bluuebunny/crossref_metadata_2025_split huggingface dataset:
Checkpoint inhibitors in metastatic renal cell carcinoma patients including elderly subgroups: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Authors: Yip Steven , Wells Connor , Moreira Raphael Brandao , Wong Alex , Srinivas Sandy , Beuselinck Benoit , Porta Camillo , Sim Hao-Wen , Ernst D. Scott , Rini Brian I. , Yuasa Takeshi , Basappa Naveen S. , Kanesvaran Ravindran , Wood Lori , Canil Christina M. , Kapoor Anil , Fu Simon Yuen Fai , Choueiri Toni K. , Heng Daniel Yick Chin 
Published: September 2018

4580 Background: Immuno-oncology (IO) checkpoint inhibitor treatment outcomes are poorly characterized in the real world metastatic renal cell cancer (mRCC) patient population, including geriatric patients. Methods: Using the IMDC database, a retrospective analysis was performed on mRCC patients treated with IO, as listed below. Patients received one or more lines of IO therapy, with or without a targeted agent. Duration of treatment (DOT) and overall response rates (ORR) were calculated. Cox regression analysis was performed to examine the association between age as a continuous variable and DOT. Results: 312 mRCC patients treated with IO were included. In patients who were evaluable, ORR to IO therapy was 29% (32% first-, 22% second-, 33% third-, and 32% fourth-line treatment (Tx)). Patients treated with second-line IO therapy were divided into favorable, intermediate, and poor risk using IMDC criteria; the corresponding median DOT rates were not reached (NR), 8.6 mo, and 1.9 mo, respectively (p<0.0001). Based upon age, hazard ratios were calculated in the first- through fourth-line therapy setting, ranging from 1.03 to 0.97. Conclusions: The ORR to IO appears to remain consistent, regardless of line of therapy. In the second-line, IMDC criteria appear to appropriately stratify patients into favorable, intermediate, and poor risk groups for DOT. Premature OS data will be updated. In contrast to clinical trial data, longer DOT is observed in real world practice. Age may not be a factor influencing DOT. [Table: see text]
Incidence of T3a upstaging and survival after partial nephrectomy: Size-stratified rates and implications for prognosis.
Authors: Srivastava Arnav , Patel Hiten , Kates Max , Schwen Zeyad , Joice Gregory , Semerjian Alice , Pierorazio Phillip M. , Gorin Michael A. , Allaf Mohamad 
Published: September 2018

4588 Background: The use of partial nephrectomy (PN) to treat renal cell carcinoma has grown in the past decade, with expansion to larger tumors. Performing PN for larger tumors may increase the number of patients up-staged to pT3a after surgery, who may have underwent radical nephrectomy (RN), if known preoperatively. We aimed to estimate the proportion of patients up-staged to T3a disease after PN, stratified by size. We also compared size-stratified survival of up-staged pT3a patients to those with T1a, T1b, or T2 disease. Methods: From 1998 – 2013, we identified patients undergoing PN or RN from the Surveillance Epidemiology and End Results registries. The proportion of patients receiving PN found to have pT3a disease was quantified by size. Cox proportional hazards models compared cancer-specific (CSS) and overall survival (OS) for PN patients with pT1a, pT1b, and pT2 disease to size-stratified pT3a patients. Also, we compared PN patients with pT3a disease to RN patients with pT3a disease. Results: From the 28,854 patients undergoing PN, the estimated proportion up-staged to pT3a increased along with tumor size: 4.2% for T1a, 9.5% for T1b, and 19.5% for T2. Among those receiving PN, survival analysis showed worse CSS for up-staged pT3a patients versus stratified pT1a (HR = 1.87, p = 0.02), pT1b (HR = 1.91, p = 0.01), and pT2 (HR = 2.33, p = 0.01) patients. When assessing OS, only in tumors < 4cm did the pT3a cohort demonstrate worse OS (HR = 1.25, p = 0.04). Comparing PN and RN for pT3a disease, size-adjusted analysis revealed no difference in CSS or OS. Lastly, among pT3a patients undergoing PN, patients with larger tumors, measuring 4 – 7cm (OS: HR = 1.44, p = 0.04) or 7 – 16cm (OS: HR = 2.64, p < 0.01), had worse survival than those with tumors < 4cm. Conclusions: A greater proportion of patients experience T3a up-staging after PN with increasing initial T stage. Up-staged pT3a patients have worse CSS after PN compared to those with similarly sized localized tumors. Also, pT3a patients after PN showed similar survival to pT3a patients after RN. However, pT3a patients undergoing PN had worse survival with increasing tumor size, reinforcing the need for improvements in identifying patients at risk of up-staging.
A randomized phase II cross-over study of abiraterone + prednisone (ABI) vs enzalutamide (ENZ) for patients (pts) with metastatic, castration-resistant prostate cancer (mCRPC).
Authors: Chi Kim N. , Annala Matti , Sunderland Katherine , Khalaf Daniel , Finch Daygen , Oja Conrad D. , Vergidis Joanna , Zulfiqar Muhammad , Beja Kevin , Vandekerkhove Gillian , Gleave Martin , Wyatt Alexander William 
Published: September 2018

5002 Background: ABI and ENZ are indicated as 1st line therapy for mCRPC but have not been directly compared. Optimal sequencing of these agents has not been prospectively evaluated and predictive biomarkers are lacking. Methods: Multicenter, phase 2 study randomizing treatment-naïve mCRPC pts to ABI vs ENZ, with cross over at PSA progression. Primary endpoints: response and time to PSA progression (TTPP, PCWG3 criteria) after 2nd line therapy. Reported here are secondary endpoints: PSA ≥50% decline (PSA50) from baseline, TTPP with 1stline therapy, and correlation with deep targeted sequencing of 73 mCRPC genes in circulating tumor DNA (ctDNA). Results: Accrual completed October 2016 with 202 pts randomized (ABI:ENZ = 101:101). Median follow-up 12.8 months. Baseline characteristics were similar between arms: median for age was 75 years (range 49-94), PSA 36.1 (1.7-2817), HGB 130 (89-165), ALK PHOS 105 (31-6600), LDH 207 (77-3098). ECOG PS was 0-1 in 83%, presence of metastases in bone/liver/lung in 83%/6%/10%. With 1stline therapy for ABI vs ENZ, PSA50 at 12 weeks was 53% vs 73% (P = 0.004), no PSA decline occurred in 21% vs 15% (P = 0.243), and median TTPP was 7.4 vs 8.0 months (HR = 0.88, 95% CI 0.61, 1.27). Baseline ctDNA fraction was >2% in 60% of patients, and associated with worse TTPP (HR 1.80, P=0.005). Baseline pathogenic ctDNA alterations in AR, TP53, RB1, and DNA repair (BRCA2, ATM) genes were associated with a shorter TTPP (univariate analysis: TABLE). On multivariate analysis including clinical factors, TP53 and BRCA2/ATM alterations remained significant (HR = 2.54 (95%CI 1.55-4.19) and HR = 2.68 (1.58-4.54)). Pts with a PSA increase as best response were enriched for alterations in DNA repair (P <0.001), TP53 (P = 0.005), RB1 (P = 0.04), and (in 1 pt) a genomically truncated AR. Conclusions: There was a difference in PSA response for 1stline ABI vs ENZ, but no difference for TTPP. Baseline pathogenic ctDNA alterations, particularly in TP53 and BRCA2, identify pts with poor outcomes. Clinical trial information: NCT02125357. [Table: see text]
Whole exome sequencing (WES) of circulating tumor DNA (ctDNA) in patients with neuroendocrine prostate cancer (NEPC) informs tumor heterogeneity.
Authors: Beltran Himisha , Romanel Alessandro , Casiraghi Nicola , Sigouros Michael , Benelli Matteo , Xiang Jenny , Demichelis Francesca 
Published: September 2018

5011 Background: We recently identified mechanisms underlying the clonal evolution of castration-resistant prostate adenocarcinoma (CRPC-Adeno) to a neuroendocrine resistance phenotype (Beltran et al, Nat Med 2016). We aimed to develop a non-invasive approach to identify patients that are developing NEPC. Methods: We performed whole exome sequencing of matched ctDNA, germline DNA, and metastatic biopsies from patients with CRPC-Adeno and NEPC. After applying ad hoc partial duplication filtering, we used FACETS and extended CLONET to calculate the fraction of tumor DNA and clonality of genomic lesions. Results: 64 CRPC patients were prospectively enrolled. The spectrum of alterations captured by WES of ctDNA was consistent with those commonly observed in CRPC validating the feasibility of the approach. The similarity of copy number alterations between tumor tissue and ctDNA was higher in NEPC compared to CRPC-Adeno (p = 0.0001) suggesting less heterogeneity in NEPC. There was enrichment of RB1 and TP53 loss in NEPC ctDNA and ARgains in CRPC-Adeno. The overall fraction of mutations shared by ctDNA and tumoral tissue was ~80%. We compared three different tumor biopsy time-points of patient PM161—CRPC-Adeno (lymph node), CRPC-Adeno (bone), NEPC (liver). Unexpectedly the baseline ctDNA profile (at time of CRPC-Adeno) displayed genomic features most similar to the NEPC liver biopsy. These data suggest that NEPC alterations are detectable in the circulation potentially prior to the development of NEPC clinical features. We compared the ctDNA of another patient PM0 with 6 sites of NEPC metastases obtained 6 days later at autopsy; the relative contribution of tumor alterations in ctDNA was highest for the liver metastasis (similarity 0.59) versus other sites suggesting differential contribution of metastatic sites in the circulation, with implications for the interpretation of single site clinical biopsies. Conclusions: This is the first study to show that WES of ctDNA is feasible in CRPC and can help elucidate intra-patient heterogeneity and identify the spectrum and frequency of NEPC genomic changes. ctDNA may improve the detection of patients transforming towards NEPC.
Impact of timing of administration of bone supportive therapy on pain palliation from radium-223.
Authors: Yap Kelly Khai Li , Wong William , Ji Lingyun , Groshen Susan G. , Quinn David I. , Pinski Jacek K. , Bryce Alan Haruo , Dorff Tanya B. 
Published: September 2018

5023 Background: Skeletal-related events (SREs) drive morbidity in patients with metastatic castration-resistant prostate cancer (mCRPC). In the ALSYMPCA study, Radium-223 (Ra223) was found to palliate pain in addition to prolonging survival and reducing SREs. Earlier onset of pain relief was noted when zoledronic acid (ZA) was administered within 24-48 hours of samarium; we evaluated whether the timing of bone supportive therapy (BST) affected pain palliation fromRa223. Methods: We identified patients who received Ra223 at University of Southern California or Mayo Clinic Arizona. Data extracted: Ra223 administration dates, pain scores, pain medications, ZA or denosumab administration dates, alkaline phosphatase (ALP) levels, prostate specific antigen (PSA) levels, and concurrent prostate cancer therapy. Patients were evaluable for pain response if they had at least 2 pain scores documented before and after Ra223 with pain medication use data. Pain response was defined as > 2 point decrease in pain on a 10 point scale; flare was defined as > 2 point increase followed by return to baseline or lower. Results: Of 65 patients, 20 had baseline pain score > 0 and 34 were evaluable. Median #doses Ra223 was 5 (range 2-6). 18 patients received concurrent abiraterone (abi) or enzalutamide (enza), 16 did not. Pain response occurred in 6/6 (100%) patients who received BST within 1 month prior to first Ra223 dose and 4/8 (50%) patients who did not receive BST. Pain flare occurred in 6/21 patients (29%) without BST and 2/13 (15%) with BST. 6/10 (60%) patients with pain response had ALP decline but there was no consistent pattern of ALP changes in patients with flare. 8/8 patients with pain response had no PSA decline (6 increased, 2 stable). 6/12 (50%) and 2/22 (9%) patients on abi/enza had pain response and flare respectively, and 4/8 (50%) and 6/19 (32%) patients without concurrent abi/enza had response/flare. Conclusions: BST within 1 month prior to first Ra223 may be associated with increased likelihood of pain palliation and may prevent pain flare. PSA/ALP changes do not predict pain response. Concurrent use of abi/enza does not increase the likelihood of pain response and may decrease the likelihood of flare.
Rovalpituzumab tesirine (Rova-T) as a therapeutic agent for Neuroendocrine Prostate Cancer (NEPC).
Authors: Puca Loredana , Sailer Verena , Gayvert Kaitlyn , Isse Kumiko , Sigouros Michael , Nanus David M. , Tagawa Scott T. , Mosquera Juan Miguel , Saunders Laura , Beltran Himisha 
Published: September 2018

5029 Background: TheNotch ligand Delta like ligand 3 (DLL3) is aberrantly expressed on the cell surface of small cell lung cancer (SCLC), and the DLL3-antibody drug conjugate, Rova-T, has shown promise for patients with SCLC (Rudin et al, Lancet Onc 2017). NEPC is a late stage subtype of castration resistant prostate cancer with limited therapeutic options. Based on clinical and molecular similarities with SCLC, we investigated expression of DLL3 and the use of Rova-T in NEPC. Methods: We evaluated mRNA and/or protein expression of DLL3 in a cohort of 395 patients (535 samples) ranging from benign prostate (BEN), localized prostate adenocarcinoma (PCA), castration resistant adenocarcinoma (CRPC), and NEPC and correlated with pathologic and genomic features. Prostate cancer cell lines and patient-derived organoids were treated with Rova-T (SC16LD6.5) in vitro and in vivo. Results: DLL3 was expressed at the mRNA and/or protein level in 0/143 BEN (0%), 4/266 PCA (1%), 8/76 CRPC (10%), 33/50 NEPC (66%). DLL3 IHC was of higher intensity in NEPC and co-localized with classical NE marker expression (SYP, CGA). DLL3 was amongst the most differentially expressed genes by RNA-seq in NEPC versus CRPC (p = < 0.0001, fold change = 71), correlated with ASCL1 expression (r = 0.88) and RB1 genomic loss (83%), and inversely with AR expression. Although treatment with the Notch inhibitor DAPT suppressed Notch target gene expression in NEPC, DAPT did not have significant effect on cellular proliferation. siRNA knockdown of DLL3 or DAPT did not alter AR signaling or NE markers. Rova-T (SC16LD6.5) was active in DLL3-positive NEPC cell lines with an IC50 of 580pM compared to the control IgG1LD6.5 (IC50 = 6.3nM), whereas CRPC lines were insensitive. Conclusions: DLL3 is a cell surface protein aberrantly expressed in the majority of NEPC and a subset of CRPC, and is not expressed in primary prostate cancer or benign tissues. The DLL3 antibody-drug conjugate Rova-T demonstrates preferential preclinical activity in NEPC compared to prostate adenocarcinoma. These data support further investigation of Rova-T as a potential therapeutic agent for NEPC. A phase I trial with dedicated NEPC arm is currently accruing patients (NCT02709889).
Circulating tumor cell subsets and macrophage polarization to predict efficacy of cabozantinib in advanced prostate cancer with visceral metastases.
Authors: Posadas Edwin M. , Chen Jie-Fu , Tripathi Manisha , Lu Yi-Tsung , Montes Alexander , Go Ann , Ureno Alexander , Cavassani Karen Angelica , Sievert Margarit , Rogatko Andre , Limvorasak Suwicha , Oppenheim Amy , Moldawer Nancy P. , Chung Leland WK , Bhowmick Neil , Tseng Hsian-Rong , Figlin Robert A. 
Published: September 2018

5031 Background: The presence of VM in metastatic, castration-resistant prostate cancer (mCRPC) predicts poor survival. Cabozantinib (cabo) is a multi-kinase inhibitor that has clinical activity that did not improve survival in an unselected mCRPC population. Subgroup analyses suggested that the benefit may exist for patients (pts) with mCRPC-VM. The effect of cabo includes the tumor microenvironment, monocytes in particular, which in turn can alter tumor behavior. Methods: We conducted a single-arm study of cabo in men with mCRPC-VM. Pts received cabo 60 mg daily. Radiographs were used to assess response. Correlative blood samples were collected for the enumeration and characterization of circulating tumor cells using the NanoVelcro Assay and analysis of circulating monocytes by FACS. Results: A total of 17 pts enrolled with 16 evaluable for response. At 12 weeks, 19% experienced partial responses (PR), 44% stable disease (SD), and 38% progressive disease. The clinical benefit rate (PR+SD) at 12 weeks was 63%. Safety profile was consistent with previous reports. CTCs were detected in 80% of pts. NanoVelcro CTC counts showed reduction by week 8 in both PR+SD (88%) and PD (71%) groups with re-emergence at progression. Among pts with liver metastases, very-small-nuclear CTCs ( < 8.5 μm) were seen in 29% of pts with clinical benefit compared to 60% in non-benefiters. Analysis of monocyte polarization after initiation of therapy showed that reduction of M1 polarization was associated with improvement in bone pain and/or bone scan. Conclusions: In heavily-pretreated mCRPC-VM, cabo provided clinical benefit with acceptable toxicity. Circulating biomarkers related to both tumor and microenvironment may be useful in identifying patients who benefit from this type of therapeutic approach. Clinical trial information: NCT01834651.
Avelumab in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Fakhrejahani Farhad , Madan Ravi Amrit , Dahut William L. , Bilusic Marijo , Karzai Fatima , Cordes Lisa M , Strauss Julius , Schlom Jeffrey , Gulley James L. 
Published: September 2018

5037 Background: Despite recent progress, mCRPC remains a lethal disease. While programmed cell death 1 (PD-1) and PD-1 ligand (PD-L1) inhibitors have shown activity in variety of cancers, to this point there is minimal evidence of activity in mCRPC. This is a report of avelumab, anti-PDL1 in mCRPC patients (pts). Methods: This is an expansion cohort of the first in human, phase I trial (JAVELIN Solid Tumor; EMR100070-001) that evaluated 10 mg/kg of avelumab in pts with mCRPC who had progressive disease (PD) on previous treatment. Pts who had PD on an androgen receptor antagonist (ARA) could enroll on trial and continue their ARA. Avelumab was administered as a 1-hour intravenous infusion every 2 weeks (w) with restaging scans every 6 w. Prostate cancer working group 2 criteria were used to determine PD. Results: 18 patients were enrolled on this cohort; the median age of pts was 67 years. Median on study PSA was 11ng/mL. 11 pts had Gleason score (GS) ≥ 8 and 7 had GS of 7. 3 pts had previous chemotherapy with docetaxel, 8 pts received previous vaccine treatment including 4 pts with sipuleucel-T and 4 pts with Prostvac. Overall avelumab treatment appears safe and tolerable. 15 pts experienced grade ≤ 2 treatment related adverse events (TRAEs), fatigue being the most common one. 4 pts developed treatment related hypothyroidism, 3 with grade 2 and 1 with grade 1. In addition, 2 pts had grade 3 asymptomatic TRAEs (amylase & lipase elevations). 7 pts had stable disease (SD) > 24 w post treatment, 6 pts had PD after first restaging scans at 6 w which was reconfirmed in 2nd restaging scan at 12 w. PSA doubling time (PSADT) prior to avelumab was compared with PSADT after 3 months (m) of treatment. Among 17 pts with available data, 3 pts had a prolonged PSADT which was defined at 3 m (twice as high as on-study PSADT), 7 pts had stable PSADT and 7 had decreased PSADT. 5 of 18 pts enrolled while on enzalutamide with a rising PSA. Among these pts 1 had prolonged PSADT, 2 had a stable PSADT and 2 with decreased PSADT after 3 m of follow up. 3 of 5 pts had SD > 24 m, 1 had SD for 13 w and 1 had PD at first restaging scans. Conclusions: These data provide safety data of avelumab on a population of pts with mCRPC. Immune analysis is under way to determine correlation with immune responses in the pts on this trial that had prolonged SD. Clinical trial information: NCT01772004.
A phase II trial of abiraterone acetate (AA) without prednisone in castration resistant prostate cancer (CRPC).
Authors: McKay Rana R. , Werner Lillian , Jones Alexandra , Choudhury Atish Dipankar , Pomerantz Mark , Sweeney Christopher , Bubley Glenn J. , Slovin Susan F. , Morris Michael J. , Kantoff Philip W. , Taplin Mary-Ellen 
Published: September 2018

5040 Background: AA blocks CYP17 and suppresses adrenal androgens and glucocorticoids. Given the risk of mineralocorticoid excess (ME), AA is administered with corticosteroids. In this phase II multicenter, single-arm study, we assess the safety of AA without steroids in CRPC. The primary objective is to determine the proportion of men requiring prednisone to manage ME. Methods: Eligible patients had CRPC with controlled blood pressure (BP) ( < 140/90 on ≤3 agents) and a normal or ≥3.5 mmol/L potassium. Patients initially received AA (1000 mg daily) alone. Patients who developed a BP ≥ 140/90 were treated with anti-hypertensives (HTN) and/or a mineralocorticoid antagonist (MA) prior to steroids. Hypokalemia was treated with supplementation or a MA. Patients with persistent or severe ME were initiated on prednisone (5 mg twice daily). To assess response to steroids, prednisone was added to AA at PSA progression. Therapy was continued until radiographic progression, toxicity, or withdrawal. Results: 60 patients were enrolled of whom 51 (83%) had metastases 16 (27%) received prior chemotherapy, 6 (10%) enzalutamide, and 4 (7%) ketoconazole. Grade (G) 3-4 adverse events (AEs) of interest included HTN (G3 n = 8, 13%; G4 n = 1, 2%), hypokalemia (G3 n = 4, 7%; G4 n = 0), fatigue (G3 n = 1, 2%; G4 n = 0). There was no G ≥3 edema. 9 patients (15%) initiated prednisone for toxicity: HTN (n = 3, 5%), hypokalemia (n = 4, 7%), fatigue (n = 2, 3%). Baseline PSA was 15.4 ng/mL. Time to nadir PSA was 2.5 months (IQR 1.4, 6.3) and median nadir PSA was 2.1 ng/mL. 67% of patients (n = 40) experienced a ≥50% PSA decline and 35% (n = 21) experienced a ≥90% decline. 19 patients (32%) initiated prednisone for PSA progression. Median time to prednisone initiation in patients with PSA progression was 6.1 months (IQR 4.9, 11.7); 5 patients (8.3%) had a PSA decline and 1 achieved a ≥50% decline. Levels of corticosteroids will be reported. Conclusions: In CRPC, AA without steroids is feasible, however clinically significant AEs, particularly HTN, can occur in a minority of patients. HTN and hypokalemia can be treated with anti-HTN agents or potassium without steroids in the majority. Use of AA without prednisone needs to be balanced with the potential risk of toxicity. Clinical trial information: NCT02025010.