bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigation of a novel irreversible pan-HER inhibitor combined with chemotherapy in bladder cancer models.
Authors: Grivas Petros , Day Kathleen C. , Daignault Stephanie , Shakir Nazia , Paul Alyssa , Kunju Priya , Smith David C. , Hussain Maha , Day Mark L.
Published: March 2020

4545

Background: Human Epidermal Receptors (HER) play an important role in bladder cancer (BCa) progression and may mediate chemotherapy resistance. Dacomitinib (Dac) is a novel, potent, irreversible pan-HER inhibitor with activity in several solid tumors, currently in phase III trials in NSCLC. We showed that Dac has single agent anti-tumor activity in human BCa models in vitro and in vivo, inducing apoptosis and G1 arrest. We hypothesized that Dac has additive effects with Gemcitabine (G) and Cisplatin (C) in BCa xenografts. Methods: UM-UC-6 (UC6) or UM-UC-9 (UC9) xenografts were established in age-matched NOD/SCID mice. A week after injection, mice had small tumors, were randomized and treated with i. G 50mg/kg + C 2mg/kg via 3 weekly intra-peritoneal injections (IPI) + daily p.o. buffer for 3 weeks; ii. Dac 6mg/kg p.o. daily for 3 weeks + 3 weekly IPI (saline); iii. GC (same dose/schedule) + Dac starting 1 day after GC (based on cell cycle effect and kinetics); iv. no treatment (control). Mice were monitored daily, weighed weekly, sacrificed at 4 weeks and tumors were weighed. 3 tumors/group were stained for EGFR, HER2, Ki67, E-cadherin, ALDH, p-EGFR, p-ERK, p-Akt. 3rd GC dose in UC6 model was given at 50% due to weight loss; all GC doses were given at 50% in UC9 model. Mann-Whitney test with multiple comparison adjustments was used for analysis. Results: Dac- and GC+Dac-treated mice had no significant weight loss. UC6 tumor weights were significantly lower in Dac and GC+Dac vs control (p<0.0001) or GC (p<0.0001), corresponding to decreased p-ERK %cell expression and staining intensity. GC and control had similar tumor weights (p=0.19). 5 Dac and 3 GC+Dac UC6-injected mice had no tumor at 4 weeks. UC9 tumor weights were significantly lower in Dac (p=0.002, 6x reduction) or GC (p=0.0006; 7x reduction) vs control. GC+Dac had significantly lower tumor weights vs GC (p=0.005), Dac (p=0.06) or control (p<0.0001; 17x reduction). Conclusions: Dac had dramatic singe-agent activity in UC6 xenograft that was GC-resistant. Dac+GC was superior to GC in UC9 xenograft, supporting clinical evaluation. Further investigation of Dac anti-tumor activity and predictive biomarker discovery in additional bladder cancer models is pursued.
Aggressive surgical management of germ cell tumors with somatic-type malignancy: Pathologic features, prognostic factors, and survival outcomes.
Authors: Rice Kevin R , Magers Martin J , Beck Stephen , Einhorn Lawrence H. , Ulbright Thomas M. , Foster Richard
Published: March 2020

4554

Background: Germ cell tumors (GCT) with somatic-type malignancy (SM) are rare occurring in approximately 3-8% of GCT cases. Prognostic factors and optimal management remain poorly-defined. Methods: The Indiana University (IU) testis cancer database was queried from 1979 to 2011 for patients demonstrating atypical histology at orchiectomy or subsequent resection of metastatic disease. Patients with transformation to PNET only were excluded due to distinct management. Chart review, pathologic review, and survival analysis were performed. Results: 122 patients met study inclusion criteria. Primary tumor site was testis in 112, retroperitoneum in 8, groin in 1, and pineal gland in 1. The most common SM histologies were sarcoma (71) and carcinoma (32). At GCT diagnosis, 24, 44, 45 patients had stage I, II, and III disease, respectively. Stage was unknown in 9. Median time from GCT diagnosis to SM was 13 months (Range, 0-397). This interval was longest for carcinomas (94.5 months) and sarcomatoid yolk sac tumors (113 months). Only 11 of 83 patients (13.3%) receiving cisplatin-based chemotherapy for measurable disease demonstrated an initial complete response. First resection at IU was reoperative in 45 patients (36.9%). 69 patients (56.6%) required extirpation of abdominal viscera/vascular structures or distant metastases. At a median follow-up of 71 months, the 5-year cancer specific survival (CSS) was 63%. Predictors of poorer CSS included SM diagnosed at late relapse (p = 0.014), referral to IU for reoperative RPLND (p = 0.022), and tumor grade (p = 0.043). SM histology subtype, stage, risk category, and number of resections for SM were not predictive of CSS. Conclusions: GCT with SM is associated with poorer CSS than traditional GCT. Established prognostic factors for GCT lose their predictive value in the setting of SM. SM can occur at any point in the course of GCT, but has a propensity for delayed presentation with later onset being associated with poorer CSS. Aggressive and serial surgical resections are often necessary to optimize CSS. Tumor grade is an important prognostic factor, particularly in sarcoma cases.
Comparing diagnosis, management, and outcomes of synchronous versus metacrhonus brain metastases from testicular germ cell tumors (TGCT): Multinstitutional experience from the Spanish Germ Cell Cancer Group (SGCCG).
Authors: Aparicio Jorge , Girones Regina , Roure Pere , Germa-Lluch Jose R. , Vazquez-Estevez Sergio , Saenz Alberto , Sastre Javier , Arranz Arija Jose Angel , Gallardo Enrique , Gonzalez-Billalabeitia Enrique , Sanchez-Hernandez Alfredo , Terrasa Josefa , Hernandez Ana , Santander Carmen , Cillan Elena , Sagastibelza Naira , Almenar-Cubells Daniel , Lopez Brea Marta , Maroto José Pablo ,   Spanish Germ Cell Cancer Group (SGCCG)
Published: March 2020

4560

Background: Metastases of testicular germ cell tumors (TGCT) to brain are a rare event. Prognostic is poor and there is little evidence on optimal management of these patients. Methods: A retrospective review of case records of germ cell tumor patients within the Spanish Germ Cell Cancer Group from 1994 to 2012 was conducted. Results: Thirty-tree cases of testicular germ cell tumors from 17 institutions were reported. Nineteen patients (57%) presented with brain metastases at primary diagnosis (group 1: synchronous), thirteen (40%) developed brain metastases at relapse (group 2: metachronous) and only one patient developed brain metastasis during cisplatin based-chemotherapy (3%) (excluded from the analysis). Main demographics and comparison between series are shown on table. Median serum BHCG levels at initial diagnosis were higher in group 1(279.083 versus 175.873), whereas those of AFP were higher in group 2(1320 versus 4181). The most common histology in the primary tumor was choriocarcinoma for group; versus embryonal carcinoma for group 2. Patients had neurological symptoms at diagnosis of brain metastases (63% synchronic/93% metachronus). Performance status was also poor (PS 2-3: 52,6%group 1-62,2% group 2). Four patients (21%) in group 1 had a solitary brain lesion vs seven (54%) on group 2. Median time since last dose of cisplatin to development of brain metastases on group 2 was 6 months (3-22).Median overall survival was 16 months (95% CI 5,3-26,6): group 1: 16 (95% CI 13,9-18);23 group 2 (95% CI 0-165). We have not found significant differences in survival between both groups. Overall 37,5% of patients achieved long-term survival (38,9% in group 1 versus 38,5% in group 2). Patients achieving complete response of brain metastases had a better survival (log rank p:0,003). Conclusions: Long term survival can be achieved in approximately 1/3 of patients with brain metastases. Chemotherapy remains the cornerstone of treatment. Selection bias because of the retrospective nature of review should make us be careful with the conclusions.
Testosterone (T), luteinizing hormone (LH), and follicle stimulating hormone (FSH) levels in testicular cancer survivors (TCSs) 11 and 19 years after orchiectomy.
Authors: Sprauten Mette , Brydoy Marianne , Haugnes Hege Sagstuen , Langberg Carl Wilhelm , Dahl Olav , Klepp Olbjorn Harald , Bremnes Roy M. , Cvancarova Milada , Fossa Sophie D. , Oldenburg Jan
Published: March 2020

4562

Background: Hypogonadism, i.e., low T-, high LH- and/or FSH-levels, is frequently observed in TCSs and is associated with cardiovascular disease, osteoporosis and reduced quality of life. Little is known about the impact of aging on hypogonadism in TCSs. Methods: T, LH, and FSH levels were retrieved twice from 874 TCSs median 11 (S11) and 19 (S19) years after orchiectomy and categorized based on cut-offs calculated from 570 healthy controls (C), separately for each decadal age group. Treatment was categorized into surgery (S), radiotherapy (RT) or cisplatin-based chemotherapy (CT). Impact of treatment and aging on T, LH and FSH levels was assessed by comparing proportions of TCSs grouped into the C quartiles by ordinal logistic regression and expressed with odds ratios (OR) and 95% confidence interval (CI). Results: TCSs had lower T and higher LH and FSH levels than C at S11 and S19 (p<0.05, except for LH after S at S11) (Table).Approximately 50% of TCSs had T levels in the lowestquartile at S11 and S19. The proportion of TCSs with T below the 2.5% cut-off threshold for C increased from S11 to S19, for the S (9.7 - 12.5%), RT (9.4 - 16.3%) and CT group (12.5- 19.9%). Conclusions: TCSs had lower T and higher LH and FSH levels than C of similar age indicating an impact of treatment. Importantly, proportions of TCSs in the highest LH quartile and below the 2.5% cut-off for T-level increased from S11 to S19, indicating an accelerated hormonal aging. Continued follow-up of hormone levels is important. [Table: see text]
Rates of dose adjustment in patients treated with tivozanib versus sorafenib in the phase III TIVO-1 study.
Authors: Hutson Thomas E. , Nosov Dmitry , Harza Mihai , Esteves Brooke , Strahs Andrew Louis , Berkenblit Anna , Motzer Robert John
Published: March 2020

4564

Background: Tivozanib hydrochloride (tivozanib) is a potent, selective, tyrosine kinase inhibitor of all three vascular endothelial growth factor receptors, with a long half-life. Superior progression-free survival (PFS) and overall response rate (ORR) with tivozanib versus sorafenib were demonstrated in a phase III trial (TIVO-1) in patients with advanced renal cell carcinoma (PFS: 11.9 vs 9.1 months in ITT population, 12.7 vs 9.1 months in patients who received no prior systemic treatment for mRCC; ORR: 33% vs 23% in ITT population). Hypertension was more common with tivozanib, while lower rates of certain off-target adverse events (AEs) relative to sorafenib were reported (J Clin Oncol 2012;30[suppl]:Abstract 4501). Here we present detailed dose adjustment data. Methods: In total, 517 patients were enrolled and randomized 1:1 to tivozanib 1.5 mg/d (once daily 3 weeks on, 1 week off) or sorafenib 400 mg/d (twice daily, continuously). Treatment duration and AEs leading to discontinuation and dose adjustment were assessed in these patients. Results: Median duration of treatment with tivozanib was 12.7 months vs 9.5 months with sorafenib; fewer patients in the tivozanib arm experienced drug reduction or dose interruption due to AEs (see Table). Treatment-related AEs, as defined by the investigator, led to drug discontinuation in 3.9% of tivozanib patients and 5.4% sorafenib patients. Conclusions: Lower rates of dose adjustment due to related AEs were observed in patients with metastatic RCC who received tivozanib compared to sorafenib. Clinical trial information: NCT01030783. [Table: see text]
Outcome of metastatic sarcomatoid renal cell carcinoma (sRCC): Results from the International mRCC Database Consortium.
Authors: Chittoria Namita , Zhu Hui , Choueiri Toni K. , Kroeger Nils , Lee Jae-Lyun , Srinivas Sandy , Knox Jennifer , Bjarnason Georg A. , MacKenzie Mary J. , Wood Lori , Vaishamayan Ulka N. , Agarwal Neeraj , Pal Sumanta Kumar , Tan Min-Han , Rha Sun Young , Yuasa Takeshi , Donskov Frede , North Scott A. , Rini Brian I. , Heng Daniel Yick Chin
Published: March 2020

4565

Background: Sarcomatoid differentiation in metastatic RCC (sRCC) is associated with poor prognosis. Robust data regarding outcome in the targeted therapy era is lacking. Methods: Clinical features, prognostic factors, and treatment outcomes in mRCC patients with and without sarcomatoid histology treated with targeted therapy were retrospectively analyzed and compared. Results: 2,286 patients were identified (non-sRCC(n=2,056); sRCC(n=230)). sRCC patients had significantly worse Heng prognostic group distribution compared to non-sRCC (11% vs 19% favorable risk, 49% vs 57% intermediate risk, and 40% vs 24% poor risk; p<0.0001). Time from original diagnosis to relapse (excluding synchronous metastatic disease) in the sRCC patients was 18.8 months compared to 42.9 months in non-sRCC group; p<0.0001. There was no significant difference in the incidence of CNS metastases (6-8%) or underlying clear cell histology (87-88%). Greater than 93% of patients received VEGF inhibitors as first line therapy; 21% achieved an objective response in the sRCC group as compared to 26% in the non-sRCC group with significantly more sRCC patients (43% vs. 21%) having primary refractory disease (p<0.0001, for both). sRCC patients had significantly less use of second-line (p=0.018) and third-line (p=0.0004) systemic therapy. The median PFS / OS was 4.5 months / 10.4 months in sRCC patients and 7.8 months / 22.5 months in non-sRCC patients (p<0.0001 for both). Sarcomatoid histology was associated with a significantly worse PFS and OS after adjusting for the individual Heng risk factors in multivariable analysis (HR 1.5, p<0.0001 for both). Conclusions: Patients with sRCC have worse baseline prognostic criteria, a shorter time to relapse and worse clinical outcome to targeted therapy compared to patients with non-sRCC. Additional insight into the biology of sRCC is needed to develop alternative therapeutics.
Association of hyperbilirubinemia in pazopanib- or sunitinib-treated patients in COMPARZ with UGT1A1 polymorphisms.
Authors: Johnson Toby , Xu Chun-fang , Choueiri Toni K. , Deen Keith C. , Xue Zhengyu , Bartlett-Pandite Arundathy N. , Carpenter Christopher , Motzer Robert John
Published: March 2020

4569

Background: A phase III randomized clinical trial (COMPARZ) comparing pazopanib vs sunitinib for treatment of advanced renal cell carcinoma demonstrated similar efficacies but different safety profiles for the two therapies. Elevations in serum total bilirubin have been observed in patients receiving either therapy. UGT1A1 polymorphisms are associated with elevated bilirubin in the general population (Gilbert’s syndrome). This study investigated the association between functional UGT1A1 polymorphisms and on-therapy serum total bilirubin in the COMPARZ study. Methods: Patients homozygous or compound heterozygous for UGT1A1 *28, *37, and *6 alleles were predicted to have reduced UGT1A1 function. Logistic regression adjusted for ancestry principal components was used to compare patients with on-therapy hyperbilirubinemia (≥1.5 × upper limit of normal [ULN]; pazopanib, N = 62; sunitinib, N = 34) against patients exposed to treatment and with maximum on-therapy bilirubin ≤1 × ULN (pazopanib, N = 213; sunitinib, N = 215), excluding patients with maximum on-therapy bilirubin between 1 and 1.5 × ULN (pazopanib, N = 96; sunitinib, N = 104). Results: Patients with predicted reduced UGT1A1 function had higher baseline bilirubin and also were more likely to experience hyperbilirubinemia when receiving either pazopanib (P = 6.9×10–8) or sunitinib (P = 1.8×10–3). After adjusting for baseline bilirubin, patients with predicted reduced UGT1A1 function remained more likely to experience hyperbilirubinemia when receiving pazopanib (P = 0.015) or sunitinib (P = 0.026), with odds ratio (95% CI) 3.53 (1.28–9.76) and 4.41 (1.23–15.75), respectively. Conclusions: The data suggest that some instances of hyperbilirubinemia in patients treated with pazopanib or sunitinib may be benign manifestations of Gilbert’s syndrome. Bilirubin fractionation or, if not available, UGT1A1 genotyping, would enable further characterization of liver safety risk and help in making treatment decisions.
Multiplexed tissue protein assay as a predictor of response to targeted therapy in advanced renal cell carcinoma.
Authors: Vaishampayan Ulka N. , Derrien-Colemyn Alexandrine , Hong Ye , Sethi Seema , Chen Wei , Dickow Brenda , Gillespie John Williams , Smith Daryn W. , Tunon Peter
Published: March 2020

4577

Background: A number of prognostic biomarkers have been explored in advanced renal cancer, but to date none have been useful in therapeutic outcome prediction. Methods: Following regulatory approval, formalin-fixed paraffin embedded (FFPE) pre-therapy (sunitinib and/or mTOR inhibitors) tissue samples and clinical data on kidney cancer patients (pts) were obtained. The FFPE tissue was analyzed using layered immunohistochemistry which allows analysis of multiple biomarkers using a single tissue section. Multiplexed panels of protein biomarkers were used to probe tissue sections for proteins along the PI3K/AKT/mTOR and/or the VEGFR/PDGFR signaling pathways. Expression of biomarkers in tumor tissue was scored and predictive scores which correlated with the pt’s clinical outcome status generated. Results: Tissue samples of 51 pts treated with sunitinib (S)were analyzed. A predictive score was generated by combining the scores assigned to VEGFR1 and VEGFR2 and multiplying the sum with the score of VEGFA. A predictive score equal to or above 24, was associated with response or stable disease (SD) at 12 weeks. Patients with a score <24 were predicted to have progression (PD) on S. Using this scoring method, 27 of the 33 responders tested and 15 of the 18 non responders were accurately identified. The accuracy of the test was noted to be 82.6% and sensitivity and specificity were 81.8% and 83.3% respectively. Tissue samples of 33 pts treated with mTOR inhibitor were analyzed using the same technique. Three biomarkers in the mTOR pathway (pmTOR (Ser 2448), p4EBP1 (Ser 65), p4EBP1 (Thr 37-46)) were used to create a predictive score. Eight of 12 OR/SD pts (sensitivity 67%) and 17 of 21 PD pts (specificity 76%) were accurately predicted using a score cut-off of 6 for an accuracy of 71.5%. Statistical modeling, results of ongoing validation testing, and score correlation with time to progression will be presented. Conclusions: These results indicate that an assay based on multiplexed protein analysis of tumor tissue is capable of providing clinically applicable information to help guide therapy. Funding source: Supported in part by NCI BRIDGE Grant 5R44CA123994-06 and by NCI SBIR Contract No. HHSN261201000135C.
Overcoming sunitinib-induced resistance by dose escalation in renal cell carcinoma: Evidence in animal models and patients.
Authors: Pili Roberto , Adelaiye Remi , Miles Kiersten Marie , Ciamporcero Eric , Sotomayor Paula , Bjarnason Georg A.
Published: March 2020

4582

Background: Sunitinib is considered a first-line therapeutic option for patients with advanced clear cell renal cell carcinoma (ccRCC). However, despite the clinical efficacy, eventually tumors develop resistance and progress. Thus, we have tested the hypothesis whether sunitinib dose-escalation could overcome initial drug resistance. Methods: Human patient-derived ccRCC xenografts were implanted in SCID mice and were randomly assigned into two groups (sunitinib and vehicle). Mice were treated with sunitinib 5 days/week with a dose-escalation schema starting from 40 mg/kg to 60 mg/kg and 80 mg/kg. Tumor volumes and body weights were assessed weekly. Tumor tissues and blood were collected prior to dose increments. In selected patients treated with 50 mg sunitinib and presenting minimal toxicities, dose was escalated to 62.5 and 75 mg at the time of tumor progression. Results: Our preclinical results show that patient-derived tumors (RP-01 and RP-02), although initially responsive to sunitinib 40 mg/kg, eventually became resistant to treatment. Following dose increase to 60 mg/kg, we observed again tumor response but eventually the tumors became resistant. A similar effect was noticed when we further escalated sunitinib to 80 mg/kg. Immunohistochemistry analysis shows decreased tumor vascularization during response to sunitinib, but then hypervascularization at the time of resistance. Associated increase in expression of the methyltransferase EZH2, the histone marks H3K27me3, H3k4me2 and H3K9me2 in tumors resistant to sunitinib was observed. Analysis of sunitinib and VEGF/VEFGR2 blood and tumor levels will be reported. In parallel, our clinical experience shows that intra-patient sunitinib dose-escalation was safe and clinical benefit was observed. Details on tumor responses and toxicities will be reported. Conclusions: Overall, our results suggest that sunitinib-induced resistance may be overcome in part by increasing the dose of the VEGF receptor tyrosine kinase inhibitor in mouse models and ccRCC patients, and highlights the potential role of epigenetic changes associated with sunitinib resistance.
Phase II trial of vandetanib in Von Hippel-Lindau-associated renal cell carcinoma.
Authors: Stamatakis Lambros , Shuch Brian , Singer Eric A. , Nix Jeffrey , Truong Hong , Friend Julia C. , Fowler Sarah , Bratslavsky Gennady , Metwalli Adam R. , Shih Joanna H. , Linehan W. Marston , Srinivasan Ramaprasad
Published: March 2020

4584

Background: Germline mutations in the von Hippel Lindau (VHL) gene are associated with the development of bilateral multifocal clear-cell renal cell carcinoma (RCC). VHL patients with localized disease are surgically managed, with nephron sparing resection recommended once tumors reach 3 cm. Patients typically undergo multiple surgeries with significant cumulative morbidity. In this phase 2 trial of vandetanib, a dual VEGFR2/EGFR inhibitor, a systemic approach to these tumors was explored. Methods: Patients with VHL-associated RCC were treated with 300 mg vandetanib daily until disease progression or unacceptable toxicity. Cross sectional imaging was performed at baseline and every 12 weeks. The primary endpoint was overall renal tumor response assessed by RECIST. Results: A total of 34 subjects were enrolled, with a mean age of 47 years (range 28 – 72). The median number of targeted lesions per subject was 2 (range 1 – 6) and the mean tumor diameter was 2.3 cm (range 1.2 – 4.0). Twenty-seven (80%) subjects had baseline imaging and at least one follow-up study to allow response evaluation. Median time on study was 6.1 months (range 1.0 – 23.3). Thirteen (38%) subjects demonstrated overall reduction in tumor burden with a median reduction of 6% (range 4-54%). One (3%) subject had a PR by RECIST and 26 (77%) had stable disease as their best response. Eleven (32%) subjects were taken off study due to growth of at least one lesion that met criteria for surgical resection or disease progression. Nine (27%) subjects required dose reductions due to toxicity. Although the majority of adverse events encountered on trial were grade 2 or less, 9 (27%) subjects were taken off trial due to drug-related toxicities and 9 (27%) withdrew due to intolerable side effects. Rash (71%), and QTc prolongation (41%) were the most common adverse events noted. Conclusions: In the largest phase II study of a systemic agent for VHL-related RCC, vandetanib demonstrated anti-tumor activity. Despite a reasonable safety profile, poor tolerability necessitated drug withdrawal in a significant proportion of patients. Newer agents that selectively target the VEGF receptors may offer a more tolerable alternative and might optimize clinical benefits in this population. Clinical trial information: NCT0056695.
Double-blind randomized trial of aflibercept versus placebo with docetaxel and prednisone for treatment of metastatic castration-resistant prostate cancer (mCRPC).
Authors: Tannock Ian , Fizazi Karim , Ivanov Sergey , Thellenberg-Karlsson Camilla , Flechon Aude , Skoneczna Iwona Anna , Orlandi Francisco Jorquera , Gravis Gwenaelle , Matveev Vsevolod , Bavbek Sevil E. , Gil Thierry , Viana Luciano S. , Aren Osvaldo , Karyakin Oleg , Elliott Tony , Birtle Alison J. , Magherini Emmanuelle , Petrylak Daniel Peter , Tombal Bertrand , Rosenthal Mark ,   VENICE Investigators
Published: March 2020

5002

Background: Docetaxel/prednisone is standard first-line chemotherapy for men with mCRPC. Aflibercept is a recombinant human fusion protein that binds A and B isoforms of Vascular Endothelial Growth Factor and Placental-derived Growth Factors, thereby inhibiting angiogenesis. Methods: We performed an international double-blind randomized trial (known as VENICE) which recruited men with mCRPC, adequate organ function and no prior chemotherapy. Men were treated with docetaxel (75mg/m² intravenously every 3 weeks) and oral prednisone (5mg twice daily) and randomized 1:1 to receive aflibercept (6 mg/kg) or placebo, intravenously every 3 weeks. The primary endpoint was overall survival: 873 deaths were required to detect a hazard ratio (HR) of 0.8 with 90% power. Results: A total of 1,224 men were randomized, 612 in each arm. Median age was 68 years and baseline characteristics were well balanced between arms. Participants received a median of 8 (aflibercept) and 9 (placebo) cycles of therapy. Median relative dose intensity was >0.93 for aflibercept, placebo and docetaxel. At final analysis, median follow-up was 35 months and 873 pts had died. Median survival was 22.1 months (95.6% CI: 20.3-24.1 months) in the aflibercept arm and 21.2 months (95.6% CI: 19.6-23.8 months) in the placebo arm (stratified HR = 0.94; 95.6% CI: 0.82-1.08, p=0.38). Pre-defined secondary endpoints for aflibercept and placebo arms were similar, including PSA response rate (68.6% and 63.5%), time to first skeletal-related event (median: 15.3 and 15.0 months), and progression-free survival (median: 6.9 and 6.2 months). Quality of Life analysis using FACT-P and a trial-specific module will be reported. Higher incidence of grade 3-4 gastrointestinal disorders, hemorrhagic events, hypertension, fatigue, infections and fatal adverse events (5.6% vs. 3.3%) was observed in the aflibercept arm. Conclusions: Aflibercept in combination with docetaxel/prednisone given as first-line chemotherapy for men with mCRPC did not lead to an improvement in survival and added toxicity. Trial Registration: NCT00519285. Funding: Sanofi and Regeneron Pharmaceuticals, Inc. Clinical trial information: NCT00519285.
Correlation of 18F-fluoride PET response to dasatinib in castration-resistant prostate cancer bone metastases with progression-free survival: Preliminary results from ACRIN 6687.
Authors: Yu Evan Y. , Duan Fenghai , Muzi Mark , Gorelick Jeremy , Chin Bennett , Alumkal Joshi J. , Taplin Mary-Ellen , Herman Ben , Higano Celestia S. , Doot Robert K , Hartfeil Donna M , Febbo Phillip G. , Mankoff David A. ,   Department of Defense Prostate Cancer Clinical Trials Consortium and American College of Radiology Imaging Network
Published: March 2020

5003

Background: Dasatinib is a SRC kinase inhibitor that decreases bone turnover in men with metastatic castration-resistant prostate cancer (mCRPC). 18F-fluoride PET was used to evaluate differential response between normal and tumor bone to dasatinib. Methods: Patients with bone mCRPC underwent dynamic 18F-flouride PET imaging prior to and 12 weeks after dasatinib treatment. Up to 5 bone metastases with matching normal bone regions were selected for analysis by SUVmax, Ki, K1and Patlak flux. Their pre-treatment values and change from pre-treatment to post-treatment values were evaluated via generalized estimating equations to predict skeletal-related events (SRE) and via Cox proportional hazards modeling to predict progression-free survival (PFS) with Prostate Cancer Working Group 2 criteria, overall survival and time to SRE. Results: Eighteen patients treated with dasatinib underwent baseline 18F-flouride PET imaging; 12 had follow-up scans allowing assessment of changes due to therapy. Median age for all patients was 69 (range 48-86) years. Significant decrease in SUVmax (p=0.0002) occurred in bone metastases with dasatinib while significant increases in Patlak flux (p=0.0033) occurred in normal bone. Significant differences in changes from tumor bone compared to normal bone in response to dasatinib were noted for SUVmax (p<0.0001). Of 18 patients, 17 have either met progression criteria or death by the time of this analysis. Decrease in tumor bone SUVmax (p=0.019), Ki(p=0.022), and Patlak flux (p=0.034) from pre-treatment to post-treatment correlates with longer PFS. Conclusions: 18F-fluoride PET indicates differential effect of dasatinib on tumor compared to normal bone in men with mCRPC. In patients undergoing pre- and post-dasatinib 18F-fluoride PET imaging a decrease in bone mCRPC fluoride uptake in response to treatment correlates with PFS. Clinical trial information: NCT00936975.
Prolaris: A novel genetic test for prostate cancer prognosis.
Authors: Brawer Michael K. , Cuzick Jack M. , Cooperberg Matthew R. , Swanson Gregory P. , Freedland Stephen J. , Reid Julia E. , Fisher Gabrielle , Lanchbury Jerry S. , Gutin Alexander , Stone Steven , Carroll Peter ,   Transatlantic Prostate Group
Published: March 2020

5005

Background: The natural history of prostate cancer is highly variable and difficult to predict. Improved tools are needed to match treatment more appropriately to a patient’s risk of progression. Therefore, we developed an expression signature composed of genes involved in cell cycle progression (Prolaris) and tested its utility in prostate cancer. Methods: We developed an expression signature composed of 31 cell cycle progression and 15 housekeeper genes. An expression score (Prolaris score) was derived as the mean of all cell cycle progression genes. The signature was tested at disease diagnosis in two conservatively managed cohorts from the UK (N=337 and 349), after radical prostatectomy in two cohorts from the U.S. (N=366 Scott & White Hospital, TX and 413 USCF, CA), and after external beam radiation therapy (N=141) in a cohort from Durham VA Medical Center. All studies were retrospective. Results: The cell cycle progression signature was a highly significant predictor of outcome in all five studies. In conservatively managed patients, the Prolaris score was the dominant variable for predicting death from prostate cancer in univariate analysis (p = 6.1 x 10-22 after diagnosis by TURP, and p = 8.6 x 10-10 after diagnosis by needle biopsy). In both studies, the Prolaris score remained highly significant in multivariate analysis making it a stronger predictor of disease-specific mortality than other prognostic variables. After prostatectomy, Prolaris predicted biochemical recurrence (BCR) in univariate analysis (S&W p = 5.6 x 10-9; UCSF p= 2.23 x 10-6) and provided additional prognostic information in multivariate analysis (S&W p = 3.3 x10-6; UCSF 9.5 x10-5). After radiation therapy, Prolaris predicted BCR (Phoenix) in univariate (p=0.0017) and multivariate analysis (p=0.034). In all five studies the HR per unit change in the Prolaris score was remarkably similar, ranging from 1.89 to 2.92, indicating that the effect size for the Prolaris score is robust to clinical setting and patient composition. Conclusions: The Prolaris test predicts prostate cancer outcome in multiple patient cohorts and diverse clinical settings. In all cases, it provides information beyond clinicopathologic variables to help differentiate aggressive from indolent disease.
Effect of corticosteroid (CS) use at baseline (CUB) on overall survival (OS) in patients (pts) receiving abiraterone acetate (AA): Results from a randomized study (COU-AA-301) in metastatic castration-resistant prostate cancer (mCRPC) post-docetaxel (D).
Authors: Montgomery Robert B. , Kheoh Thian San , Molina Arturo , Li Jinhui , Bellmunt Joaquim , Ryan Charles J. , Tran Namphuong , Loriot Yohann , Efstathiou Eleni , Scher Howard I. , De Bono Johann Sebastian
Published: March 2020

5014

Background: CS have been used to mitigate mineralocorticoid-related effects and restore sensitivity to AA (Attard et al., J Clin Oncol. 2008). Prednisone (P) was also used as an active comparator in the COU-AA-301 (de Bono et al., N Engl J Med. 2011) and COU-AA-302 (Ryan et al., N Engl J Med. 2013) AA pivotal studies. CUB has also been reported to adversely influence OS in the AFFIRM study, which may reflect an influence on disease biology or unrecognized factors that are not a part of clinically based prognostic models (Scher et al., Ann Oncol. 2012). This post hoc exploratory analysis investigated whether CUB is a prognostic factor for OS in mCRPC post-D pts treated with AA + P or P alone. Methods: COU-AA-301 is a randomized double-blind study of AA (1 g) + P (5 mg po BID) vs placebo + P in mCRPC post-D. The primary endpoint was OS. All pts had received CS with D therapy. CUB included P (n = 272), dexamethasone (n = 107), and others (n = 110). 797 pts were not on CUB. Median times were estimated by the product-limit method; Cox model was used to obtain the hazard ratio (HR) and associated confidence interval (CI). Results: Pts with CUB had worse baseline disease characteristics (including adverse ECOG PS, Gleason score, analgesic score, and LDH) (all p < 0.05). Pts receiving CUB had inferior OS; AA + P improved OS independent of CUB. (Table). CUB was an independent prognostic factor in multivariate analysis (p = 0.03; HR 1.22 [95% CI: 1.02-1.45]) that was associated with lower baseline androgen levels (p < 0.0001). In a stepwise selection model, CUB was not an independent prognostic factor. Conclusions: In this study, CUB was not a strong independent prognostic factor in mCRPC post-D pts treated with AA + P or P alone. CUB was associated with worse baseline disease characteristics and inferior OS in this study, in which all pts subsequently received CS. Clinical trial information: NCT00638690. [Table: see text]
Safety of radium-223 dichloride (Ra-223) with docetaxel (D) in patients with bone metastases from castration-resistant prostate cancer (CRPC): A phase I Prostate Cancer Clinical Trials Consortium Study.
Authors: Morris Michael J. , Hammers Hans J. , Sweeney Christopher , Antonarakis Emmanuel S. , Cho Steve Y. , Pandit-Taskar Neeta , Jacene Heather , Bloma Marianne , Aksnes Anne-Kirsti , O'Bryan-Tear C. Gillies , Carrasquillo Jorge A.
Published: March 2020

5021

Background: Ra-223, a first-in-class α-emitting pharmaceutical, targets bone metastases (mets) with high-energy α-particles of very short range (< 100 µm). D is an approved chemotherapy with demonstrated survival benefit for patients progressing after castrating hormone therapy. We are exploring the hypothesis that simultaneously targeting the tumor and the bone is clinically superior to targeting either alone. We therefore conducted a phase I study of Ra-223 + D in patients with CRPC and bone mets to establish the safety of the combination. Methods: Eligible patients had confirmed symptomatic CRPC with ≥ 2 bone mets and were candidates for treatment with D. Dose escalation followed a 3 + 3 design, with no intrapatient dose escalation or overlapping of cohorts. Patients were to receive 2 combined doses of Ra-223 q6wk + D q3wk (cohort 1: Ra-223/D = 25 kBq/kg /75 mg/m2; cohort 2: Ra-223/D = 25 kBq/kg /60 mg/m2; and cohort 3: Ra-223/D = 50 kBq/kg /60 mg/m2). Dose-limiting toxicity was assessed 6 weeks after first Ra-223 + D injection. Long-term safety data were collected every 3 months after end of study treatment for up to 1 year after start of study treatment. Results: 17 patients were treated, 7 each in cohorts 1 and 3 (1 patient in each cohort discontinued early and was replaced), and 3 in cohort 2. There was no discontinuation or delay of Ra-223 due to adverse events, and so far no reports of long-term toxicity during follow-up. 4 cases of febrile neutropenia occurred during study treatment (12 wk): 3 occurred in cohort 1 (1 was 7 days after first Ra-223 + D, and 2 were in the same subject, both occurring 1 wk after first and second doses of D alone [wk 4 and 10]); 1 occurred in cohort 3, 1 week after second Ra-223 + D (wk 7). Other safety data were as expected based on Ra-223 and D monotherapy data. Conclusions: The phase IIa regimen of Ra-223 + D utilizes a regimen of D 60 mg/m2 q3wk × 10 + Ra-223 50 kBq/kg q6wk × 5. The regimen is currently being explored in a randomized 2:1 open-label expanded safety cohort comparing Ra-223 + D versus D 75 mg/ m2 alone (standard dose). Clinical trial information: NCT01106352.
Impact of prostate cancer national guidelines on brachytherapy monotherapy practice patterns.
Authors: Tseng Yolanda Diana , Paciorek Alan T , Martin Neil E , D'Amico Anthony Victor , Cooperberg Matthew R. , Nguyen Paul Linh
Published: March 2020

5024

Background: In 1999, the American Brachytherapy Society (ABS) recommended brachytherapy monotherapy (BT) be limited to low-risk prostate cancer, in part because a high-impact 1998 publication suggested that intermediate or high-risk disease had worse outcomes with BT than with external beam radiation (EBRT) or radical prostatectomy (RP). We studied temporal patterns of BT use before and after the 1999 ABS published guidelines as compared with 4 other treatment options. Methods: A retrospective analysis was performed of all men with T1c-T3cN0M0 prostate cancer treated definitively in the United States from 1990 to 2011 in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry. Logistic regression was used to estimate adjusted odds ratios (AOR) comparing BT use with other treatment groups between the 1990-1998 and 1999-2011 periods, controlling for age, disease characteristics, and clinic site type. Results: 8128 men received BT (n=1117), BT+EBRT (n=313), EBRT alone (n=596), EBRT+androgen deprivation therapy (ADT, n=613), or RP (n=5489) for modified D’Amico low (n=3506), intermediate (n=2938) or high-risk (n=1684) disease. By t-tests, BT patients were younger than either EBRT or EBRT+ADT patients (both p<0.001), older than RP patients (p<0.001), and had lower risk disease than men in any of the four treatment groups (all Cochran-Mantel-Haenszel chi-square p<0.001). BT comprised 6.1% and 16.6% of all treatments in 1990-1998 and 1999-2011, respectively (Pearson p<0.01). The odds of BT use remained increased after adjusting for potential confounders (AOR 4.50, p<0.001). Increased BT use was seen only among low (AOR 5.06, p<0.001) and intermediate-risk patients (AOR 4.59, p<0.001). Among men with low or intermediate-risk disease, BT use increased compared with EBRT (AORLOW 10.00; AORINT 12.66, both p<0.001), EBRT+ADT (AORLOW 2.90, p=0.0037; AORINT 2.15, p=0.0041) and RP (AORLOW 4.76; AORINT5.10, both p<0.001). Conclusions: Despite national guidelines to the contrary, brachytherapy monotherapy for intermediate-risk prostate cancer increased over time relative to other treatments. Further studies are needed to identify factors that contribute to this evidence-practice gap.
NCIC CTG, IND-205: A phase II study of PX-866 in patients with recurrent or metastatic castration-resistant prostate cancer (CRPC).
Authors: Hotte Sebastien J. , Eisenhauer Elizabeth A. , Joshua Anthony Michael , Kumar Vikaash , Ellard Susan , Gregg Richard William , Macfarlane Robyn Jane , Winquist Eric , Torri Vamsee , Ruether Joseph D. , Basappa Naveen S. , Kakumanu Ankineedu Saranya , North Scott A. , Kollmannsberger Christian K. , Tinker Anna , Mirchandani Deepu , Tassignon Aurelie , Hausman Diana Felice , Allan Alison L , Chi Kim N. ,   NCIC Clinical Trials Group
Published: March 2020

5042

Background: PX-866 is an irreversible, pan-isoform inhibitor of Class I PI-3K. Mutations in PIK3CA and loss of PTEN activity lead to activation of AKT signaling; alterations in these genes occur frequently in prostate cancers while activation of the PI-3K/AKT signaling pathway is implicated in prostate cancer progression and treatment resistance. Hence, novel inhibitors of the pathway such as PX-866 are of interest. Methods: In this multicenter, two-stage, phase II study, docetaxel-naïve CRPC pts received PX-866, 8mg daily on a 6-week cycle. Primary endpoint was lack of progression at 12 weeks (PCWG2 criteria). Secondary endpoints included PSA and objective response rates and change in circulating tumor cells (CTC) during treatment. If ≤5 of the first 20 pts were progression free at 12 weeks, the study would stop. Otherwise, 40 pts would be accrued and PX-866 deemed worthy of further study if ≥16 pts were progression free at 12 weeks. Results: 43 pts were accrued after the criteria to progress to stage 2 were met. Median age was 70, ECOG PS was 0/1/2 in 27/15/1 pts, 23 pts had measurable disease, 24 patients had CTC ≥5. Median number of cycles was 2 (range 1–8). Most common adverse events (AE) were diarrhea (27 pts), nausea (25), fatigue (15), vomiting (13), anorexia (15) and grade 1 hypomagnesemia (11); 7 pts discontinued because of toxicity (3 GI, 3 LFTs, 1 fatigue). Grade 3 AEs were diarrhea (5 pts), AST/ALT elevation (4), fatigue (3). 11 patients were progression free at 12 weeks. 16 of the 24 pts with measurable disease were evaluable for response; there were no objective responses but 10 pts had stable disease (2.6-13.9m). One pt had a confirmed PSA response. CTC favorable conversion (from 5 at baseline to <5) was observed in 6/24 evaluable patients (25%). Correlative studies are ongoing. Conclusions: PX-866 is well tolerated and showed modest activity in CRPC but did not meet a priori benchmarks for further development as a single agent in unselected patients. As androgen receptor inhibition promotes PI3K activity in PTEN-loss PC models, the addition of PX-866 in pts whose PSA is rising on abiraterone may reverse resistance and phase B of the study is underway to test this hypothesis clinically. Clinical trial information: NCT01331083.
A randomized phase II trial of sipuleucel-T with concurrent or sequential abiraterone acetate (AA) plus prednisone (P) in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Small Eric Jay , Lance Raymond S. , Redfern Charles H. , Millard Frederick E. , Gardner Thomas A. , Karsh Lawrence Ivan , Dawson Nancy Ann , McCoy Candice , Stubbs Andrew , DeVries Todd , dela Rosa Corazon P. , Sheikh Nadeem A. , Shore Neal D.
Published: March 2020

5047^

Background: Sipuleucel-T and AA + P are FDA-approved for asymptomatic/minimally symptomatic mCRPC. Suppression of the androgen axis can be immunostimulatory and AA suppresses circulating androgen levels; AA plus sipuleucel-T may therefore be synergistic. However P used with AA, which may be immunosuppressive, has not been studied with concurrent sipuleucelET and could impair sipuleucel-T production and/or immunologic response. P11-3 (NCT01487863) is the 1st study to evaluate the combination of sipuleucel-T and AA + P Methods: Patients (pts) with asymptomatic/minimally symptomatic mCRPC were randomized (1:1) to sipuleucel-T (3 infusions at approx 2-wk intervals) with up to 26 wks of AA + P (AA 1000mg QD + P 5mg BID) starting 1 day after the 1st sipuleucel-T infusion (concurrent, arm A) or at 10 wks following the 1st sipuleucel-T infusion (sequential, arm B). Endpoints included the effect of AA + P on product (sipuleucel-T) characteristics eg antigen presenting cell (APC) activation, measured as CD54 upregulation (primary endpoint), APC (measured as CD54+ cells) and total nucleated cell (TNC) counts, as well as safety and immunologic responses. Results: 31 pts in arm A and 32 pts in arm B completed sipuleucel-T treatment by the interim analysis (Nov 2012). Baseline characteristics were similar in the 2 arms. 60/63 pts received all 3 infusions of sipuleucel-T. No significant differences in median cumulative APC activation, APC count or TNC count were seen between the arms. Increased CD54 upregulation with the 2nd and 3rd treatments were indicative of a prime boost effect in both arms. Similar profiles of antigen-specific humoral and cellular immune responses were generated with no difference in magnitude of response between the arms (p>0.05). The incidence of adverse events (AEs) and serious AEs was similar in both arms. Conclusions: These data suggest sipuleucel-T can be successfully manufactured during concurrent AA + P. Product potency and prime boost effect were similar to sipuleucel-T alone. Immune responses and AEs were similar in both arms. It is not known if sipuleucel-T will provide similar efficacy with concurrent or sequential AA + P. Clinical trial information: NCT01487863.
Detecting lower in addition to the highest Gleason score prostate cancer on core biopsy and the risk of prostate cancer-specific mortality.
Authors: Aizer Ayal A. , Phillips John , Chen Ming-Hui , Zhang Danjie , Loffredo Marian , D'Amico Anthony Victor
Published: March 2020

5051

Background: We evaluated the risk of prostate cancer-specific mortality (PCSM) following definitive treatment in men with at least one prostate biopsy core with a Gleason score (GS) lower than the highest GS identified. This pattern termed “ComboGS” in a concurrent submission was shown to be associated with a significant reduction in the odds of upgrading at radical prostatectomy (RP). Methods: In this validation cohort 666 men with localized or locally advanced prostate cancer, men were diagnosed via a transrectal, ultrasound-guided needle prostate biopsy (median 6, IQR 5-6 cores) and treated definitively between 1989-2000 with either RP or radiation (RT) or RT and hormones (HT) at a regional radiation oncology center. Patients could be referred into this center from 6 community based hospitals in Southeastern Massachusetts and Rhode Island. Community based pathologists from these 6 health care facilities assigned the biopsy GS used for the analyses in this study. Multivariable competing risks regression was performed (Table) to assess the impact of ComboGS on the risk of PCSM adjusting for age, established PC prognostic factors, and treatment. Results: After a median follow up of 4.6 years (IQR 2.5-6.7 years), 168 men (25.2%) died, 41 (24.4%) of PC. ComboGS was associated with a decreased risk of PCSM (Adjusted Hazard Ratio (AHR) 0.40, 95% Confidence Interval (CI) 0.19-0.85, p=.017). Estimates of PCSM were significantly lower in men with versus without ComboGS when the highest GS was ≥7 (p<.001) but not 6 or less (p=.71). Specifically these 5-year estimates were 14.4% and 4.8% versus 1.9% and 2.7% respectively. Conclusions: In addition to lower odds of upgrading at RP, using an independent data set the ComboGS assessed by community based pathologists serving 6 hospitals was found to also be associated with a decreased risk of PCSM. [Table: see text]