bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

138 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

143 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

146 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

151 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

155 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

157 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

159 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 
Published: March 2017

162 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

165 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.