background: High risk localized Pca patients are more likely to relapse and suffer morbidity/mortality from metastatic disease after prostatectomy. Adjuvant ADT can reduce this risk. We hypothesized that MP in addition to two years of ADT could further reduce mortality from PCa. Methods: Participants with clinically localized (T1-T3, N0, M0) PCa received radical prostatectomy. Eligibility required ≥ 1 high risk criteria defined as Gleason sum ≥8; pT3b or pT4 or N1; Gleason 7 with positive margin; any one of these preoperative findings: PSA>15ng/ml, biopsy Gleason >7, biopsy Gleason >6 with PSA>10. ADT arm consisted of bicalutamide and goserelin for 2 years. ADT+MP arm received ADT plus 6 cycles of M 12mg/m2+ P 5mg BID. Primary endpoint was survival (OS). Median OS was anticipated to be 10 years in ADT arm requiring 680 patients/arm to detect a hazard ratio of 1.30 with 92% power and one-sided α=0.05. Results: S9921 enrolled patients from 10/99 to 1/07 when the DSMC recommended stopping due to increased incidence of leukemia in the ADT+MP arm. Of 983 patients randomized, 22 ineligible. 481 eligible on ADT and 480 on ADT+MP. Patients were stratified by stage (≤pT2, ≥pT3, N0 or N+), Gleason score, and intent to receive adjuvant radiation (RT) (Y/N). Median age was 60 years, 84% were white, presurgical PSA was 7.6 ng/ml, 16% had positive nodes, 26% intended to receive RT, 63% had positive margins. 11 ADT and 20 ADT+ MP received no protocol treatment. Median follow-up is 11.2 years. Conclusions: Survival was greater than anticipated in both arms. MP increases the risk of leukemia. There is no evidence that MP improves PCa specific survival when added to 2 years of adjuvant ADT. Clinical trial information: NCT00004124. [Table: see text]
Preclinical discovery and validation of high-dose androgen drug synergies for the treatment of prostate cancer.
Authors: Nyquist Michael D. , Corella Alexandra N , Coleman Ilsa , Gao Shuai , Tharakan Robin , Riggan Luke , Cai Changmeng , Nelson Peter , Mostaghel Elahe A. 
Published: March 2017

202 Background: Recent clinical studies have taken advantage of the dichotomous ability of androgen receptor signaling to elicit growth-suppressive and differentiating effects by giving hyper-physiological levels of testosterone. This approach has demonstrated safety, improved quality of life, and met primary endpoints for efficacy in clinical trials; however, novel strategies to enhance and optimize the anti-tumor efficacy of this approach are needed. Methods: We performed high-throughput drug screening in PCa cell lines to identify agents showing synergy with high-dose androgen treatment. Results: The Survivin inhibitor YM155, demonstrated a potent synergy with high-dose androgen. YM155 IC50 values shifted from 24 nM without R1881 to 3.85 nM with 160 pM R1881.Using qRT-PCT and ChIP-qPCR we establish the mechanism of this synergy was due to the direct upregulation of YM155 transporter SLC35F2 by androgen receptor transcriptional activity. Knockdown and overexpression of SLC35F2 dramatically modulated sensitivity to YM155. In two xenograft models SLC35F2 and tumor DHT levels are highly correlated and castration-induced decreases in tumor androgens cause an identical decline in levels of SLC35F2. In CRPC metastases SLC35F2 expression significantly correlated with AR activity score (r = 0.62, p < 0.001). However, ~1/3 of tumors examined had transcripts for AR and SLC35F2, 1/3 AR+ but SLC35F2 negative, and 1/3 are negative for both. Conclusions: We describe a novel synergy between YM155 and high-dose androgen therapy mediated by the direct upregulation of YM155 transporter SLC35F2 by androgen receptor and implicate SLC35F2 expression as a potential biomarker for YM155 sensitivity. Whether ligand independent AR variants (AR-Vs) can constitutively mediate SLC35F2 expression is unknown, but if so would also provide a means of stratifying identifying men likely to respond to YM155.This study demonstrates a novel paradigm for precision medicine in the pharmacologic induction of drug sensitivity in a tissue restricted manner. Hormonal induction of carrier-mediated drug transport is a completely novel and unexplored concept that is poised to exploit androgen-based treatment strategies.
Long-term efficacy and safety of enzalutamide (ENZ) monotherapy in hormone-naïve prostate cancer (HNPC): 3-year, open-label, follow-up results.
Authors: Tombal Bertrand F. , Borre Michael , Rathenborg Per , Werbrouck Patrick , Van Poppel Hendrik , Heidenreich Axel , Iversen Peter , Braeckman Johan , Heracek Jiri , Baron Benoit , Krivoshik Andrew , Hirmand Mohammad , Smith Matthew Raymond 
Published: March 2017

220 Background: A phase 2 study of the androgen receptor inhibitor ENZ as monotherapy in patients with HNPC [NCT01302041] showed a high prostate-specific antigen (PSA) response rate, regardless of baseline metastases, and favorable tolerability. In a 1- and 2-year follow-up, ENZ maintained long-term reductions from baseline in PSA, with minimal impact on total-body bone mineral density (BMD). Herein, results from a pre-specified 3-year follow-up are reported. Methods: A total of67 patients with HNPC and non-castrate testosterone ( ≥ 230 ng/dL) received ENZ 160 mg/day until disease progression or unacceptable toxicity. The primary end point of PSA response ( ≥ 80% decline from baseline) was analyzed at week 25 and 1, 2, and 3 years. Other end points were best overall tumor response, BMD, body composition, quality of life, and safety. Results: At the 3-year visit, 42 (62.7%) patients remained on the study medication. Of those, 38 (90.5%; 95% confidence interval 77.4%, 97.3%) maintained a PSA response. Of the 26 patients with metastases at baseline, 17 (65.4%) had a complete or partial response as best overall response at 3 years. In patients who completed the 3-year visit, minimal changes from baseline were observed in total-body BMD or in BMD of the femoral neck, trochanter, spine L1–L4, or forearm (median and mean changes ranged from –3.6% to 1.3% and –2.7% to –0.1%, respectively). The EORTC QLQ-C30 global health status results showed a small decrease at 3 years versus baseline (–3.96 points), consistent with the 2-year results. At 3 years, measurements for total body fat increased (median, 14.7%; mean, 16.5%) and total body lean decreased (median, –6.3%; mean, –6.5%) from baseline. Physical functioning, fatigue, and dyspnea worsened ( > 10 points) at 3 years, similar to results at 2 years. The most frequently reported adverse events ( > 10%) were gynecomastia, fatigue, hot flush, nipple pain, hypertension, diarrhea, nausea, pain in extremity, back pain, and constipation. Conclusions: In patients with HNPC treated with ENZ for 3 years, the efficacy of ENZ as monotherapy was maintained. Overall, BMD, global health status, and safety results were similar to those at 2 years. Clinical trial information: NCT01302041.
Real-world treatment with abiraterone acetate in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC).
Authors: Boegemann Martin , Hatzinger Martin , Hercher Dirko , Matus Geoffrey , Everaert Els Grieta , Dopchie Catherine , Sheehan Denise , Birtle Alison J. , Garcia Alvarez Laura , Zou Lu , Kluska Martin , Antoni Laurent , Pissart Geneviève , Lukac Martin , Dearden Lindsay 
Published: March 2017

239 Background: In the COU-AA-302 trial, abiraterone acetate plus prednisone (AAP) resulted in extension of radiographic progression-free survival (rPFS) and overall survival in chemotherapy-naïve mCRPC patients compared to prednisone alone. However, limited data on AAP treatment and outcomes is available in the real-world in this setting. The aim of this study is to describe the duration of AAP treatment in routine clinical practice in mCRPC patients prior to chemotherapy. Methods: The study was designed as a retrospective chart review of mCRPC patients identified through oncology and urology practice in Belgium, France, Germany and the UK. This first analysis reports baseline patient characteristics at AAP initiation for the first 224 patients. Treatment duration, PFS and rPFS were estimated using Kaplan-Meier curves. Potential factors associated with treatment duration were explored using the log-rank test. Results: Data from 224 mCRPC patients treated with AAP (Belgium: 67; Germany: 150; UK: 7; none from France) across 19 centres was considered in this initial analysis. At baseline, the median age was 75.5 years (interquartile range [IQR]: 69.0-82.0) and the median PSA level was 50.0 ng/mL (IQR: 21.0-121.0). Patients with visceral metastases (9.8%) and ECOG 2-3 (9.4%) were included in this study, in contrast to those included in the COU-AA-302 study. Median duration of AAP treatment was 11.6 months (95% confidence interval [CI]: 10.2-12.8), whilst median PFS and rPFS were 11.9 months (95% CI: 10.8-13.3) and 16.5 months (95% CI: 13.5-20.0), respectively. Reasons for discontinuing AAP involved PSA progression (52.2%), radiographic progression (38.9%), symptomatic progression (27.8%), non-toxic death (19.4%) and toxicity (2.2%). Treatment duration was significantly longer in mCRPC patients with either baseline ECOG status 0, lower PSA, alkaline phosphatase, aspartate aminotransferase, or lactate dehydrogenase levels (p < 0.05). Conclusions: The results of this study suggest similar treatment duration and rPFS for mCRPC patients in this real-life cohort with poorer clinical features compared to those observed in the COU-AA-302 trial population.
Population-based analysis of treatment toxicity among men with castration-resistant prostate cancer.
Authors: Nam Robert , Wallis Christopher J.D. , Saskin Refik , Bansal Symron , Emmenegger Urban , Satkunasivam Raj 
Published: March 2017

252 Background: There is little phase 4 data regarding the toxicity and effectiveness of contemporary metastatic castrate-resistant prostate cancer (mCRPC) treatments. We examined hospital admissions and emergency room (ER) visits and survival among patients in the Province of Ontario treated with abiraterone, enzalutamide, docetaxel, or cabazitaxel for mCRPC. Methods: We performed a population-based, retrospective cohort study of 2439 men over the age of 65 treated with abiraterone, enzalutamide, docetaxel, or cabazitaxel for mCRPC from 2003-2015 in Ontario, Canada. Outcomes were toxicity (hospitalizations and ER visits) and overall survival. We used multivariable Cox proportional hazards models with time-varying exposures to calculate hazard ratios (HR). Results: Among 2439 patients, cumulative exposure was greatest for docetaxel (n = 1886 (77.3%); 11,436 person-months), followed by abiraterone (n = 893 (36.6%); 5143 person-months), enzalutamide (n = 52 (2.1%); 351 person-months) and cabazitaxel (n = 18 (0.7%); 61 person-months). Abiraterone exposure was not significantly associated with any-cause (HR 0.88, 95% CI 0.72-1.07) or treatment-related (HR 1.09, 95% CI 0.87-1.37) hospitalizations or ER visits. Enzalutamide was not significantly associated with any-cause (HR 1.20, 95% CI 0.69-2.07) or treatment-related (HR 0.85, 95% CI 0.43-1.68) toxicity. Docetaxel exposure was associated with a significantly increased risk of any-cause (HR 1.29, 95% CI 1.15-1.44) and treatment-related (HR 1.52, 95% CI 1.33-1.74) toxicity. Cabazitaxel exposure was also associated with treatment-related (HR 5.94, 95% CI 1.87-18.92) but not any-cause (HR 2.37, 95% CI 0.59-9.63) toxicity. Patients who began CRPC treatment after the introduction of oral therapies had improved overall survival compared with those treated prior to their introduction (aHR 0.70, 95% CI 0.64-0.77). Conclusions: Among patients with metastatic CRPC, treatment with chemotherapy (docetaxel or cabazitaxel) is associated with an increased risk of hospitalizations and emergency room visits. We failed to show a significantly increased risk for patients treated with oral agents (abiraterone or enzalutamide).
Survival outcomes for de novo versus primary progressive metastatic prostate cancer.
Authors: Gupta Kanika , Finianos Antoine Nafez , Clark Brandon , Simmens Samuel J. , Aragon-Ching Jeanny B. 
Published: March 2017

258 Background: We reported initial findings on the phenotypic differences between de novo versus primary progressive metastatic prostate cancer (Finianos et al., ASCO GU; abstr 285). We sought to determine the differences in the phenotypic characteristics of these 2 cohorts of patients and update the data with overall survival and patterns of response to androgen deprivation therapy (ADT) in patients presenting with de novo versus primary progressive prostate cancer. Methods: A retrospective chart review in a single-institution center for a period of 2 years was undertaken. Phenotypic characteristics included age at diagnosis, race, overall survival, treatment patterns, and response to ADT. Analysis was by t-test, Mann-Whitney U test, and Fisher’s Exact test. Results: A total of 90 patients were included in this cohort with de novo, dn (n = 38) and primary progressive, pp (n = 52) patients. There were no significant differences between the 2 cohorts with regard to the median age at diagnosis (dn = 66, pp = 61, p = 0.11), alkaline phosphatase level (dn = 135.5, pp = 86, p = 0.27), BMI (dn = 28.47, pp = 27, p = 0.78), creatinine (dn = 1.02, pp = 0.99, p = 0.34), LDH (dn = 188, pp = 166, p = 0.34), and testosterone on metastasis (dn = 276, pp = 31, p = 0.16). However, de novo cancers were diagnosed with higher mean gleason scores (dn = 8.36, pp = 7.7, p = 0.004), had higher median PSA upon diagnosis (dn = 63.1, pp = 8.8, p < .0001) and higher PSA on metastasis (dn = 61.7, pp = 12.5, p = .0002), and had a statistically significant decreased duration of hormone sensitivity (dn = 642 days, pp = 1783 days, p = < .0001). Patients with d e novo cancers also had a shorter median survival than primary progressive cancers (dn = 2257 days, pp = 4217 days, p = 0.02). Conclusions: Patients who present with de novo metastatic prostate cancer appear to develop early castration resistance and have worse overall survival than those who present with primary progressive disease. We are exploring the molecular differences in terms of androgen receptor expression as a potential etiology for development of early castration resistance.
Efficacy of eplerenone (Epe) in the management of mineralocorticoid excess (MCE) in men with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone (AA) without prednisone (P).
Authors: Gill David Michael , Gaston David , Hahn Andrew W. , Bailey Erin B. , Buckley Tyler Howard , Johnson Eric , Batten Julia A. , Alex Anitha , Boucher Kenneth M. , Stenehjem David D. , Agarwal Neeraj 
Published: March 2017

261 Background: AA is approved for Mcrpc with co-administration with P to prevent MCE toxicity such as hypertension, hypokalemia and edema. However, use of P is often not desirable by the relatively asymptomatic patients because of potential for detrimental effects of long term corticosteroid therapy. Epe is a non-steroidal mineralocorticoid antagonist demonstrated to abrogate MCE. Here we report real world experience of use of Epe with AA in men with mCRPC who wished to avoid concomitant P. Methods: Incidence and grade (CTCAE v4) of MCE, along with baseline demographics, disease characteristics, and progression free survival (PFS) in men with mCRPC treated with AA (1000 mg daily), not willing to be treated with P (and thus received treatment with Epe 50 mg daily) were collected retrospectively, and compared with those treated with AA + P (10 mg daily) during the same time period (Table). Continuous variables were assessed by Wilcoxon rank sum or student t-test, and categorical variables were assessed by Fischer’s Exact test or chi-square as appropriate. PFS was compared by Kaplan-Meier. Results: Baseline and disease characteristics, median PFS, and toxicities of all grades were similar in both cohorts (Table). Conclusions: In real world population of men with mCRPC treated with AA, corticosteroids may be avoided by concomitant treatment with Epe. Data need further validation in a larger cohort. [Table: see text]
Impact of use of phosphodiesterase type 5 inhibitors (PDE5-I) after radical prostatectomy (RP) on biochemical recurrence-free (BCRF) and overall survival (OS): A retrospective study from the Northwestern University SPORE in prostate cancer.
Authors: Roston Arden B. , Helenowski Irene B. , Catalona William , Leikin Robin , Gurley Michael , Trapp Luke , Jovanovic Borko , Kuzel Timothy M 
Published: March 2017

27 Background: The correlation between PDE5-I use to improve erectile function post RP and BCRF and OS on prostate cancer (PCa) patients (pts) has yielded conflicting results among prior retrospective cohort studies (Michl, 2015). Recent data suggests that these drugs may have an impact on immunity that may explain possible benefits. This study’s purpose was to determine whether PDE5-I use affects BCRF and OS for pts treated with RP for PCa. Methods: This is an IRB approved retrospective cohort study analyzing a subset of pts consented to the SPORE in PCa at Northwestern University’s Lurie Cancer Center. Inclusion criteria included men diagnosed with PCa and treated with RP with curative intent between 2003-2015. Study population (n = 2,410) showed 834 (34.6%) received a PDE5-I post-RP, while 1,576 (65.4%) did not. Pts were grouped based on PDE5-I use and no PDE5-I use after RP. A PDE5-I user must have filled at least 2 prescriptions or completed at least 2 inpatient administrations of a PDE5-I. Continuous variables were summarized by descriptive statistics and differences between groups were assessed via the Wilcoxon rank sum test. Categorical variables were reported by frequencies and percentages and compared via Fisher’s exact test. OS and BCRF survival were summarized for 10-yr rates using Kaplan-Meier estimates. The difference in BCRF and OS between groups was evaluated via log-rank test. Results: Mean age at RP was 60, and 90.95 % were Caucasian. Except for pairwise comparisons for significance of Gleason 3+3 vs. 3+4 histology with higher prevalence of 3+4 in the PDE5-I group (p = 0.0004) and a higher percent of clinical stage T2b-c than T2a in the no PDE5-I group (p = 0.01), no differences were noted in demographics. The 10-yr BCRF survival among PDE5-I users was 92.53% compared to 79.63% among non-users after RP (p < 0.0001). The 10-yr OS rate among PDE5-I users was 97.22% compared to 92.69% among non-users (p = 0.008). Conclusions: This retrospective analysis suggests that PDE5-I use improves biochemical recurrence free survival and overall survival in pts treated with RP for PCa.