bluuebunny/crossref_metadata_2025 huggingface dataset:
Meta-analysis of randomized clinical trials (RCT) for the adjuvant treatment of renal cell carcinoma (RCC) with vascular endothelial growth factor receptor tyrosine-kinase inhibitors (VEGFR TKIs).
Authors: Almeida Daniel Vargas , Oliveira Cleyton Z. , Soares Andrey , MARIANO RODRIGO COUTINHO , Jardim Denis L , Bastos Diogo Assed , Maluf Fernando C. , Werutsky Gustavo , Monteiro Fernando Sabino M , Souza Vinicius Carrera , de Velasco Guillermo , Fay Andre P. , Sasse Andre Deeke , Schutz Fabio A. B. ,   Latin America Cooperative Oncology Group - Genitourinary (LACOG-GU)
Published: May 2019

4579

Background: Although surgery is the cornerstone in the treatment of most cases of localized kidney cancer, up to 30% of patients will experience disease recurrence at three years of follow-up. Three RCTs with VEGFR TKIs (ASSURE, PROTECT and ATLAS) failed to demonstrate improvement in disease-free survival (DFS). Only S-TRAC trial showed a significant improvement in DFS, and was approved by the Food and Drug Administration (FDA). However, the matter remains controversial among genitourinary oncologists. Therefore, we performed a meta-analysis to better evaluate the potential benefit of adjuvant VEGFR TKIs after curative intent nephrectomy. Methods: Eligible studies were searched in PubMed databases and limited to phase 3 RCT published from January 1996 to December 2018 of US FDA-approved VEGFR TKIs reporting on patients with RCC treated in the adjuvant setting. A summary hazard-ratio (HR) of disease-free survival (DFS) was calculated using 95% CIs by random-effects or fixed-effects models on the basis of the heterogeneity of included studies. Results: Four RCT (ASSURE, S-TRAC, PROTECT and ATLAS trials) were selected for analysis, including a total of 4,820 patients. A VEGFR TKI (sunitinib, sorafenib, pazopanib or axitinib) was administered in 2,737 patients, and 2,083 received placebo. The summary DFS HR for the overall population was 0.89 (95% CI 0.79-1.00; p = 0.06). When including the report of the ASSURE with the sub-group analysis with high-risk patient population (n = 3,946), the summary HR for DFS was 0.84 (95% CI 0.75-0.95, p = 0,0044). No evidence of publication bias was found. Conclusions: This is the first meta-analysis including the four RCTs in RCC adjuvant setting. This meta-analysis failed to demonstrate improvement in DFS for patients receiving a VEGFR TKI after curative intent nephrectomy. A modest benefit in DFS was observed in a selected sub-group of patients with higher risk for recurrence. There is no data regarding overall survival.
Metastatic penile (mPSCC), uterine cervical (mCSCC), and skin (mSSCC) squamous cell carcinomas: A comparative genomic profiling (CGP) study.
Authors: Jacob Joseph , Bratslavsky Gennady , Shapiro Oleg , Liu Nick , Elvin Julia Andrea , Vergilio Jo-Anne , Killian Jonathan Keith , Ngo Nhu , Lin Douglas I. , Ramkissoon Shakti , Severson Eric Allan , Ali Siraj Mahamed , Chung Jon , Schrock Alexa Betzig , Reddy Prasanth , Alexander Brian , McGregor Kimberly , Miller Vincent A. , Necchi Andrea , Ross Jeffrey S.
Published: May 2019

4585

Background: We compared the genomic alteration (GA) profiles of mCSCC, mPSCC and mSSCC to study impact on the targeted and immunotherapy options for the men and women suffering from these refractory cancers. Methods: 78 mPSCC, 604 mCSCC and 338 mSSCC underwent CGP using a hybrid-capture based assay. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and and microsatellite instability (MSI) was determined on 114 loci. Results: The HPV+/CDKN2A- status was significantly more frequent in the mCSCC than mPSCC or mSSCC (P < 0.0001). The GA/tumor frequencies were similar for mCSCC and mPSCC, but significantly higher in mSSCC (P < 0.0001). TP53 mutations were more common in mSSCC (UV light exposure) and mPSCC (likely due to loss of an original HPV+ status). TERT, NOTCH1 and FAT1 GA were more frequent in mPSCC and mSSCC whereas PIK3CA GA were more common in mCSCC. MTOR pathway targets (GA in STK11, FBXW7 and PTEN) were more common in mCSCC than mPSCC or mSSCC. MSI high status was extremely rare in all cases. TMB ≥ 10/20 mut/Mb frequencies were noteworthy in mPSCC and mCSCC but extraordinarily high in mSSCC. Examples of patients with mCSCC, mPSCC and mSSCC responding to targeted and immunotherapies will be presented. Conclusions: Although mCSCC, mPSCC and mSSCC share a variety of clinicopathologic features, the 3 tumor types can be sharply differentiated on CGP. The TP53, CDKN2A and HPV status of the tumor types differ significantly with HPV+ higher in the mCSCC group. There are opportunities for targeted therapies in all groups predominantly identified in the MTOR pathway. The relatively high numbers of cases with significantly elevated TMB in all 3 tumor types suggest that immunotherapies would be beneficial in a large subset of patients. [Table: see text]
Impact of darolutamide (DARO) on pain and quality of life (QoL) in patients (Pts) with nonmetastatic castrate-resistant prostate cancer (nmCRPC).
Authors: Fizazi Karim , Shore Neal D. , Tammela Teuvo , Kuss Iris , Le Berre Marie-Aude , Mohamed Ateesha F. , Odom Dawn , Bartsch Jennifer , Snapir Amir , Sarapohja Toni , Smith Matthew Raymond
Published: May 2019

5000

Background: DARO is a structurally distinct androgen receptor antagonist for which in vitro and phase 1/2 studies suggest low risk of adverse events (AEs) and drug–drug interaction. In the ARAMIS study of DARO in nmCRPC, metastasis-free survival (MFS) was significantly prolonged vs placebo (PBO) (40.4 vs 18.4 mo; hazard ratio [HR] 0.41; 95% confidence interval [CI] 0.34–0.50; P < 0.001) and interim overall survival (OS) favored DARO (HR 0.71; 95% CI 0.50–0.99; P = 0.045). Methods: 1509 pts were randomized 2:1 to DARO 600 mg (two 300 mg tablets) twice daily (n = 955) or PBO (n = 554) while continuing androgen deprivation therapy (ADT). Primary endpoint was MFS. Secondary endpoints included OS and time to pain progression (assessed by Brief Pain Inventory Short Form). QoL was assessed by European Organisation for Research and Treatment of Cancer QoL Prostate Cancer module (EORTC-QLQ-PR25) at baseline (BL) and every 16 wks until end of treatment. Analysis of time to deterioration in EORTC-QLQ-PR25 subscales, defined as first occurrence of a minimally important difference (half the standard deviation of BL value), used Kaplan–Meier estimators and stratified Cox proportional hazard models. Results: DARO significantly delayed pain progression vs PBO (40.3 vs 25.4 mo; HR 0.65; 95% CI 0.53–0.79; P < 0.001); this was maintained beyond end of study treatment. Time to deterioration of EORTC-QLQ-PR25 outcomes showed statistically and clinically significant delays with DARO vs PBO for urinary symptoms (25.8 vs 14.8 mo; HR 0.64; 95% CI 0.54–0.76; P < 0.01). Time to deterioration of hormonal treatment-related symptoms was comparable with DARO vs PBO (18.9 vs 18.4 mo; HR 1.06; 95% CI 0.88–1.27; P = 0.52). DARO was well tolerated. Exposure-adjusted incidences (pts per 100 years’ exposure) of AEs of interest were similar/lower with DARO vs PBO (fatigue/asthenic conditions [11.3 vs 11.1], hypertension [4.7 vs 5.1], hot flush [3.7 vs 4.1], fracture [3.0 vs 3.5], falls [2.7 vs 4.1], cognitive disorder [0.3 vs 0.2], and seizure [0.2 vs 0.2]). Conclusions: For nmCRPC pts, DARO prolongs MFS, is well tolerated, maintains QoL, and delays worsening of pain and disease-related symptoms compared with PBO. Clinical trial information: NCT02200614.
PSMA heterogeneity and DNA repair defects in prostate cancer.
Authors: Paschalis Alec , Sheehan Beshara , Riisnaes Ruth , Nava Rodrigues Daniel , Gurel Bora , Bertan Claudia , Ferreira Ana , Lambros Maryou B. , Seed George , Yuan Wei , Dolling David , Welti Jon , Neeb Antje , Sumanasuriya Semini , Rescigno Pasquale , Bianchini Diletta , Tunariu Nina , Carreira Suzanne , Sharp Adam , De Bono Johann S.
Published: May 2019

5002

Background: Prostate-specific membrane antigen (PSMA) is a promising target for theranostics in metastatic castration resistant prostate cancer (mCRPC). Methods: Membranous PSMA (mPSMA) expression was immunohistochemically evaluated in castration sensitive (CSPC) (n = 38) and mCRPC (n = 60) tissue biopsies, and associations with molecular aberrations (next-generation sequencing; NGS) and clinical outcome were determined. Results: mPSMA expression was significantly higher (p = 0.005) in mCRPC biopsies (median H-score [interquartile range]; 55.0 [2.8-117.5]) compared to CSPC biopsies (17.5 [0.0-60.0]). Furthermore, patients with higher mPSMA expression ( > median H-score) at diagnosis had higher Gleason Grade (p = 0.04) and shorter OS (p = 0.006). Critically, 42% (16/38) of CSPC biopsies and 27% (16/60) of mCRPC biopsies were completely negative for mPSMA expression. In addition, CSPC and mCRPC biopsies expressing mPSMA demonstrated marked intra-tumor heterogeneity in expression levels, commonly exhibiting areas without detectable PSMA (CSPC – 100%; mCRPC – 84%), while heterogeneous mPSMA expression between metastases from the same patient was also observed. Subsequent genomic analysis showed that mCRPC patients with deleterious DNA damage repair (DDR) aberrations have higher (p = 0.016) mPSMA expression (87.5 [25.0-247.5]) than those without these (20 [0.3-98.8]). Furthermore, 9 of the 11 patients (82%) responding to PARP inhibition had a mPSMA H-Score above the median. The association between mPSMA expression and DDR aberrations was validated in an independent cohort with known DDR aberrations. Tumors with DDR aberrations had significantly higher mPSMA (ATM 212.5 [136.3-300] p = 0.005; BRCA2 300 [165-300] p = < 0.001) than unselected mCRPC biopsies (55.0 [2.75-117.5]). Finally, analyses of 122 mCRPC biopsy transcriptomes confirmed a negative correlation between PSMA and BRCA2 mRNA expression (p = 1.5x10-5). Conclusions: mPSMA expression in CSPC and mCRPC exhibits marked intra- and inter-patient heterogeneity, limiting the clinical utility of PSMA-targeted theranostics. We show for the first time that DDR gene aberrations associate with high mPSMA expression and may serve as predictive biomarkers for PSMA-targeted therapies.
TAXOMET: A French prospective multicenter randomized controlled phase II study comparing docetaxel plus metformin versus docetaxel plus placebo in mCRPC.
Authors: Pujalte Martin MARC , Borchiellini Delphine , Viotti Julien , Guillot Aline , Paoli Jean Baptiste , Besson Dominique , Hilgers Werner , El Kouri Claude , Cavaglione Gerard , Priou Frank , Lharidon Tifenn , Largillier Remy , Deville Jean-Laurent , Hoch Benjamin , Schiappa Renaud , Tanti Jean François , Bost Frederic , Ferrero Jean-Marc
Published: May 2019

5004

Background: Docetaxel (DOCE) is a standard of care in metastatic castration-resistant prostate cancer (mCRPC). Several retrospective cohort studies suggest a decrease in PC incidence and mortality with metformin (MET). MET has also demonstrated anti-tumor activity in PC preclinical models, with increase apoptosis when added to DOCE. The addition of MET could enhance DOCE efficacy in mCRPC patients (pts). Methods: TAXOMET is a phase II prospective multicentric randomized controlled trial. Non-diabetic mCRPC pts were assigned 1:1 to receive DOCE 75mg/m2 every 21 days + prednisone (P) 5 mg twice a day and either MET 850mg twice a day (arm A) or placebo (arm B), up to 10 cycles. The primary end point was PSA response rate (≥50% decrease). Main secondary endpoints included objective response rate (ORR, according to RECIST v1.1), clinical and biological progression-free survival (PFS), overall survival (OS), toxicity and quality of life (QoL). Comparisons between arm A and B were performed using Chi² test for qualitative data and Log-rank test for survival data. Results: From January 2013 to December 2015, 99 pts were randomized (50 pts in arm A and 49 pts in arm B) in 10 french centers, and 95 pts were evaluable. No difference was observed between arm A and arm B in PSA-response rate (72% in both arms), ORR (28% in both arms), clinical or biological mPFS (7.3 months vs 5.8 months p = 0.848) and mOS (24.2 months (95CI: 17.2 – 33.7) vs 19.7 months (95CI: 14.8 – 36.8), p = 0.53), respectively. There was no difference between arms in adverse events, except a trend for diarrhea to be more common with MET (70% in arm A vs 50% in arm B, p = 0.072), but few grade 3-4 events. There was no difference in QoL according to QLQ-C30 score between the two arms during the treatment period. Conclusions: This is the first prospective randomized controlled trial to evaluate the combination of MET with DOCE+P in mCRPC. The addition of MET has no meaningful clinical benefit in this setting. Clinical trial information: NCT01796028.
TOPARP-B: A phase II randomized trial of the poly(ADP)-ribose polymerase (PARP) inhibitor olaparib for metastatic castration resistant prostate cancers (mCRPC) with DNA damage repair (DDR) alterations.
Authors: Mateo Joaquin , Porta Nuria , McGovern Ursula Brigid , Elliott Tony , Jones Robert J , Syndikus Isabel , Ralph Christy , Jain Suneil , Varughese Mohini Anna , Parikh Omi , Crabb Simon J. , Miranda Susana , Seed George , Bertan Claudia , Espinasse Aude , Chatfield Peter , Bianchini Diletta , Hall Emma , Carreira Suzanne , De Bono Johann S. ,   on behalf of the TOPARP Investigators Group
Published: May 2019

5005

Background: We previously reported the antitumor activity of olaparib (400mg BID) against molecularly unselected mCRPC (TOPARP-A; Mateo et al NEJM 2015). We now report TOPARP-B, a phase II trial for patients with mCRPC preselected for putatively pathogenic DDR alterations. Methods: Patients with mCRPC progressing after ≥ 1 taxane chemotherapy underwent targeted sequencing of tumor biopsies and were deemed eligible when alterations (germline or somatic; mono- or bi-allelic) in any DDR gene were detected. Patients were randomized 1:1 under a “pick-the-winner” design to 400mg or 300mg of olaparib BID, aiming to exclude ≤30% response rate (RR) in either arm. The primary endpoint RR was defined as radiological response (RECIST 1.1) and/or PSA50% fall and/or CTC count conversion (Cellsearch; ≥5 to < 5), confirmed after 4-weeks. Analyses of RR per gene alteration subgroup was pre-planned. Secondary endpoints included progression-free survival (PFS), tolerability. Results: Overall, 98 patients (median age 67.6y) were randomized, with 92 patients treated and evaluable for the primary endpoint (70 RECIST-evaluable; 89 PSA50%-evaluable; 55 CTC-evaluable). All had progressed on ADT; 99% were post-docetaxel, 90% post-abiraterone/enzalutamide, 38% post-cabazitaxel. The overall RR was 54% (95%CI 39-69%, meeting threshold for primary endpoint) in the 400mg cohort and 37% (95%CI 23-53%) in the 300mg cohort. With a median follow-up of 17.6 months (mo), the overall median PFS (mPFS) was 5.4 mo. Subgroup analyses per altered gene identified indicated response rates for: BRCA1/2 of 80% (24/30; mPFS 8.1mo); PALB2 57% (4/7; mPFS 5.3mo); ATM 37% (7/19; mPFS 6.1mo); CDK12 25% (5/20; mPFS 2.9mo); others [ATRX, CHEK1, CHEK2, FANCA, FANCF, FANCG, FANCI, FANCM, RAD50, WRN] 20% (4/20; mPFS 2.8mo). The highest PSA50% response rates were observed in the BRCA1/2 (22/30; 73%) and PALB2 (4/6; 67%) subgroups. Conclusions: Olaparib has antitumor activity against heavily pre-treated mCRPC with DDR gene defects, with BRCA1/2 aberrant tumors being most sensitive but with confirmed responses in patients with other DDR alterations. Clinical trial information: NCT01682772.
Cardiovascular morbidity in a randomized trial comparing GnRH-agonist and antagonist among patients with advanced prostate cancer.
Authors: Margel David , Peer Avivit , Ber Yaara , Sela Sivan , Shavit Grievink Liat , Tabachnik Tzlil , Witberg Guy , Baniel Jack , Kedar Daniel , Duivenvoorden Wilhelmina CM , Rosenbaum Eli , Pinthus Jehonathan H
Published: May 2019

5015

Background: Androgen-deprivation therapy (ADT) used in prostate-cancer may increase risk of cardiovascular disease (CVD). Limited preclinical and retrospective clinical data suggest that use of gonadotrophin-releasing hormone (GnRH)-antagonist may be associated with lower risk of CVD compared to GnRH-agonist. Methods: We conducted a randomized open-label study comparing the one year incidence of major cardiovascular and cerebrovascular event (MACCE) in prostate-cancer patients with pre-existing CVD commencing on GnRH-agonists or antagonists. Patients were followed every 3 months for the development of MACCE defined as either death, myocardial infarction (MI), cerebrovascular event (CVA), or percutaneous-coronary intervention (PCI). Serum levels of N-terminal pro-B-type natriuretic peptide (NTproBNP) were analyzed at baseline, 3, 6 and 12-months. Results: Eighty patients were enrolled (41 randomized to GnRH-antagonist, 39 to GnRH-agonist). Patients in both arms had similar age, baseline cardiovascular and prostate-cancer characteristics. During follow-up 15 patients developed a new cardiovascular event. Of these, nine patients developed MACCE (two deaths, one MI, two CVAs, and four PCI). Twenty percent (n = 8) of patients randomized to GnRH-agonists had a MACCE compared to 3% (n = 1) randomized to antagonists (log-rank p = 0.013). The absolute risk reduction for MACCE at 12 months using GnRH-antagonist was 18% (95%CI 5-31). Baseline levels of NTproBNP predicted events (AUC = 0.73 95%CI 0.54-0.91 p = 0.03) and increased over time only among patients with CV events. Conclusions: This is the first prospective study to test cardiovascular outcome among prostate-cancer patients receiving ADT. We demonstrated that in patients with pre-existing CVD, GnRH-antagonists was associated with development of fewer cardiovascular events compared to GnRH-agonists. Clinical trial information: NCT02475057.
HSD3B1 and overall survival (OS) in men with low-volume (LV) metastatic prostate cancer (PCa) treated with androgen deprivation therapy (ADT) or chemohormonal therapy in the CHAARTED Randomized trial.
Authors: Hearn Jason W.D. , Sweeney Christopher , Almassi Nima , Reichard Chad A. , Reddy Chandana A. , Hobbs Brian , Jarrard David Frazier , Chen Yu-Hui , Dreicer Robert , Garcia Jorge A. , Carducci Michael Anthony , DiPaola Robert S. , Sharifi Nima
Published: May 2019

5020

Background: The HSD3B1(1245A > C) variant allele, whose frequency varies by race, encodes a missense sequence that stabilizes the rate-limiting enzyme responsible for extragonadal androgen synthesis, thus enhancing intratumoral dihydrotestosterone (DHT) synthesis. Multiple retrospective studies have found that men inheriting the HSD3B1(1245C) variant allele exhibit early resistance to ADT. We sought to validate these findings with prospective data from the Chemohormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED). Methods: Men with newly metastatic PCa were randomized to receive either ADT plus docetaxel at a dose of 75 mg/m2 every 3 weeks for 6 cycles (arm A) or ADT alone (arm B). We determined germline HSD3B1 genotype in the subset of men with LV disease ( < 4 bone metastases, no visceral metastases). We analyzed freedom from castration-resistant prostate cancer (CRPC) and OS according to HSD3B1 genotype using Cox and Kaplan-Meier methods. Results: 197 patients with LV disease had blood samples available and were genotyped, including 97 in arm A and 100 in arm B. Docetaxel did not improve OS of LV men. Of the 197 men, 47% were homozygous wild-type (WT), 43% were heterozygous, and 10% were homozygous variant. When all 197 men were analyzed as one goup, the median time to CRPC was 39.7 mos. in homozygous WT men vs. 25.0 mos. in men with one or more copies of the variant allele (HR 1.27, 95% CI 0.89 to 1.82; p = 0.187). Although OS data are still maturing, at 52 months OS was 83% (95% CI 75% to 91%) in homozygous WT men vs. 64% (95% CI 55% to 74%) in men with one or more variant alleles. There was a suggestion that docetaxel delayed development of CRPC among men with at least 1 variant allele (20.3 vs. 40.7 mos.; HR 0.66, 95% CI 0.40 to 1.04; p = 0.08). Benefit for men with high-volume disease was not evident. Conclusions: Inheritance of the HSD3B1(1245C) allele that augments DHT synthesis may be associated with lower OS in men treated with ADT with or without docetaxel for LV newly metastatic PCa. Additional study is warranted in patients with LV disease. Clinical trial information: NCT00309985.
Profiling of genomic alterations in MAPK/ERK signaling in a large cohort of metastatic prostate cancer (mPC) patients.
Authors: Lin Edwin , Hahn Andrew W , Sonpavde Guru , Lilly Michael B. , Nussenzveig Roberto , Ledet Elisa , Pal Sumanta K. , Grivas Petros , Rich Thereasa A. , Raymond Victoria M. , Sartor A. Oliver , Yandell Mark , Agarwal Neeraj
Published: May 2019

5032

Background: All mPC patients eventually progress on current treatments and prognosis remains poor. In vitro models and small patient cohorts have shown that mPC progression is associated with increased MAPK/ERK signaling. However, in clinical mPC, the genomic alterations that cause aberrant MAPK/ERK signaling and their frequency are poorly defined. We hypothesize that profiling of genomic alterations in MAPK/ERK in a large cohort of heavily pretreated progressive mPC patients will provide a robust measure of importance, and reveal recurrent patterns of alteration. Given the large number of drugs that target MAPK/ERK, these may be incorporated into novel combinatorial treatments for mPC. Methods: 2,679 plasma samples from 2,309 men with mPC were assessed by a validated ctDNA NGS panel that sequences 73 clinically relevant cancer genes (Guardant360, Redwood City, CA) and profiles indels, amplifications, and fusions with high sensitivity and specificity. Genes were assigned to gene sets corresponding to biological pathways and molecular functional classes using the REACTOME database, followed by calculation of summary statistics. Interdependencies between genetic alterations at inter- and intra-gene set levels were discovered by a Bayesian network approach. Results: 56% of mPC samples harbored alterations in MAPK/ERK signaling genes. These included receptor tyrosine kinases (RTKs), MAP kinase cascade, and cell cycle control genes. Gene amplifications were the most frequent alterations in RTK, RAF, and cell cycle control genes, a novel finding. Bayesian network analysis revealed positive interdependencies between all MAPK/ERK genes. In RTK genes, co-amplifications were especially frequent between MET & EGFR and PDGFRA & KIT. Conclusions: In a large cohort of mPC patients, we show that MAPK/ERK gene alterations are present in over half of mPC patients. RTKs, BRAF, and CDK4/6 amplifications are among the most frequent events, display recurrent patterns of co-alteration, and are targetable by existing drugs. Future work to assess the biological and clinical significance of these recurrent patterns of alteration will pave the way for novel combinatorial treatments.
Interlesional response assessment with 18F-sodium fluoride (18F-NaF) PET/CT in men with chemotherapy-naive bone metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide (ENZA).
Authors: Kyriakopoulos Christos , Heath Elisabeth I. , Ferrari Anna C. , Perlman Scott , Mayer Tina M. , Stein Mark N. , Modelska Katharina , Duggan William , Jeraj Robert , Liu Glenn
Published: May 2019

5036

Background: 18F-NaF PET/CT provides spatial and quantitative information on osteoblastic activity in men with bone mCRPC; thus, it can be used to assess interlesional response heterogeneity, a critical clinical issue. Here we assess the proportion of men treated with ENZA with responding lesions by 18F-NaF PET/CT at the time of prostate-specific antigen (PSA), standard radiographic, or clinical progression. Methods: Men with progressive mCRPC with ≥ 2 lesions on bone scintigraphy were enrolled and treated with ENZA 160 mg daily at 3 US sites. 18F-NaF PET/CT scans were obtained at baseline (PET1), week 13 (PET2), and at the time of PSA progression (increase of ≥ 25% and ≥ 2.0 ng/mL above nadir), standard radiographic or clinical progression, or at 2 years without progression (PET3) using Quantitative Total Bone Imaging (QTBI). The primary endpoint was the proportion of men with ≥ 1 responding bone lesion (defined as a lesion with a total NaF standardized uptake value [SUV] less than baseline) on PET3. Evaluable men had scans at PET1 and PET3. Results: A total of 23 men (median age, 72 years [range, 51-93]; median PSA, 20.5 ng/mL [range, 3.9-133.6]) were enrolled. The study met its primary objective; 22 of 22 (100%) evaluable men had ≥ 1 responding bone lesion on QTBI at PET3. Total disease burden changed from a mean baseline SUV of 5700 (range, 507-22,850) to 5590 (range, 213-17,090) at PET2 and 6020 (range, 118-16,650) at PET3. The proportion of progressive lesions increased from a mean 7.8% (range, 0-29) at PET2 to 9.4% (range, 0-32) at PET3. Conclusions: Although PSA response with ENZA is high, many men experience a mixed response to treatment. While overall functional disease burden improves during treatment, an eventual increase in global burden is seen at the time of progression as measured by 18F-NaF PET/CT. At the primary endpoint analysis the proportion of progressing lesions is low, supporting both the hypothesis that a substantial number of lesions continue to benefit from treatment and the concept of treating beyond progression and selectively targeting nonresponding lesions while keeping patients on ENZA. Clinical trial information: NCT02384382.
Randomized phase II trial of a DNA vaccine encoding prostatic acid phosphatase (pTVG-HP) versus GM-CSF adjuvant in patients with PSA-recurrent prostate cancer.
Authors: Liu Glenn , Fong Lawrence , Antonarakis Emmanuel S. , Eickhoff Jens C. , Wargowski Ellen G. , Johnson Laura E. , Jeraj Robert , McNeel Douglas G.
Published: May 2019

5037

Background: Phase I/II studies of pTVG-HP showed safety and increases in prostatic acid phosphatase (PAP)-specific T cells. Based on these, we conducted a multi-center, randomized phase II trial using pTVG-HP with GM-CSF adjuvant vs GM-CSF alone in patients with PSA-recurrent, non-metastatic, non-castrate, prostate cancer (stage M0). Methods: 99 patients with M0 prostate cancer (negative CT and bone scan) with PSA doubling time (DT) of < 12m were randomly assigned to pTVG-HP + GM-CSF vs GM-CSF. Treatments were every 2 wk x 6, and then quarterly for up to 24m. Primary endpoint was 2-year MFS. Secondary endpoints included median MFS, changes in PSA DT, and immune response to PAP antigen. Additional analysis included quantitative changes in bone lesion activity by NaF PET/CT. Results: Few grade 3/4 events were observed and were not statistically different between arms. 2-year MFS between control and pTVG-HP was 42.3% and 41.8% (p = 0.97). Median MFS was not different (18.3m control versus 18.9m pTVG-HP, HR = 1.6, p = 0.13). Changes in PSA DT, and immunity to the PAP target, were not different between study arms. A pre-planned subset analysis showed median MFS was significantly longer in patients with rapid PSA DT ( < 3m) treated with pTVG-HP (6.1m versus 12.0m, n = 21, HR = 4.4, p = 0.03). In patients with baseline metastases detected on NaF PET/CT, total activity (SUVtotal) increased 17% with GM-CSF alone, but decreased 29% with pTVG-HP from baseline to month 6 (n = 27, p = 0.07). Conclusions: This trial did not demonstrate an overall increase in 2-year MFS following treatment with pTVG-HP, but suggested a modest effect in patients with rapidly progressive disease. NaF PET/CT imaging suggests that pTVG-HP has a detectable effect on decreasing metastatic activity in bone. A separate trial suggests that pTVG-HP is an immune activating agent that improves activity of PD-1 blockade. A trial using pTVG-HP in combination with nivolumab in patients with M0 prostate cancer is currently underway. Clinical trial information: NCT01341652.
Complex biologic heterogeneity of de novo hormone naïve metastatic prostate cancer (HNPCa): Comparison of early progressors and prolonged responders to initial systemic treatment.
Authors: Chapin Brian Francis , Wang Xuemei , Zhang Miao , Corn Paul Gettys , Zurita Amado J. , Elsheshtawi Mohamed A , Davis John W. , Pettaway Curtis Alvin , Adibi Mehrad , Gleave Martin , Cooperberg Matthew R. , Smaldone Marc C. , Mcguire Sean Eric , Tu Shi-Ming , Wang Jennifer , Subudhi Sumit Kumar , Efstathiou Eleni , Logothetis Christopher , Troncoso Patricia , Aparicio Ana
Published: May 2019

5055

Background: Given the absence of biologically based biomarkers current therapy allocation strategies for men with mHNPCa are based on anatomic distribution and volume of metastases. We sought to determine the strength of the association between clinical predictors (including met volume) and outcomes in men with mHNPCa at extremes of response to initial systemic therapy (ST). Methods: Data from a population screened for a phase II trial of Best ST +/- local therapy in mHNPCa was analyzed (NCT01751438). Pts had to have sustained responses to ST (≥6 mos) in order to be randomized. Early Progressors (EP, castration resistant progression <6 mos from start of ST per PCWG2) were not randomized. Prolonged Responders (PR) were defined as those with progression free survivals (PFS) > median for the 109 randomized pts. Baseline demographics were compared between groups (Fisher’s exact test for categorical and Wilcoxon rank-sum test for continuous variables) and Kaplan Meier estimates of OS determined. Immunohistochemistry and genomic sequencing of untreated tumor biopsies are ongoing. Results: Of 208 screened pts, 27 (13%) were identified as EPs, with a median PFS of 5.9 mos (95%CI: 5.3-6.5). The median PFS for the randomized cohort was 16.8 mos (95%CI: 12.7-37.6). 55 (50%) pts were identified as PRs, with median PFS not reached (NR) at a median follow up of 31 mos (range: 7.5-75). Patients’ demographics are below (Table), grouped by EP and PR cohorts. Median OS was 24.8 mos vs NR in the Eps compared to PRs (p<0.001). Conclusions: The EP group was enriched for high risk features and had a worse outcome. However, 33% of men in the EP group had low volume disease and 22% in the PR group had high volume disease. This suggests that clinical volume is an inadequate predictor of biologic response and highlights the need for biologic sub-typing of de novo mHNPCa. [Table: see text]
Impact of germline DNA-repair gene BRCA2 and CHEK2 mutations on time to castration resistance in patients with metastatic hormone-naïve prostate cancer: A single center analysis.
Authors: Matveev Vsevolod Borisovich , Lyubchenko Liudmila , Kirichek Andrey
Published: May 2019

5056

Background: Germline mutations in DNA repair genes are common in patients with andvanced and metastatic prostate cancer (mPCa). Although BRCA mutation carriers have worse outcomes than noncarriers when conventionally treated for local or locally advanced PCa, recent studies reported conflicting results regarding their aggressiveness in patients with advanced disease. This study aimed to examine the impact of germline BRCA1/2 and CHEK2 mutations on time to castration-resistance in patients with mPCa, receiving hormonal androgen deprivation therapy (ADT). Methods: A total of 76 patients with hormone-naive mPCa treated with first line ADT by luteinizing hormone-releasing hormone analogue (LHRHa) between 2014 and 2017 were recruited. Median follow-up was 34,8 mo. We focused on age, volume of metastatic spread, histologic grade, family history. All patients were genotyped for germline mutations in the BRCA1, BRCA2 and CHEK2 genes by polymerase chain reaction real-time and the Sanger sequencing. We used the standard definition of castration-resistance PCa (CRPC). Median time to CRPC were estimated using the Kaplan-Meier method, generated curves were compared using the log-rank test. Cox regression analyses were used to assess the prognostic value of BRCA1/2 and CHEK2 mutations. Results: Pathogenic and likely pathogenic germline mutations in the BRCA2 and CHEK2 gene were identified in 19 (25 %) patients. No cases of BRCA1 mutations were detected. Median time to CRPC was significantly shorter in BRCA2 and CHEK2 mutation carriers (7.9 mo, 95 % confidence interval (CI) 2.6 – 13.3), than in non-carriers (48.7 mo, 95 % CI 31.1 – 68.3, p < 0,001). There was no significant difference in median time to CRPC in BRCA2 (7.9 mo, 95 % CI 0.0 - 16.3) and CHEK2 mutation carriers (6.1 mo, 95 CI 5.0 - 7.2, p = 0,448) meanwhile both were shorter than in non-carriers (p = 0.002 and < 0,001). Multivariate analysis confirmed both BRCA2 (hazard ratio [HR]: 2.63; 95 CI 1.32-5.26, p = 0.006) and CHEK2 (HR 6.66, 95 CI 2.35-18.89, p < 0.001) mutations as an independent prognostic factor for time to CRPC, particularly in mPCa with low-volume metastatis spread (HR 3.09, 95 % CI 1.36–7.05, р = 0.007 and HR 14.1, 95 % CI 3.65-54.4, p < 0.001). Conclusions: BRCA2 and CHEK2 carriers had worse outcomes (shortened time to CRPC) than noncarriers when conventionally treated for metastatic PCa by standard first-line hormone treatment with LHRHa.
Clinical outcomes and genomic analysis in patients with very high-risk clinically localized prostate cancer treated by radical prostatectomy.
Authors: Velho Pedro Isaacsson , Lim David , Wang Hao , Kaur Harsimar B , Markowski Mark Christopher , Carducci Michael Anthony , Antonarakis Emmanuel S. , Pritchard Colin C. , Lotan Tamara L. , Eisenberger Mario A.
Published: May 2019

5067

Background: Very high risk prostate cancer is associated with poor response to local and systemic treatments, however few cases have been molecularly profiled. We studied patients with primary Gleason pattern 5 disease (PG5; Gleason scores 5+5 or 5+4) after undergoing radical prostatectomy (RP). Methods: Consecutive PG5 cases were retrospectively studied. Clinical-pathologic features, tumor somatic sequencing (UW Oncoplex), germline sequencing and PTEN, TP53 and ERG status by immunohistochemistry were correlated with biochemical relapse (BCR), metastasis-free survival (MFS), time to castration-resistance (TCR) and overall survival (OS). Kaplan–Meier curves were used in time-to-event data. Univariate and multivariable (MVA) Cox proportional-hazards models (95% confidence intervals (CI Clinical-pathological variables were selected for the multivariate analysis using stepwise method and were used to adjust the effect of each mutation. Results: Of 60 patients with available tissue and follow-up, 90% had non-organ confined disease, 58% had seminal vesicle invasion (SVI), 27% had lymph node involvement, and 15% had ductal or intraductal histologic features. Overall, 43% developed metastasis with a TCR of 12 months. On multivariable analysis of clinical-pathologic variables, only ductal/intraductal histology (HR = 4.43; 95% CI: 1.76-11.15; p = 0.002) and SVI (HR = 5.14; 95% CI: 1.83-14.47 p = 0.002) were associated with metastasis. Of patients with somatic sequencing data, 22% (11/49) had homologous recombination (HR) and 12% (6/49) had mismatch repair (MMR) gene alterations. In addition, 33% (16/49) had TP53 mutation and 51% (29/57) had PTEN loss. Only TP53 mutation and PTEN loss were associated with metastasis on univariable analysis and no genomic alterations remained significant in multivariable analyses. Conclusions: Patients with PG5 have poor outcomes and more than one third have mutations in DNA repair genes. The unusually high incidence of actionable HR and MMR alterations provides the rationale for the design of adjuvant clinical trials in this population. [Table: see text]
WNT activating pathway mutations confer resistance to first-line antiandrogen therapy in castration-resistant prostate cancer (CRPC).
Authors: Isaacsson Velho Pedro , Mirkheshti Nooshin , Qazi Fahad , Shaukat Farah , Fu Wei , Wang Hao , Carducci Michael Anthony , Markowski Mark Christopher , Denmeade Samuel R. , Marshall Catherine Handy , Lotan Tamara L. , Eisenberger Mario A. , Antonarakis Emmanuel S.
Published: May 2019

5068

Background: Wnt signaling is a cellular pathway responsible for embryogenesis and neoplasm. When activated, in about 10-20% of mCRPC, the WNT signaling pathway may cause androgen-independent growth and consequently antiandrogen resistance. To further characterize the clinical features and biology of this subtype of mCRPC, we studied mutations in genes of this pathway, including APC, CTNNB1, RNF43, ZNRF3 and RSPO2, in patients who received treatment at Johns Hopkins Hospital (JHH). Methods: Patients with CRPC who received first-line antiandrogen (abiraterone or enzalutamide) therapy for CRPC at JHH were retrospectively studied. Pathological staging, extension of primary disease, tumor somatic genomic data by Next Generation Sequencing (NGS) were correlated with clinical outcomes such as time to PSA progression, PSA response and overall survival (OS). Cox regression was used to test associations between variables and clinical outcomes and Kaplan-Meier method was used for time-to-event data. Results: Of 137 pts who received first-line antiandrogen therapy for CRPC, 10.9% (15 pts) had NGS with at least one activating WNT pathway alteration, including mutations in APC (6 pts), CTNNB1 (8 pts) and RNF43 (3 pts). Patients with WNT mutations had fewer T3/T4 tumors (30.8% vs. 51.4%, p = 0.24), but were balanced in other aspects. The median time to PSA progression in WNT activated patients was 6.5 months vs. 9.6 months in WNT negative patients (HR 2.3, 95% CI 1.3 - 4.1, p = 0.003). The presence of WNT mutations (HR 2.3, 95% CI 1.2 - 4.3, p = 0.007) and previous chemotherapy (HR 1.8, 95% CI 1.2 – 2.7, p = 0.003) were independently associated with shorter time to PSA progression. PSA50 response was numerically worse in WNT activated patients (53% vs 75%, p = 0.12). The OS in patients with WNT mutations was 23.6 months vs 27.7 months in patients without WNT mutations (HR 2.2, 95% CI 1.1 - 4.5, p = 0.01). Conclusions: Patients with WNT pathway mutations may have worse outcomes to first-line abi/enza compared to patients without these aberrations. Time to PSA progression and OS were inferior in WNT activated population. Our data reinforce the necessity to develop effective WNT pathway inhibitors to test in clinical trials for WNT activated patients.
ATM loss in primary prostate cancer: Analysis of >1000 cases using a validated clinical-grade immunohistochemistry (IHC) assay.
Authors: Antonarakis Emmanuel S. , Kaur Harsimar B , Hicks Jessica , Pritchard Colin C. , De Marzo Angelo M , Isaacs William B. , Lotan Tamara L.
Published: May 2019

5069

Background: ATM is a protein kinase acting as the main signal transducer of double-strand DNA break repair, in addition to mediating other cellular functions. Germline and somatic pathogenic mutations in ATM occur in a significant fraction of prostate cancers, and targeted therapies for ATM-deficient tumors ( e.g. ATR inhibitors) appear promising. Because DNA sequencing assays frequently cannot distinguish mono-allelic from bi-allelic ATM alterations, a clinical-grade protein IHC assay for ATM loss is needed to select men for these trials and better characterize ATM-deficient tumors. Methods: We validated an automated dichotomously-scored IHC assay to detect ATM protein loss in primary prostate cancer using prostate cancer cell lines with and without bi-allelic ATM inactivation and 49 high-grade (primary Gleason pattern 5) prostate tumors with known ATM genomic status. We then examined the frequency of ATM loss among 23 tumors with pathogenic germline ATM mutations, as well as > 1000 additional primary prostate carcinomas using tissue microarrays (TMA). Results: ATM loss by IHC was found in 14% (7/49) of primary Gleason pattern 5 (5+4 = 9 and 5+5 = 10) tumors. Of these, all cases with adequate tumor content and DNA yield had underlying pathogenic ATM mutations. Of the remaining 42 cases without ATM protein loss, none had ATM alterations. Among men with pathogenic germline ATM mutations, 74% (17/23) had ATM loss by IHC. Of these, 76% (13/17) had homogeneous loss of ATM protein in all tumor cells within a dominant tumor nodule, suggesting that ATM loss was an early clonal event. On TMA analysis, 90% (944/1044) of tumors were evaluable for ATM status by IHC. Among these, ATM loss was seen in 3.3% (31/944), and was significantly more common in tumors with Gleason scores 9-10 (20/198; 10.1%) than in those of all other Gleason grades (11/746; 1.5%) ( P< 0.0001). Conclusions: Validated ATM IHC is a sensitive assay for detecting underlying genomic ATM alterations. ATM protein loss appears to be an early event occurring in the majority of tumors with underlying germline pathogenic ATM mutations, and is significantly enriched in high-grade prostate cancers (especially Gleason grades 9-10).
Implications of the United States Preventive Services Task Force (USPSTF) recommendations on prostate cancer (PCa) stage migration.
Authors: Sheng Iris Yeong- Fung , Chen Yu-Wei , Ornstein Moshe Chaim , Gilligan Timothy D. , Rini Brian I. , Garcia Jorge A.
Published: May 2019

5071

Background: Prostate specific antigen (PSA) screening has been controversial, given unrefined screening guidelines leading to overdiagnosis and overtreatment of “indolent” PCa. In 2008, the USPSTF recommended against PSA screening for men aged ≥75 and in 2012 broadened this recommendation to include all men. The impact of these changes is unstudied. We hypothesize that these screening changes could delay the diagnosis of advanced PCa. Methods: The Surveillance, Epidemiology and End Results Program (SEER) was used to identify men (age 55-69) diagnosed with PCa between 2004-2015. PCa stage was categorized as nodal (N1M0) and metastatic (NxM1). Trend analysis was stratified based on year 2004-2008 (group 1), 2009-2012 (group 2), and 2012-2015 (group 3). Using group 2 as a reference, multivariable logistic regression was used to identify predictors for N1M0 and NxM1 in each group. Results: From 2004-2015, there were 603,323 eligible men diagnosed with PCa (group 1: 262,240 men, group 2: 210,045 men, group 3: 131,038 men). In group 1, 1.4% had N1M0 and 2.8% had NxM1. In group 2, 1.6% had N1M0 and 3.7% had NxM1. In group 3, 1.4% had N1M0, and 6.1% had NxM1. The adjusted odds ratio (AOR) of N1M0 was 0.78 (95%CI 0.74-0.82; p<0.0001) in group 1 and 1.71 (95%CI 1.63-1.80; p<0.0001) in group 3. Similar AOR trends were seen in NxM1 (group 1, 0.71; 95%CI 0.68-0.73, p< 0.0001 vs. group 3, 1.70; 95% CI 1.63-1.75, p<0.0001). (Table) Subset analysis of non-eligible patients (age >70 and <55) showed a similar stage migration. Conclusions: With each USPSTF recommendation, there have been significantly more diagnoses of advanced PCa; suggesting stage migration. The sequelae of having advanced PCa include more aggressive treatments, increased financial burden, and reduced quality of life. Future population studies are warranted to investigate whether the updated 2018 USPSTF recommendation now encapsulates the best target population.[Table: see text]
Identification, incidence and clinical outcomes of patients (pts) with hypermutated prostate cancer (PC).
Authors: Fu Simon Yuen Fai , Ritch Elie , Herberts Cameron , Yip Steven , Khalaf Daniel , Warner Evan W , Taavitsainen Sinja , Annala Matti , Vandekerkhove Gillian , Kushnir Igal , Ferrario Cristiano , Wyatt Alexander William , Chi Kim N.
Published: May 2019

5072

Background: A small proportion of metastatic PC exhibit outlier somatic mutation (mut) rates exceeding the average of 4.4 mut/Mb. The incidence, clinical course and treatment response of pts with hypermutation (HM) is poorly characterised. Methods: We performed targeted sequencing from a panel of PC genes using plasma cell-free DNA samples collected from metastatic castration-resistant prostate cancer (mCRPC) pts and calculated somatic mutation burden. HM samples were additionally subjected to whole exome sequencing to determine trinucleotide mutational signatures and microsatellite instability (MSI). Clinical data was retrospectively collected and compared to a control cohort of 199 mCRPC pts. Results: 671 samples from 434 pts had ctDNA > 2% and were evaluable. 32 samples from 24 pts had > 11 mut/Mb and fell above the 95th percentile for mutation burden with a median mutation burden of 34 mut/Mb. 11 pts had deleterious mutations or homozygous deletions in mismatch repair (MMR) genes and 4 further pts had evidence of MMR deficiency (MMRd) from mutational signatures and MSI status. The remaining 9 pts had either BRCA2 mutations (n = 4), Kataegis (localized hypermutation, n = 3), or undefined causes for HM (n = 2). The incidence of MMRd was 3.5% (15/434), and germline MMRd was 0.2% (1/434). For MMRd pts with available clinical data (10/15) at diagnosis, the median age was 73.6 y, 70% had Gleason score ≥8, and 50% presented with M1 disease. Comparing the MMRd with the control cohort, median time from ADT to CRPC was 9.1 m (95% CI 6.9–11.4) vs. 18.2 m (95% CI 15.1–21.3), p = 0.001; median time from CRPC to death was 13.1 m (95% CI 0.3–25.9) vs. 40.1 m (95% CI 32.4–47.8), p < 0.001. Conclusions: HM and MMRd can be identified using liquid biopsy and could help to select pts for immunotherapy.
The rate of tumor growth, g, as a biomarker for overall survival (OS) in prostate cancer (PC) in clinical trials as well as in real-world data from the Veterans Administration Medical Centers (VAMCs).
Authors: Leuva Harshraj , Zhou Mengxi , Wilkerson Julia , Sigel Keith , Hsu Ta-Chueh , Aggen David Henry , Langhoff Erik , Park Yeun-Hee Anna , Bates Susan Elaine , Fojo Antonio Tito
Published: May 2019

5074

Background: Novel assessments of efficacy are needed to improve determination of treatment outcomes in clinical trials and in real-world settings. Methods: Cancer treatments usually lead to concurrent regression and growth of the drug-sensitive and drug-resistant fractions of a tumor, respectively. We have exploited novel methods of analysis that assess these two simultaneous processes and have estimated rates of tumor growth ( g) and regression ( d) in over 30,000 patients (pts) with diverse tumors. Results: In prostate cancer (PC) we have analyzed both clinical trial and real-world data from Veterans. Using clinical trial data from 6819 pts enrolled in 15 treatment arms we have established separately and by combining all the data that g correlates highly (p<0.0001) with overall survival (OS) – slower g associated with better OS. In PC, abiraterone (ABI) and docetaxel (DOC) are superior to placebo, prednisone and mitoxantrone. ABI (median g =0.0017) is superior to DOC ( g=0.0021) in first line (p=0.0013); and ABI in 2nd line ( g=0.0034) is inferior to ABI in 1st line ( g=0.0017; p<0.0001). Finally, using combined clinical trial data as a benchmark we could assess the efficacy of novel therapies in as few as 30-40 patients. Amongst 7457 Veterans, the median g on a taxane ( g=0.0022) was similar to that from clinical trials ( g=0.0012). Although only 258 Veterans received cabazitaxel (CAB), g values for CAB ( g=0.0018) and DOC ( g=0.0023) were indistinguishable (p=0.3) consistent with their identical mechanism of action. Finally, outcomes with DOC in African American (AA) ( g=0.00212) and Caucasian ( g=0.00205) Veterans were indistinguishable (p=0.9) and comparable across all VAMCs. Conclusions: The rate of tumor growth, g, is an excellent biomarker for OS both in clinical trials and in real-world settings. g allows comparisons between trials and for large trial data sets to be used as benchmarks of efficacy. Real-world outcomes in the VAMCs are similar to those in clinical trials. In the egalitarian VAMCs DOC efficacy in PC is comparable in AA and Caucasian Veterans -- indicating inferior outcomes reported in AAs are likely due to differential health care access, not differences in biology.