bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II randomized, double-blind, placebo-controlled study of tivantinib in men with asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Monk Paul , Liu Glenn , Stadler Walter Michael , Geyer Susan Michelle , Sexton Jennifer L. , Wright John Joseph , Villalona-Calero Miguel Angel , Wade James Lloyd , Szmulewitz Russell Zelig , Gupta Shilpa , Mortazavi Amir , Dreicer Robert , Pili Roberto , Cooney Matthew M. , Dawson Nancy Ann , George Saby , Garcia Jorge A. 
Published: February 2017

146 Background: Tivantinib is a putative non-ATP competitive inhibitor of c-MET receptor tyrosine kinase that has additional cytotoxic mechanisms including tubulin inhibition. Prostate cancer demonstrates higher c-MET expression as the disease progresses to more advanced stages and to castration resistance. Methods: 80 patients (pts) with asymptomatic or minimally symptomatic mCRPC were assigned (2:1) to either tivantinib 360 mg PO BID or placebo (P). The primary endpoint was progression free survival. PCWG2 guidelines were utilized for determining eligibility and progression. Results: Of the 80 pts enrolled, 78 (52 tivantinib, 26 P) received treatment and were evaluated. Median age was 67 yrs (range: 43 to 85). Baseline characteristics were balanced between arms for ECOG PS, Gleason score, PSA, LDH, hemoglobin, Alk Phos, prior treatment, bone and organ involvement. More African Americans and those with lymph node involvement were randomly assigned to placebo. Median follow up is 8.2 months (range: 1.4 to 27.6). To date 59 patients have progressed. Patients treated with tivantinib had significantly better PFS vs. those treated with placebo (medians: 5.6 mo vs 3.8 mo, respectively; HR = 0.53, 95% CI: 0.32 to 0.89; p=0.015). Toxicity was mild overall. Grade 3 febrile neutropenia was seen in 1 patient on tivantinib while grade 3 and 4 neutropenia were recorded in 1 patient each on tivantinib and placebo. Grade 3 sinus bradycardia was recorded in two men on the tivantinib arm. 8 deaths (3 P and 5 tivantinib) have been recorded and were all considered unrelated to therapy. Conclusions: Tivantinib significantly improved PFS in men with asymptomatic or minimally symptomatic mCRPC. Given the favorable toxicity profile and evidence of anti-tumor activity, investigation of tivantinib with other agents may be a rational strategy. Clinical trial information: NCT01519414.
A phase III, multicenter, randomized, controlled study of maximum androgen blockade with versus without zoledronic acid in treatment-naïve prostate cancer patients with bone metastases: Results of ZAPCA study.
Authors: Kamba Tomomi , Kamoto Toshiyuki , Shimizu Yousuke , Namiki Shunichi , Fujimoto Kiyohide , Kawanishi Hiroaki , Sato Fuminori , Narita Shintaro , Satoh Takefumi , Saito Hideo , Sugimoto Mikio , Teishima Jun , Masumori Naoya , Egawa Shin , Sakai Hideki , Okada Yusaku , Terachi Toshiro , Ogawa Osamu ,   ZAPCA Study Group
Published: February 2017

150 Background: Zoledronic acid (ZA) is proved to be useful for the prevention of skeletal-related events (SREs) in men with castration-resistant prostate cancer and bone metastases, but its early use combined with androgen deprivation therapy (ADT) in men with hormonal treatment-naïve prostate cancer and bone metastases is controversial. Methods: A total of 227 men with hormonal treatment-naïve prostate cancer and bone metastases were randomly assigned in a 1:1 ratio to receive zoledronic acid (4mg intravenously every 4 weeks up to 2 years) along with ADT (LH-RH analogue + bicalutamide, MZ group) or ADT alone (MAB group). Stratification factors were PSA (<200ng/ml vs. ≥200ng/ml), EOD (extent of diseases) grade (1,2 vs. 3,4) and Gleason score (<7 vs. ≥8). The primary end point was time to treatment failure (TTTF), defined as 3 consecutive rise of PSA from the nadir, clinical progression, SRE, death or cessation of protocol therapy for any reason. Results: The median follow-up was 41.1 months. The median TTTF was 12.4 months in MZ group (95% CI, 10.6 to 16.6) and 9.7 months in MAB group (95% CI, 8.9 to 12.6; hazard ratio, 0.754; 95% CI, 0.567 to 1.003; log-rank P= .051). In a subset of men with baseline PSA levels <200ng/mL, the median TTTF was 23.7 months in MZ group (95% CI, 15.2 to 31.3) and 9.8 months in MAB group (95% CI, 6.6 to 17.0; hazard ratio, 0.575; 95% CI, 0.354 to 0.933; log-rank P= .023). An exploratory multivariate analysis using Cox proportional hazards model identified MZ group, age less than 80, and EOD ≤2 as independent factors associated with better TTTF. Conclusions: In men with hormonal treatment naïve prostate cancer with bone metastases, concurrent use of ZA with ADT did not show a significant advantage over ADT alone regarding TTTF. However, in a subgroup of men with lower baseline PSA levels, ZA significantly prolonged TTTF, compared with ADT alone. Clinical trial information: NCT00685646.
Assessment of corticosteroid (CS)-associated adverse events (AEs) with long-term (LT) exposure to low-dose prednisone (P) given with abiraterone acetate (AA) to metastatic castration-resistant prostate cancer (mCRPC) patients (Pts).
Authors: Fizazi Karim , Chi Kim N. , De Bono Johann Sebastian , Gomella Leonard G. , Miller Kurt , Rathkopf Dana E. , Ryan Charles J. , Scher Howard I. , Shore Neal D. , De Porre Peter , Londhe Anil , McGowan Tracy , Pehlivanov Nonko , Charnas Robert Louis , Todd Mary Beth , Montgomery Robert B. 
Published: February 2017

169 Background: AA is the prodrug of abiraterone, which inhibits CYP17A1 and testosterone synthesis and prolongs survival of mCRPC pts. A low dose of P is given when AA is administered to mCRPC pts. LT use of moderate-/high-dose CS has an established AE profile. We investigated whether LT use of low-dose P with or without AA led to CS-associated AEs. Methods: 2,267 mCRPC pts in COU-AA-301 and COU-AA-302 received 5 mg bid P, representing 2,006 pt-yrs of P exposure. 1,333 pts received AA + P. We utilized an inclusive Standardized MedDRA Queries–oriented approach to identify 112 preferred terms for known CS-associated AEs from both databases. CS-associated AEs during 3-mo exposure intervals and across all exposure to P were assessed. Results: The overall incidence of CS-associated AEs for any P exposure was 25%, 26%, and 23% for all pts, AA + P, and P alone, respectively. The incidence of grade ≥ 3 CS-associated AEs with any P exposure was 5%, 5%, and 4% for all pts, AA + P, and P alone, respectively. The most common grade ≥ 3 CS-associated AEs occurring in ≥ 0.1% of all pts were hyperglycemia (2%), cataract (0.4%), diabetes mellitus (0.4%), gastrointestinal hemorrhage (0.3%), adrenal insufficiency (0.1%), hip fracture (0.1%), melena (0.1%), and spinal osteoporotic compression fracture (0.1%). The overall incidence of weight increase (grade 1/2 only) was 4%, 4%, and 5% for all pts, AA + P, and P alone, respectively. Most were grade 1 (3.4%).When assessed by duration of exposure (3-mo intervals up to ≥30 mo), grade ≥ 3 CS-associated AEs fluctuated between 1% and 2%, but no discernable trend was observed. The observed change in weight from baseline showed no apparent increase over time. Conclusions: With over 2,000 pt-yrs of exposure, low-dose P given with or without AA is associated with an overall low incidence of CS-associated AEs. The frequencies of CS-associated AEs were low with increased duration of exposure to P. Clinical trial information: NCT00638690 , NCT00887198 .
Prostate cancer incidence in 340 hypogonadal men treated with testosterone undecanoate injections (TU) for up to 7 years: Observational data from a registry study.
Authors: Haider Ahmad 
Published: February 2017

17 Background: Concerns regarding the safety of testosterone treatment, particularly regarding prostate cancer (PCa) in middle-aged and elderly men, still hamper the use of testosterone in hypogonadal men. In this study, we investigated prostate parameters incl. incidence of PCa in hypogonadal patients on long-term treatment with TU. Methods: In a prospective, cumulative registry study, 340 men (age: 57.37 ± 7.03 years) with testosterone ≤12.1 nmol/L received TU 1,000 mg every 12 weeks following an initial interval of 6 weeks for up to 7 years. Prostate volume (PV) and PSA were measured and digital rectal examination (DRE)/ transrectal ultrasound (TRUS) performed before treatment initiation and then regularly every 3-6 months. In case of suspected PCa, biopsies were performed. Results: PV increased from 28.96 ± 10.41 to 29.88 ± 13.85 ml by model-adjusted 2.59 ± 0.2 ml (p<0.0001). This increase was statistically significant compared to the previous year for the first four years. PSA increased from 1.74 ± 0.94 to 1.96 ± 1.03 ng/ml by model-adjusted 0.23 ± 0.52 ng/ml (p<0.0001). 53 biopsies were performed in testosterone-treated patients. Of these, 5 (9.4%) were positive and 48 (90.6%) negative. The proportion of PCa in testosterone-treated patients in our registry study was 1.5% with an incidence of 30.7 per 10,000 patient years. In hypogonadal patients without testosterone treatment, 314 biopsies were performed. Of these, 111 (35.4%) were positive and 203 (64.6%) negative. In eugonadal patients, 584 biopsies were performed. Of these, 263 (40.4%) were positive and 321 (55%) negative. In total, 951 prostate biopsies were performed in our practice from 2004 through 2013, of which 379 (39.9%) were positive and 572 (60.1%) negative. Conclusions: Long-term treatment with TU in hypogonadal men undergoing regular monitoring according to EAU guidelines does not increase the incidence of PCa.
Combining active immunotherapy and immune checkpoint inhibitors in prostate cancer.
Authors: Singh Harpreet , Madan Ravi Amrit , Dahut William L. , O'Sullivan Coyne Geraldine Helen , Rauckhorst Myrna , McMahon Sheri , Heery Christopher Ryan , Schlom Jeffrey , Gulley James L. 
Published: February 2017

172 Background: Results of recent clinical trials have intensified interest in immunotherapy in oncology. A number of cancer immunotherapies have been approved recently, while others are in late stage clinical development. The poxvirus-based active immunotherapy, PROSTVAC is generally well tolerated and is currently being evaluated in a global Phase 3 randomized, placebo-controlled trial. Ipilimumab, an approved immune checkpoint inhibitor in melanoma, is also being evaluated in a Phase 3 trial in chemo-naïve mCRPC. Methods: Results of two Phase 2 trials in men with mCRPC who were treated with PROSTVAC alone were compared with results from a Phase 1 combination study in mCRPC patients treated with PROSTVAC plus escalating doses of ipilimumab. Patients were enrolled in the Phase 1 combination study when docetaxel was the only FDA-approved mCRPC treatment that improved overall survival (OS). Results: In a multicenter Phase 2 trial, 125 men were randomized 2:1 to receive PROSTVAC or placebo. Patients treated with PROSTVAC had improved OS compared to placebo (25.1 vs 16.6 months; HR 0.56; 95% CI 0.37-0.85).Similar data was seen in a second phase 2 trial of PROSTVAC, where 32 patients with mCRPC had a median OS of 26.6 months (predicted median OS by the Halabi nomogram was 17.4 months). In a Phase 1 combination study of 30 mCRPC patients with similar baseline characteristics (predicted median OS of 18.5 months), patients were treated with PROSTVAC plus escalating doses of ipilimumab. The observed median OS was 31.3 months for all dose cohorts and 37.2 months for patients treated at 10 mg/kg based on updated overall survival data. Furthermore, there appears to be a tail on the curve with approximately 20% of patients at 10 mg/kg alive at 80 months. Conclusions: The comparison of data from three independent trials of PROSTVAC active immunotherapy in three similar patient populations provides hypothesis-generating data that the addition of an immune checkpoint inhibitor may have a positive effect on overall survival through a potential synergy in mechanism of action. The updated long term survival data is further evidence of improved OS with PROSTVAC. Future randomized trials are being planned to prospectively evaluate this hypothesis. Clinical trial information: NCT00113984.
Dynamic changes in biomarkers for immune response to sipuleucel-t (SipT) for metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Hepgur Mehmet Faith , Dorff Tanya B. , Cai Jie , Reed Mary , Chan Betty , Quinn David I. 
Published: February 2017

181 Background: SipT prolongs OS in asymptomatic or minimally symptomatic CRPC without regularly inducing PSA declines. Elevated CD54 count, CD54 upregulation (UPREG) and total nucleated cells (TNC), markers of immune activation in the product, have been shown to correlate with longer survival. We prospectively collected clinical characteristics and inflammatory markers as part of an audit to identify possible predictors of immune response in patients receiving SipT. Methods: 92 men with CRPC had blood drawn routinely before and after SipT treatment at USC. Circulating tumor cells (CTC), PSA, prostatic acid phosphatase (PAP), albumin (Alb), hemoglobin (Hb), serum alkaline phosphatase (SAP), LDH, C-reactive protein (CRP) and β2-microglobulin (β2m) were evaluated in a reference lab. SipT product parameters, CD54, UPREG and TNC were measured by Dendreon. These datasets were analyzed using Spearman coefficients for continuous variables and the Kruskal-Wallis test for categorical variables. Results: 92 pts who received SipT were included. Median age was 69 (48-90). 43% had Gleason 8-9. 42% had ECOG Performance Status (PS) 0, 44% PS 1, and 13% PS 2. 26% had received prior chemotherapy and 18% had used opioids. 84% had bone mets, 42% had lymphadenopathy, and 12% had visceral mets. Increases in the PSA, PAP, LDH and Alb was directly correlated with increased CD54 counts, increases in the CTC was directly correlated with increased TNC, whereas decrease in SAP was correlated with increased upregulation of dendritic cells. Conclusions: Our results show that increased tumor markers immediately after treatment are more common in high CD54 product pts. This may represent a “flare” due to immune activation. [Table: see text]
Long-term survival update of the Scandinavian Prostate Cancer Group 6 study: Bicalutamide 150 mg daily versus placebo in hormone-naïve, non-metastatic prostate cancer.
Authors: Thomsen Frederik Birkebæk , Brasso Klaus , Christensen Ib Jarle , Johansson Jan-Erik , Angelsen Anders , Tammela Teuvo L. J. , Iversen Peter 
Published: February 2017

2 Background: The optimal timing of endocrine therapy in non-metastatic prostate cancer (PCa) is not clear. There is a need for more data from randomized trials. Methods: A randomized, double-blind, parallel-group trial comparing bicalutamide 150 mg once daily with placebo in addition to standard of care in patients with hormone-naïve, non-metastatic PCa. Kaplain-Meier analysis was used to estimate overall survival (OS) and multivariate Cox proportional hazard model was performed to analyse time-to-event (death). Results: 1,218 patients were included into the SPCG-6 study, 607 patients were randomised to bicalutamide and 611 patients to placebo. The majority (81.4%) were managed on watchful waiting. After median 14.6 years follow-up, 866 (71.1%) patients died, 428 (70.5%) in the bicalutamide arm and 438 (71.7%) in the placebo arm, p=0.87. In patients with localised disease (cT1-2, N0/Nx) survival favoured randomisation to the placebo arm (HR=1.19 (95% CI: 1.00-1.43), p=0.056). Bicalutamide significantly improved OS and reduced the risk of death by 23% relative to the placebo arm in patient with locally advanced disease (cT3-4, any N; or any cT, N+) with a median survival difference of 1.8 years (HR=0.77 (95% CI: 0.63-0.94, p=0.01). The survival benefit of bicalutamide in patients with locally advanced PCa was present throughout the study period. In multivariate Cox proportional hazard model OS was dependent on age (HR 1.55 (95% CI:1.20-1.85)), baseline PSA (localised PCa HR for 2 x increase in PSA 1.09 (95% CI:1.02-1.16), locally advanced PCa HR 1.23 (95% CI:1.14-1.33)), WHO histological grade (moderate vs. well HR 1.27 (95% CI:1.08-1.49), poor vs. well HR 1.92 (95% CI:1.51-2.45)), and randomisation to placebo in locally advanced disease (HR=0.76 (95% CI: 0.61-0.95)). Conclusions: The addition of early bicalutamide to standard of care resulted in a significant OS benefit in patients with locally advanced PCa, whereas patients with localised PCa derived no survival benefit from early bicalutamide. The survival benefit of bicalutamide therapy increased with higher baseline PSA. Clinical trial information: NCT00672282.
Evaluation of the ERα agonist, GTx-758 (250 mg daily), in men with metastatic (mCRPC) and nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Yu Evan Y. , Hancock Michael L. , Babicz Tamas , Aronson William J. , Papai Zsuzsanna , Geczi Lajos , Getzenberg Robert H. 
Published: February 2017

201 Background: LHRH agents used for androgen deprivation therapy (ADT) were intended to lower total testosterone (T) levels to those achieved by orchiectomy. Studies have now demonstrated that a significant percentage of men do not reach orchiectomy equivalent levels and that lower serum T levels correlate with improved outcomes. GTx-758 (Capesaris®) is an oral estrogen receptor α agonist that has the potential to increase sex hormone binding globulin (SHBG), lower T levels, and ameliorate estrogen deficiency side effects associated with ADT. Methods: In an ongoing Phase 2 open label study (G200712, NCT01615120), men with high risk nmCRPC and mCRPC were continued on their current form of ADT along with either 125 mg or 250 mg of GTx-758 daily, for at least 90 days. Men at increased risk for venous thromboembolic events (VTE) are being excluded. The primary endpoint of this trial is the proportion of men with a PSA decline ≥50%, while secondary endpoints include serum total and free T, SHBG, bone turnover and hot flashes. Results: As of October 2014, the 250 mg cohort of GTx-758 has completed enrollment of 28 patients, 20 of which (1 nmCRPC and 19 mCRPC) are evaluable, having been on study ≥90 days. The principal mechanism of drug action, induction of SHBG is confirmed in these patients with median SHBG levels increasing to 297% of baseline. 250 mg GTx-758 impacts T levels in an additive fashion to LHRH agents, as while on study, 4/4 subjects with total T levels >20 ng/dL have fallen below that level and 9/10 subjects with serum free T levels >0.7 pg/ml have fallen below that level. Six of the 20 (30%) subjects have exhibited a ≥50 decrease in PSA level while 17/20 (85%) had PSA declines of varying magnitude. The bone turnover biomarker C-telopeptide decreased in 81% of the subjects. 250 mg of GTx-758 has been generally well tolerated with one reported possibly drug related SAE (VTE). Conclusions: While the Phase 2 clinical trial is ongoing, these preliminary findings indicate that 250 mg of GTx-758 is generally well tolerated and has additive activity to LHRH agents to further decrease testosterone, increase SHBG, lower PSA and decrease bone turnover. Clinical trial information: NCT01615120.
Characterization of abiraterone responses in African American castrate-resistant prostate cancer.
Authors: Stolten Michael , Ledet Elisa M. , Feibus Allison H. , Lewis Brian E. , Silberstein Jonathan L. , Sartor Oliver 
Published: February 2017

203 Background: African American (AA) men have a higher incidence and mortality from prostate cancer (PCa) compared to other racial groups. Abiraterone acetate (Abi) is approved for treatment of mCRPC. While some AA patients were included in Abi trials, the majority of patients have been Caucasian (CA). To date, there have been no reports of Abi responses exclusively in AA men. This study evaluated Abi responses in AA men with mCRPC. Methods: PSA values during Abi treatment as well as baseline hemoglobin (Hgb), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) were tabulated. Prior therapy with docetaxel (Doc) or enzalutamide (Enza) was recorded. PSA response, progression and duration were assessed and compared between racial groups. PSA response, duration of response, and progression were defined by PCWG2 criteria. PSA half-life (PSAHL) based on time to nadir was calculated to assess rate of PSA decline. Results: A total of 74 Abi patients with mCRPC (n = 20 AA; n = 54 CA) were assessed from a single institution. Median AA baseline Hgb, ALP, LDH, and PSA were 11.8 (r = 6.4-15.4), 220 (r = 88-713), 209 (r = 157-401), and 48.41 (r = 4.8-1460) respectively. Median CA baseline Hgb, ALP, LDH, and PSA were 12.35 (r = 7.6-15), 165.5 (r = 70-1699), 218 (r = 133-528), and 44.84 (r = 1.71-2890) respectively. There were no significant differences in baseline labs between AA and CA. Prior use of Doc or Enza was 30% and 5% for AA; 31% and 4% for CA. PSA response was not significant for PSA decline of >30% (>30%: AA = 40%; CA = 44%), >50% (>50%: AA = 35%; CA = 30%), or >90% (>90%: AA = 20%; CA = 9%). In addition, no significant differences between the time to nadir (AA median = 209 days; CA median = 218 days), rate of PSA decline (AA PSAHL median = 72.4 days; CA PSAHL median = 80.1 days), or time to progression was observed. The median treatment length was 278 days and median time to progression was 66 days for AA men; 264 days and 88 days for CA men. Conclusions: Abi response rates, duration of response, and time to progression were not statistically different in AA men compared to CA men in patients with mCRPC. Larger studies are needed to fully evaluate this observation.
Association of germline variation with androgen ablation (AA) failure in advanced hormone-sensitive prostate cancer (HSPC).
Authors: Kochuparambil Samith Thomas , Zhang Ben Yiming , Riska Shaun M. , Mahoney Douglas W. , McDonnell Shannon , Lee Adam M , Quevedo Fernando , Costello Brian Addis , Pitot Henry Clement , Ribeiro Ricardo , Medeiros Rui , Monteiro Catia , Nogueira Augusto , Mauricio Joaquina , Fraga Avelino Manuel , Calais Da Silva Fernando Eduardo , Cerhan James Robert , Kohli Manish 
Published: February 2017

209 Background: Predictive markers of response to AA are not known. In a prior study, we found that 8 single nucleotide polymorphisms (SNPs) from 4 candidate hormone-related genes (JAK2, TRMT11, NKX3-1 and HSD17B12) were associated with response to AA in HSPC in a North American cohort of 519 subjects. We attempt to replicate these findings in a cohort of Portuguese patients. Methods: The Portuguese cohort consisted of 308 HSPC patients, and the primary endpoint was time to AA failure, defined as time from initiating continuous AA to two serial PSA increases over the nadir, initiation of chemotherapy for progressive disease, or clinical or imaging based progression, whichever came first. For each SNP, we calculated hazard ratios (HRs) and 95% confidence intervals (CI) for time to AA failure using a recessive model with adjustment for Gleason score (GS). Results: The median age of the Portuguese cohort was 69 years (range 43, 85). The GS distribution was 35% subjects with GS≥8; 35% with GS=7 and 30% with GS<7. Median time to AA failure for the cohort was 1.8 years (IQ range: 0.3, 3.6). Association of each SNP with time to AA failure is shown in the Table. None of the SNPs replicated. However, there was a suggestive inverse association for rs10503733 (NKX3.1) with time to AA failure (P=0.07). Conclusions: While we were not able to replicate our initial findings, there was an unexpected association with rs10503733 (NKX3.1 gene) that may warrant additional clinical validation. [Table: see text]