bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term survival update of the Scandinavian Prostate Cancer Group 6 study: Bicalutamide 150 mg daily versus placebo in hormone-naïve, non-metastatic prostate cancer.
Authors: Thomsen Frederik Birkebæk , Brasso Klaus , Christensen Ib Jarle , Johansson Jan-Erik , Angelsen Anders , Tammela Teuvo L. J. , Iversen Peter
Published: February 2017

2

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

201

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

203

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

209

Background: Predictive markers of response to AA are not known. In a prior study, we found that 8 single nucleotide polymorphisms (SNPs) from 4 candidate hormone-related genes (JAK2, TRMT11, NKX3-1 and HSD17B12) were associated with response to AA in HSPC in a North American cohort of 519 subjects. We attempt to replicate these findings in a cohort of Portuguese patients. Methods: The Portuguese cohort consisted of 308 HSPC patients, and the primary endpoint was time to AA failure, defined as time from initiating continuous AA to two serial PSA increases over the nadir, initiation of chemotherapy for progressive disease, or clinical or imaging based progression, whichever came first. For each SNP, we calculated hazard ratios (HRs) and 95% confidence intervals (CI) for time to AA failure using a recessive model with adjustment for Gleason score (GS). Results: The median age of the Portuguese cohort was 69 years (range 43, 85). The GS distribution was 35% subjects with GS≥8; 35% with GS=7 and 30% with GS<7. Median time to AA failure for the cohort was 1.8 years (IQ range: 0.3, 3.6). Association of each SNP with time to AA failure is shown in the Table. None of the SNPs replicated. However, there was a suggestive inverse association for rs10503733 (NKX3.1) with time to AA failure (P=0.07). Conclusions: While we were not able to replicate our initial findings, there was an unexpected association with rs10503733 (NKX3.1 gene) that may warrant additional clinical validation. [Table: see text]
Novel live tumor cell diagnostic test utilizing biophysical and molecular biomarkers to assess local, advanced, and metastatic prostate cancer.
Authors: Knopf Kevin B. , Manak Michael S. , Su Wendell R. , Meyyappan Thiagarajan , Min Andrew , Saphirstein Robert J. , Hogan Brad J. , Whitfield Matt J. , Varsanik Jonathan S. , Foroohar Mani , Kella Naveen , Hernandez Ray , Rieger-Christ Kimberly M. , Sullivan Travis B. , Rashid Hani H. , Mouraviev Vladimir , Albala David , Chander Ashok C. , Sant Grannum R.
Published: February 2017

211

Background: Over-treatment of prostate cancer affects 144,000 patients annually in the U.S. due to the inaccuracy of current diagnostics for risk stratification. Functional molecular and biophysical biomarkers combined with clinically actionable diagnostic platforms are used for evaluating the local invasiveness and metastatic potential of cells derived from biopsy. Such a diagnostic test may improve patient outcomes in low-to high-risk prostate cancers according to D’Amico’s definition. This study describes the development of a novel phenotypic diagnostic using a set of biomarkers measured with a proprietary live cell assay coupled with innovative machine vision algorithms for patient tumor samples using a unique microfluidic platform. Methods: We assessed 60 prostate cancer samples collected post radical prostatectomy (RP). We report the assay details for culturing live tumor cells ex vivo, enabling automated imaging of phenotypic biomarkers. The test is designed to sustain survival of prostate tumor cells from fresh biopsy/surgical samples for up to three days prior to analysis of phenotypic characteristics. Results: We show that this test distinguishes live normal and tumor cells via molecular and biophysical biomarkers. The primary biomarkers are calculated using objective machine vision algorithms and are used to derive secondary metrics termed “Metastatic Potential (MP) and Oncogenic Potential (OP)”. In comparing clinical measures with results of this test, concordance analysis show that OP and MP are statistically significant in distinguishing between Gleason 6 and Gleason 7 with 85% sensitivity and 80% specificity. Conclusions: This phenotypic diagnostic generates scoring metrics of MP and OP that correlate with 1) aggressive vs. indolent Gleason 6, 2) seminal vesicle invasion, 3) occurrence of margins after RP, 4) lymph node invasion and 5) systemic metastatic process. These results will further help stratify patient tumors to improve clinical decision-making in low to intermediate- and high-risk prostate cancer populations, and potentially avoid unnecessary surgery or radiation, ultimately leading to improved patient quality of life.
Activity of new agents (NAs) as third-line treatment in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) showing a primary resistance (PRes) to NAs-based second line therapy after docetaxel (DOC): Preliminary results from a multicenter Italian study.
Authors: Caffo Orazio , De Giorgi Ugo , Facchini Gaetano , Fratino Lucia , Gasparro Donatello , Basso Umberto , Alesini Daniele , Tucci Marcello , Ortega Cinzia , Verderame Francesco , Procopio Giuseppe , Lo Re Giovanni , Campadelli Enrico , Omarini Claudia , Donini Maddalena , Morelli Franco , Zucali Paolo A. , Sartori Donata , Conteduca Vincenza , Galligioni Enzo
Published: February 2017

216

Background: The androgen receptor machinery remains the ultimate target of NAs in mCRPC post-DOC, abiraterone acetate (AA), cabazitaxel (CAB), and enzalutamide (ENZ). It is postulated that some mechanisms of resistance may be common to all NAs. This may be crucial in planning their sequential use, mainly when a PRes to one of them is observed. The present study assessed the activity of NAs in pts who previously experienced a PRes to another NA administered after DOC. Methods: We collected data of pts who received sequentially two NAs after DOC in 32 Italian hospital. For each pt we recorded the clinical outcomes of all treatments received after DOC. For the study purpose, we consider with PRes all pts progressing within 3 months after second line NA start. All other pts were considered as without PRes. Results: A consecutive series of 271 mCRPC pts, median age 71 yrs (46-91), with bone (89%), nodal (56%) or visceral (19%) mets, was collected. All pts received NAs as second line after DOC (AA 54% – CAB 34%– ENZ 12%) and 54 (20%) showed a PRes. Among these, third line treatment [AA (31%), CAB (42%), and ENZ (27%)], produced a biochemical and an objective response rate of 11% in both cases, with a median progression free survival (PFS) and a median overall survival (OS) of 4 mos and 8 mos, respectively. No statistically significant differences were observed in terms of clinical outcomes on the basis of NA sequences (see Table). Conclusions: It appears from this preliminary data, that the activity of NAs in pts showing a PRes to second line NAs is very limited, regardless the NA is administered. [Table: see text]
Pathologic correlation of 89Zr-Df-IAB2M antiprostate-specific membrane antigen (PSMA) minibody in patients with metastatic prostate cancer.
Authors: Morris Michael J. , Solomon Stephen Barnett , Durack Jeremy C. , O' Donoghue Joseph A. , Lyashchenko Serge K. , Shutian Ruan , Carrasquillo Jorge A. , Lewis Jason Stuart , Martinez Danny F. , Parada Nicole A. , Keppler Jennifer , Wu Anna , Reuter Victor E. , Weber Wolfgang , Scher Howard I. , Larson Steven M. , Pandit-Taskar Neeta
Published: February 2017

220

Background: IAB2M is a novel anti-PSMA minibody (Mb) based on the humanized J591 antibody that targets the extracellular domain of PSMA. The Mb has been engineered to remove Fc-Rn interactions and reduce the molecular weight relative to J591. The result is faster blood pool clearance, for a more favorable imaging schedule, while retaining bivalent targeting of PSMA. We have previously reported on the pharmacokinetics, dosimetry, and lesion uptake of IAB2M(Pandit-Taskar et al, WMIS 2014). Here we report the correlation between imaging and pathology of biopsies of PSMA avid lesions. Methods: Following standard imaging (SI) of CT/MRI, bone scintigraphy (BS), and FDG PET, 5 mCi of 89Zr-Df-IAB2M was administered intravenously. Escalating minibody doses of 10, 20, and 50 mg were delivered, with cohort expansion at 10 and 20 mg. Whole body PET/CT scans were serially performed at various time points:1-2 h, 24 h, 48 h, and 72-144 h post injection. Metastases identified on PET were confirmed, where possible, with bx’s in the following preference: concordant IAB2M and FDG positivity, IAB2M, and FDG mismatch, or a mismatch between SI and any PET. Results: 24 patients (pts) with metastatic prostate cancer were scanned (11 at 10, 7 at 20, and 6 at 50 mg Mb doses). A total of 15 bxs (7 soft tissue, 8 bone) were performed on 14 pts; the histopathologic correlation is summarized in the table below. 13 lesions were identified by IAB2M, 11 by FDG, and 14 by SI. Of these, 12/13 (92.3%), 10/11 (90.9%), 12/14 (85.7%) were biopsy positive for cancer, respectively. 2 bone lesions were not identified by IAB2M, evident on other imaging modalities, and were both neg by bx. Overall bx concordance (pos/pos, neg/neg) with imaging was: IAB2M 14/15 (93%) vs. BS/CT 13/15 (86%) vs. FDG 12/15 (80%). Conclusions: An ongoing analysis of IAB2M imaging showed a high concordance with pathologic findings in patients with metastatic prostate cancer. Clinical trial information: NCT01923727. [Table: see text]
Dose escalation of five-fraction SABR for prostate cancer: Biochemical outcome and toxicity comparison of two prospective trials.
Authors: Musunuru Hima Bindu , Quon Harvey Charles , Zhang Liying , Cheung Patrick , Tang Colin I , Pang Geordi , Mamedov Alexandre , D'Alimonte Laura , Deabreu Andrea , Loblaw D. Andrew
Published: February 2017

224

Background: To compare the biochemical outcomes and toxicities of two different 5 fraction stereotactic ablative body radiotherapy (SABR) schedules for the treatment of localized prostate cancer. Methods: Two sequential phase I/II studies of 5-fraction SABR for the treatment of low and intermediate risk (LR and IR) prostate cancer have been conducted. In the first trial, 84 LR patients(pts) received 35 Gy in 5 fractions, once per week over 29 days (Group 1). In the second trial, 30 pts (18 LR, 11 IR) received 40 Gy in 5 fractions, once per week over 29 days (Group 2). Treatment was delivered to the prostate with intensity modulated radiotherapy using daily image guidance and a 4mm (Group 1) or 5 mm (Group 2) CTV-PTV margin. PSA nadir and bRFS(nadir+2 definition) were compared between the two groups. Acute (CTCv3.0), late (RTOG) and cumulative toxicity for late grade ≥ 2 GU/GI toxicities were also compared. Results: Median follow up was 74 (IQR 67-81) and 36 (IQR 32-39) months. Median PSA nadir was 0.4 ng/ml and 0.3 ng/ml. Time to PSA nadir was 54 and 32.5 months. 44.0% in group 1 and 30% in Group 2 experienced benign PSA bounce. There were 3 and 0 PSA failures in Groups 1 and 2. 2-, 4- and 6-year bRFS was 100%, 98.7% and 95.9% and 100%, 100% and not reached in groups 1 and 2, respectively (p=0.91). The only acute grade 3 toxicity was noticed in Group 1 (1 pt, GU). Late grade 4 GI toxicity was noted in Group 1 (1 pt, GI, fistula). Up to 4 years of follow-up, Group 2 pts have had a greater percentage of grade 2+ cumulative GU (5.0% vs 24.2%) and GI (7.6% vs 26.2%) toxicities. Conclusions: Pts receiving a dose escalated SABR had slightly lower PSA nadir and similar bRFS - longer follow up is needed to better estimate biochemical outcomes in Group 2. There seemed to be a greater risk of grade 2 toxicities in the higher dose cohort but grade 3+ toxicities were not increased. Quality of life analyses will be presented separately. Clinical trial information: NCT01578902 , NCT01146340 .[Table: see text]
Current era clinical outcomes of castration-resistant prostate cancer in real-life population study in Quebec, Canada.
Authors: Rocha Joice , Vanhuyse Marie , Aprikian Armen G. , Cury Fabio L. , Dragomir Alice
Published: February 2017

226

Background: Prostate cancer (PCa) death is mainly due to castration-resistant PCa (CRPC) which results from disease progression despite androgen ablation therapy (ADT). Little is known about clinical outcomes and trends of real-life CRPC management in the present era, which has become very complex. Our study aimed to analyze healthcare services use, clinical outcomes and survival trends in real-life management of CRPC in Quebec, Canada. Methods: The study cohort consisted of 7,123 patients which shown evidence of CRPC from January/2001 to July/2013, selected from the public healthcare insurance programs the Régie de l’Assurance Maladie du Québec (RAMQ) databases. Survival was evaluated by Kaplan-Maier and the difference in survival between pre-/post-docetaxel (Doc) (2002-2005 vs 2008-2011) era by log-rank test. The association between Doc exposure and survival was evaluated by Cox proportional hazards model adjusted for several co-variables. Results: Chemotherapy was offered to 17% of patients, while 45% were kept on maximal androgen blockade (MAB) alone, or offered Abiraterone (3%). Androgen targeted therapies (MAB or Abiraterone) were the treatment of choice for the elderly population (mean age 78.8 and 78 ±7, respectively) while chemotherapy was offered to younger patients (mean age 72 ±7.3). Survival rates at 1 and 2 years after the initiation of chemotherapy were 52% and 26% in post-Doc era vs 46% and 17% in the pre-Doc period. In patients receiving first line chemotherapy only, hospitalization due to PCa was a poor prognostic predictor (HR: 2.0; 95%CI: 1.5-2.6), as expected. In addition among patients without previous hospitalization the risk of death was higher in the pre- vs post-Doc era (HR: 1.7 CI: 1.003-2.851). Conclusions: Patient age seems to be a strong determinant in CRPC therapy selection. In patients without serious complications leading to hospitalization, survival was greatly improved in the post-Doc era. Our data also supports that patients older than those in the TAX327 trial (72 vs 68) may equally benefit from chemotherapy. This is encouraging as we hope to observe comparable results for new approved therapies for CRPC.
Treatment patterns of new metastatic castration-resistant prostate cancer (mCRPC) therapies: Real-world evidence from three datasets.
Authors: Ellis Lorie , Lafeuille Marie-Helene , Gozalo Laurence , Lefebvre Patrick , Malangone-Monaco Elisabetta , Wilson Kathleen , Foley Kathleen A. , McKenzie R. Scott
Published: February 2017

228

Background: Little information exists regarding the sequences in which new mCRPC therapies with evidence of survival benefits are used. This study aims at describing the sequence of mCRPC medication use as observed in 3 healthcare datasets. Methods: Healthcare claims datasets (Dataset #1 and #2) and a community oncology electronic medical record (Dataset #3) were used to identify PC patients with ≥ 1 claim for a study drug (abiraterone acetate--AA, cabazitaxel--CAB, docetaxel – DOC, enzalutamide – ENZ, and sipuleucel T – SIP) occurring after 9/1/2012. The index date was the 1st study drug claim. Patients were excluded if a study drug claim occurred prior to 9/1/2012. Descriptive statistics summarized the proportion of patients receiving one vs. two or more lines of therapy. The prevalence of 1st line therapy and of 1st to 2nd-line sequences was analyzed. Results: Analysis of 3 unique datasets with > 5,900 PC patients revealed most patients received a single line of therapy. AA and DOC were the most common 1st line agents. The five most-prevalent 1st- to 2nd-line sequences identified in each database are shown in the table below. The most commonly observed 1st- to 2nd-line sequences were AA-ENZ, AA-DOC, and DOC-AA. Conclusions: Real world treatment selection for 5 mCRPC medications was consistent across 3 datasets. The majority of PC patients had a prescription/claim for a single agent. AA and DOC were the most commonly selected 1st line treatments. A 2nd-line agent was observed in 14-33% of patients. Similar patterns of 1st-2nd line sequences were observed between datasets. Further research is warranted with longer follow-up and consideration of other treatment interventions. [Table: see text]
Pharmacokinetics, activity, and safety of ODM-201 in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer: An open-label phase I trial with long-term extension.
Authors: Massard Christophe , Penttinen Heidi , Bono Petri , Vjaters Egils , Lietuvietis Vilnis , Tammela Teuvo L. J. , Vuorela Annamari , Nykänen Pirjo , Pohjanjousi Pasi , Fizazi Karim
Published: February 2017

230

Background: The open phase I trial, ARAFOR, with long-term extension evaluated pharmacokinetics (PK), antitumor activity and safety of ODM-201 in chemotherapy-naïve patients with progressive mCRPC. Methods: PK phase: Patients received one 600 mg dose of ODM-201 capsules (6 x 100 mg) in fed state and one dose of either tablet formulation (TabA or TabB, 2 x 300 mg) in fed and fasted state in random order. Extension: Patients received ODM-201 600 mg (capsule) twice daily until disease progression/ intolerable adverse event (AE). A data cut-off date Apr 4, 2014 was used for analyses. Results: 30 patients were enrolled in PK and treated in the extension phase. Baseline characteristics: median age 68 yrs, ECOG score 0 in 67%, and ECOG 1 in 33% patients, median PSA 18.2 ng/mL. Median time from PC diagnosis to start of ODM-201 treatment was 39 months. Median time on ODM-201 treatment was 9.5 months (trial is on-going). ODM-201 plasma concentration–time curves were similar for the capsule, TabA, and TabB at fed state. Median tmax at fed state was longer than in fasted state (5–6 h vs. 4 h). Absorption was slower and plasma exposure about 2-fold greater at fed state compared to fasted state (AUCt, AUC¥ and Cmax values). All 30 patients completed the first 12 weeks of the extension phase. Prostate-specific antigen (PSA) responses (≥50% reduction from baseline) were seen in 25 (83%) patients (PSA reductions ≥90% in 9 [30%] patients). At 12 weeks, RECIST responses in soft tissue were noted in 6 patients (29%) and stable disease in 13 (62%) patients, 3 (11%) had improvement in skeletal metastases and 18 (67%) stabilised bone disease. 21 (70%) reported at least 1 AE, and treatment-related AEs occurred in 6 (20%) patients. No treatment-related AEs of grade 2 or higher were reported. Conclusions: Tablet and capsule formulations showed comparable single-dose pharmacokinetics. Dose level of 600 mg twice daily (capsule) showed significant antitumor activity and had a favourable safety profile. Updated results from the extension phase will be presented. A phase 3 ARAMIS trial at a dose of 600 mg twice daily in men with non-metastatic CRPC is currently ongoing. Clinical trial information: NTC01784757.
Identification of susceptibility loci in hereditary prostate cancer families using copy number variation and linkage analysis.
Authors: Ledet Elisa M. , Bailey-Wilson Joan , Sartor Oliver , Li Marilyn M. , Mandal Diptasri
Published: February 2017

232

Background: Family history is one of the most significant predictor of prostate cancer risk. With approximately 10% of prostate cancer cases attributable to inheritable genetic factors. However, disease gene identification for prostate cancer has been extremely challenging due to both disease and genetic heterogeneity. Therefore, the goal of this study was to employ an array of genetic tools in order to characterize germline variants in seven high-risk families with prostate cancer. Methods: To overcome the effects of ethnic disparity, genetic heterogeneity, incomplete penetrance, and missing heritability, we utilized a comprehensive approach that combines both array comparative genomic hybridization (aCGH) analysis and linkage analysis to identify genetic components of prostate cancer. Seven prostate cancer cases were studied using aCGH to search for germ-line copy number variants (CNVs) associated with hereditary prostate cancer. The study subjects were from 7 large, high-risk, clinically homogenous families with European ancestry from Southern Louisiana. Genotyping for linkage analyses was done using Illumina Infinium II SNP HumanLinkage-12 panel. Results: Three novel regions of CNVs were identified: 16q23, 11q22, and 2q22 in all 7 prostate cancer cases from high-risk families. Both model-based and model-free linkage analyses were performed on 4 of the most informative families (≥5 prostate cancer patients per family). Suggestive evidence of linkage was obtained at 2q14 (HLOD score of 1.94). Using aCGH, a 68 kb duplication was observed in this region in all 7 hereditary prostate cancer cases. Conclusions: These genetic findings, which were identified in multiple large, well-characterized families, provide new insight into hereditary prostate cancer. A combination of future fine mapping of the 2q14 region in a larger cohort of patients, confirmation of these novel CNVs in additional subjects, and use of next-generation sequencing approaches to search for potential disease-associated genetic alterations are needed to provide further characterization of these prostate cancer associated susceptibility loci.
Next-generation sequencing of circulating exosomal RNA from metastatic castrate-resistant prostate cancer patients.
Authors: Ledet Elisa M. , Gambhira Ratish , Dotiwala Aryeneesh , Mandal Diptasri , Sartor Oliver
Published: February 2017

233

Background: PCa has proven to be an extraordinarily complex disease, with both genetic and phenotypic heterogeneity. Exosomes are membranous nano-sized (50-100nm) vesicles derived from both normal and tumor cells, and function in cell-to-cell communication. These vesicles and their nucleic acid cargo may serve as a peripheral biomarker for genetic risk assessment of PCa prognosis and therapeutic response. The goal of this study was to characterize exosome derived RNA (exoRNA) isolated from blood of metastatic CRPC patients. Methods: Blood samples from 18 consented clinically annotated mCRPC patients and 1 normal control; exosomes were isolated with ultracentrifugation and exoRNA extracted. Following library prep, paired-end sequencing was performed using Illumina Hi-Seq 2000. A bioinformatics pipeline was used for data pre-possessing including alignment, duplicate removal, normalization and variant calling. Visualization and differential analyses were performed with SNP & Variation Suite v8.x. Results: Through preliminary analyses we identified 39 genes commonly expressed in the exosomes of these mCRPC patients. These include PDPK1, USP9X, MAGI2, HMGA2 and PTGFR all of which have been previously expressed in prostate cancer. In exoRNA there is evidence of extensive chromosomal rearrangement resulting in a myriad of gene fusions and isoforms. A diverse variety of lcnRNA, ncRNA and miRNA were also identified in circulating exosomes. Differential expression analyses will be presented. PCR validation is ongoing. Conclusions: The identification of PCa associated transcripts in blood derived exosomes provide evidence that exosomes and exosomal cargo may serve as biomarker in CRPC patients. Exosomes and exoRNA may provide otherwise unattainable insight into tumor evolution and disease progression. Additional studies evaluating the clinical relevance and prognostic value of exosomal RNA will be critical for biomarker development.
Characterization of therapies and timelines for men with prostate cancer-specific mortality.
Authors: Steinberger Allie E. , Ledet Elisa M. , Luk Eric , Cotogno Patrick , Stolten Michael , Desmond Daniel , Silberstein Jonathan L. , Sartor Oliver
Published: February 2017

239

Background: Careful study of treatments in men with prostate cancer (PCa)-specific mortality is scant in non-trial settings. We sought to examine the characteristics and use of selected therapies in men dying from PCa, beginning from the time of diagnosis. Unique herein is the unequivocal attribution of PCa death by a single experienced clinician. Methods: Patients dying from PCa at Tulane Cancer Center from 2008 to 2014 (n=96) were studied through retrospective chart reviews. All patients died of metastatic, castrate-resistant disease (mCRPC). Results: The median age at diagnosis for the deceased cohort was 66 years (95% CI: 64-68 years); 29% of patients initially presented with metastatic PCa. 59% of patients had definitive primary therapy (radical prostatectomy or radiation). Though most men died prior to availability of the newer FDA-approved agents, patients received a median of 7 (range: 1-14) therapies. Median survival was 60 months (95% CI: 45.8-74.2 mo) after diagnosis with a median PSA pre-death of 171 (range: 0-3530) and median age at death of 73 years (95% CI: 71-75 years). At death, 4% of men had a PSA < 4 and 20% of men had a normal LDH (< 241 U/L). Distant metastatic disease at diagnosis was a significant predictor of death (HR=4.33, p<0.001) while definitive primary therapy was a significant predictor of survival (p<0.001). Median survival for patients presenting with metastases was 39 months (range: 5-213) compared to 82.5 months (range: 6-269) for localized disease (p < 0.001). Definitive therapy, vs. none, was associated with a median survival of 81.5 months vs. 47 months (p<0.001). Of the cohort, 48% received docetaxel before death; 49% received abiraterone, 10.4% received enzalutamide, 13.5% radium-223 and 15.6% sipuleucel-T. The only significant difference between docetaxel and non-docetaxel groups was median age of diagnosis at 62 and 71, respectively (p=0.002). Conclusions: This retrospective analysis provides initial views that clarify characteristics of men dying from PCa as well as the therapies they received before death. More data is needed in multi-institutional settings to confirm these findings. Given the evolving landscape for mCRPC treatments, therapeutic choices will change over time.
Antiandrogen withdrawal (AAWD) in patients (pts) with prostate cancer (PCa): Retrospective analysis of data from the South Australian Prostate Cancer Clinical Outcome Collaborative (SA-PCCOC).
Authors: Vatandoust Sina , Kichenadasse Ganessan , O'Callaghan Michael E , Kopsaftis Tina , Walsh Scott , Borg Martin , Karapetis Christos Stelios , Moretti Kim L
Published: February 2017

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Background: In 15-30% of pts with metastatic PCa who progress on Maximal Androgen Blockade (MAB), withdrawal of the antiandrogen agent (AAWD) and continuing the LHRH agonist alone, leads to PSA decreases of ≥50% and prolonged progression free survival. Here we describe patient and disease characteristics, treatment history and outcomes of pts who have been managed with AAWD. Methods: Data were obtained from SA-PCCOC (a longitudinal, observational registry of biopsy-proven PCa cases, throughout the Australian state of South Australia since 1998). Proportions were compared using a Chi squared test. A multivariable model used competing risks (Fine and Gray) and Cox proportional Hazards models to assess overall survival and Prostate cancer specific mortality (PCSM). Survival was calculated from the date of rising PSA for patients on LHRH and AA. Results: 140 pts were found to have MAB. Of these, 31(22.1%) had AAWD. In the AAWD group, median age was 81y (51-95). Age at diagnosis, Gleason score at biopsy and diagnostic PSA were not significantly different amongst the two groups. Treatment PSA was significantly lower in the AAWD group (20.55 (range 0.6-9,995) vs 50.50 (range 0.95-4378) p= 0.02). There was a significant association of AAWD with PCSM (sHR 0.35, 95% CI 0.16-0.76; p = 0.008). Also significant in the model was prior time on hormones (sHR [per month increase] 0.96 95% CI 0.95-0.98, p<0.001). There was also a significant association of AAWD with overall survival (HR 0.22, 95% CI 0.10-0.46; p <0.001). Again, prior time on hormones was also significant (HR [per month increase] 0.96 95% CI 0.95-0.98, p<0.001). Multivariate analysis was performed on data from 80 pts (60 pts omitted due to missing data). Conclusions: Pts in whom AAWD was used were older and had lower treatment PSA. In this small cohort, AAWD was associated with both reduced PCSM and overall risk of death. The time spent on MAB also appeared to be significant. This retrospective observational study may be subject to confounding, however the observation warrants further investigation in larger cohorts and in a prospective setting.
The impact of patient characteristics on voiding symptoms, irritative symptoms, and sexual function, following stereotactic body radiotherapy for prostate cancer.
Authors: Rana Zaker Hamid , Hong Robert , McRae Donald , Bernstein Gregory , Mordkin Robert , Nasr Nadim Munir
Published: February 2017

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Background: Urinary symptoms and sexual dysfunction are the two most common complaints following prostate radiotherapy. There is limited clinical data evaluating the impact of baseline patient characteristics on response to hypofractionated treatment. This study sought to evaluate how patient age and prostate size affects voiding symptoms, irritative symptoms, and sexual function, following stereotactic body radiotherapy (SBRT). Methods: This retrospective analysis includes 102 non-metastatic patients treated with SBRT at a single institution between May 2008 and September 2014. The course of radiotherapy consisted of 36.25 Gy (range 35–40) over 5 daily fractions. International Prostate Symptom Score (IPSS) and Sexual Health Inventory for Men (SHIM) were recorded at baseline, 1, 3, 6, 9, 12, 18, 24, and 36 months after treatment. Results: Median patient age was 68 years old (range 47-88) and median prostate volume was 43 cc (range 18.7-170.7). Baseline IPSS irritative score, IPSS voiding score, and SHIM score were 5.34, 5.42, and 13.55. A statistically significant increase in voiding (7.02), irritative (7.21), and decrease in SHIM score (11.77) was observed after one month (p < .05). The IPSS irritative score and IPSS voiding scores returned to baseline in >90% of patients by 9 months and SHIM scores returned to baseline in >90% of patients by 2 years. Prostate size ≤ 50 cc showed higher baseline IPSS voiding and irritative resolution rates after 3 months (p < .05). Conclusions: While an increase in IPSS irritative score, and a decrease in SHIM score initially occurred, all symptoms return to baseline within three years. Age did not affect urinary or sexual dysfunction following radiotherapy. Patients with smaller prostate volumes had significantly better voiding and irritative outcomes when compared to larger volumes.
International survey of androgen deprivation therapy (ADT) for non-metastatic prostate cancer in 19 countries.
Authors: Liede Alexander , Hallett David , Hope Kirsty , Graham Alex , Arellano Jorge , Shahinian Vahakn B.
Published: February 2017

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Background: ADT is commonly used for non-metastatic (M0) prostate cancer (PC) patients as primary therapy for high risk disease, adjuvant therapy together with radiation, or for recurrence after initial local therapy. Intermittent androgen deprivation (IAD) is a more recently developed alternative strategy for providing ADT that is thought to potentially reduce adverse effects, but little is known about practice patterns relating to it. We aimed to describe factors related to physicians' ADT use and modality for M0 PC patients. Methods: A 45-minute online survey was completed by urologists and oncologists from 19 countries with high or increasing prevalence of M0 PC. Respondents were responsible for treatment decisions for M0 PC, and had ≥10 patients on ADT. ADT comprises gonadotropin agonist (GnRH) treatment or bilateral orchiectomy. Results: 441 physicians completed the survey representing 98,689 PC patients under their care, of which 76,386 (77%) had M0 PC. Of M0-PC patients, 38% received ADT (37% GnRH, 2% orchiectomy); among patients on GnRH, 48% received continuous ADT (≥6 months [mos]), 25% IAD, and 26% <6 mos (table). Highest rates of ADT were reported among oncologists (62%) and in Eastern Europe (68%). PSA levels (65%), Gleason score (52%), and treatment guidelines (48%) were the most common reasons for continuous ADT whereas PSA levels (54%), patient request (48%), and patient age (38%) were cited most frequently as the reason for IAD. Conclusions: This international comparison showed that ADT modalities are commonly used in the treatment of M0 PC patients, and that the decision to use ADT is influenced by high risk criteria (PSA and Gleason) and treatment guidelines. IAD use is prevalent and often driven by patient choice and PSA levels. [Table: see text]
Feasibility analysis of pathology and genetic yield from a prospective trial of tissue biopsies in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Jimenez Rafael E. , Sicotte Hugues , Barman Poulami , Sinnwell Jason P. , Eiken Patrick W , Atwell Thomas D , McMenomy Brendan P , Tan Winston , Wu Kevin , Bryce Alan Haruo , Ho Thai Huu , Pitot Henry Clement , Quevedo Fernando , Costello Brian Addis , Dronca Roxana Stefania , Moynihan Timothy J. , Wang Liewei , Qin Rui , Carlson Rachel , Kohli Manish
Published: February 2017

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Background: Evaluating tumor specific pathologic and genetic profiles in mCRPC stage is difficult due to the limited availability of mCRPC tissue. We describe findings from a prospective cohort study performed to obtain concomitant histopathology and genetic information in mCRPC. Methods: Patients with mCRPC initiating abiraterone acetate therapy underwent 2 serial (3 months apart) metastatic (met) site needle core biopsies (NCB1/2). Bone lesions were biopsied using 11-13G core needles and 18G core biopsy devices were used for non-osseous masses. Up to 4 cores were obtained at each biopsy with the 1st core (S1) sent for DNA sequencing, the 2nd (S2) for RNA sequencing, and the 3rd/4th (X3, X4) submitted for xenograft implantation. From each, 1-2 mm segments were separated and formalin-fixed for histopathologic examination (HPE). Results: A total of 54 patients, enrolled between June 2013 and July 2014, underwent 94 NCB (54 NCB1, 40 NCB2), rendering a total of 259 samples (94 S1; 75 S2; 59 X3 and 31 X4) of which 85 (32%) were positive (pos) for tumor by HPE. Positivity for tumor in S1, S2, X3, and X4 cores was 42%, 33%, 22%, and 19%, respectively. At least one core pos for met tumor was observed in 62% NCB1 and 52% NCB2 (overall 52/94; 56%). Met sites biopsied include bone (71), lymph nodes (18), liver (3), penile (1) and pelvic (1) soft tissues. HPE revealed met adenocarcinoma in 44/52, and poorly differentiated carcinoma in 8/52. Gleason grade applied to the met ranged from 3+4 to 5+5. 45/85 pos samples (53%) had > 50% tumor cellularity. Pos NCB in bone lesions was observed in 23/71 (32%), compared to 17/23 (73%) of non-bone sites (p=.0004). 85 S1 samples yielded DNA material, of which 66 (77%) had ≥10% tumoral DNA. 24 cases with negative HPE had ≥10% tumoral DNA; 7 cases with pos HPE had <10 tumoral DNA. In all, 76/94 (81%) NCB yielded tumor material either by HPE or DNA analysis. Conclusions: NCB of mCRPC is feasible and provides adequate tissue for pursuing HPE and sequencing studies. HPE of extracted material correlates with DNA sequencing data and provides complementary information on tumor features. Bone lesions yield significantly less tumoral material than non-osseous sites.
Optimal sequencing of docetaxel and abiraterone in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Maughan Benjamin Louis , Suzman Daniel L. , Nadal Rosa , Bassi Sunakshi , Schweizer Michael Thomas , Antonarakis Emmanuel S.
Published: February 2017

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Background: Currently there are multiple agents approved for the treatment of mCRPC based on prolongation of life. However, it is unclear what the optimal sequencing of these therapies is to maximize clinical benefit and survival. Here, we aimed to compare clinical outcomes among men with mCRPC who received docetaxel first followed immediately by abiraterone (doce-to-abi) or the opposite sequence (abi-to-doce). Only men that were treated with sequential therapy using these two agents (i.e. without intervening treatments) were included. Methods: A retrospective review of consecutive mCRPC patients treated at Johns Hopkins was conducted. A combined PFS (PFS = PFS1 + PFS2) was the primary endpoint, measured from the start of the first therapy (i.e. doce or abi) until the time of clinical/radiographic progression on the subsequent therapy (i.e. abi or doce). Overall survival (OS) from the start of the first therapy until death was the main secondary endpoint. Multivariable regressions were performed to determine whether one sequence was better than the other (doce-to-abi versus abi-to-doce) after adjusting for a number of baseline patient and treatment characteristics. Results: In total, 86 patients were identified that met our study criteria: 53 men received doce-to-abi and 33 men received abi-to-doce. PFS was longer in the doce-to-abi cohort: median 19.1 (95% CI 13.0–27.4) mo versus 10.4 (95% CI 9.1–11.5) mo (HR 2.6, 95% CI 1.5 – 4.5). OS was also superior in the doce-to-abi cohort: median 30.3 (95% CI 25.4–44.3) mo compared to 18.2 (95% CI 14.1–21.1) mo (HR 2.3, 95% CI 1.2 – 4.1). In multivariable analyses, superior outcomes were still observed in the doce-to-abi group with respect to PFS (HR 2.77, 95% CI 1.5–5.0, P=0.0008) and OS (HR 2.8, 95% CI 1.5–5.3, P=0.0016) after adjusting for Gleason score, baseline PSA and ECOG status at study initiation. Conclusions: This hypothesis-generating study seems to suggest superior PFS and OS in men with mCRPC receiving doce followed by abi (rather than the opposite sequence). These findings are in alignment with the results of the CHAARTED trial supporting earlier docetaxel use, but require prospective validation.
Cyberknife stereotactic radiotherapy for isolated nodal recurrence of prostate cancer.
Authors: Detti Beatrice , Bonomo Pierluigi , Giacomelli Irene , Cappelli Sabrina , Poggesi Linda , Franceschini Davide , Baki Muhammed Ali Muhammed , Carini Marco , Giulio Nicita , Serni Sergio , Baldazzi Valentina , Lucia Di Brina , Mancuso Anna , Eleonora Monteleone Pasquetti , Carta Giulio Alberto , Muntoni Cristina , Ciabatti Cinzia , Livi Lorenzo
Published: February 2017

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Background: We report a preliminary clinical experience in stereotactic body radiation therapy (SBRT) delivered using Cyberknife for isolated nodal metastases from prostate cancer. Methods: Between November 2011 and December 2013, 30 patients (39 lesions) were treated with SRT for recurrent prostate cancer with isolated nodal metastases. Prescribed doses and schedules of fractionation varied according to site of disease, ranging from 24 Gy in 1 fraction to 36 Gy in 3 fractions. Most commonly used schedules were 30 Gy in 3 fractions and 36 in Gy in 3 fractions on alternating days. Biochemical response, acute and late toxicity were analyzed. Results: At a median follow-up of 12 months (range: 2-24.9), reduction of PSA ≥ 50% was observed in 18 cases, reduction < 50% was observed in 7, while PSA was stable in 1 case and raised in 8 cases. At the time of analysis, among the 30 patients treated, 2 were dead for systemic disease; 12 patients experienced a relapse of disease in other sites and were treated with HT and salvage chemotherapy. Sixteen patients were still free of disease. In 24 cases, imaging evaluation three months after treatment was available. No in field recurrence was detected, CR was detected in three cases, PR in 14 and SD in 8 patients. The treatment with Cyberknife was well tolerated: one patient experienced G2 acute genitourinary toxicity. Late toxicity was evaluated in patients with more than 3 months of follow up and only one complained G1 proctitis. We did not observe any acute or late severe toxicity (≥G3). Conclusions: Our experience shows that SRT with Cyberknife for isolated nodal relapse from prostate cancer is a safe treatment, with promising results in terms of efficacy.