bluuebunny/crossref_metadata_2025 huggingface dataset:
Fractionated dose radiolabeled anti−prostate specific membrane antigen (PSMA) radioimmunotherapy (177Lu−J591) for progressive metastatic castration−resistant prostate cancer (mCRPC).
Authors: Batra Jaspreet S. , Karir Beerinder S. , Pinto-Chengot Kavya , Jhanwar Yuliya , Vallabhajosula Shankar , Christos Paul J. , Hodes Gillian , Lam Linda , Molina Ana M. , Beltran Himisha , Nanus David M. , Goldsmith Stanley J. , Bander Neil Harrison , Tagawa Scott T.
Published: February 2017

205

Background: Phase I and II single dose 177Lu−J591 studies have been published. Based on the theoretical advantages of dose fractionation on safety and efficacy, we initiated a phase I dose−escalation study of fractionated−dose 177Lu−J591. Methods: Men with progressive mCRPC with normal neutrophil and platelet counts were enrolled. The initial portion was 3+3 dose−escalation, with 6 cohorts of 3−6 patients receiving 2 doses 177Lu−J591, 2 weeks apart starting with 20 mCi/m2, escalating to 45 mCi/m2. After determining maximum tolerated dose (MTD), patients enrolled in 2 expansion cohorts at recommended phase II doses (RP2D). Planar imaging of 177Lu−J591 at 6−8 days following the initial dose was performed. Pre− and post−treatment PSA was measured for all patients and the highest dose−level cohorts had CTC counts (CellSearch) measured before and after treatment. Results: 48 patients enrolled with median age 74 (55−95) ), median baseline PSA 45.38 (1.93−766.5), 37.5% with prior chemo. The RP2D’s of fractionated 177Lu−J591 were 40 mCi/m2 or 45 mCi/m2 x2 with option for GCSF. Overall PSA decline ≥ 50% in 9 (18.8%), ≥ 30% in 14 (29.2%) and any PSA decline in 26 (54.2%); at RP2D doses (n = 32), 8 (25%) with ≥ 50%, 12 (37.5%) with ≥ 30%, and 20 (62.5%) with any PSA decline. Of 25 with available CTC counts, 14 declined, 8 remained stably favorable, and 3 increased. Of 12 with unfavorable baseline CTC counts, 8 (66.7%) became favorable at follow up, 2 decreased by 30% and 88% but remained ≥ 5, and 2 increased; 1 converted from < 5 to ≥ 5. Thirty-five (72.9%) had grade 3/4 hematological toxicities; 19 (59.4%) with Gr 4 heme toxicity in RP2D cohorts, with 15 (16.9%) receiving at least 1 platelet transfusion, 6 receiving GCSF, and 0 with febrile neutropenia. Overall 4 had Gr 1 transaminitis and 14 (29.2%) had grade 1 infusion reactions (without pre−medication). Accurate targeting of 177Lu−J591 at known sites of disease seen in 84.4%. Conclusions: Fractionated 177Lu−J591 is well tolerated with predictable, reversible myelosuppression, achieving a higher cumulative dose than possible with a single dose. Both PSA and CTC count control was achieved. Clinical trial information: NCT00538668.
A phase II study of cabozantinib in metastatic castration-resistant prostate cancer (mCRPC) with visceral metastases (VM) with very small nuclear circulating tumor cell (vsnCTC) association studies.
Authors: Huynh Richard , Chen Jie-Fu , Tighiouart Mourad , Sievert Margarit , Oppenheim Amy , Moldawer Nancy P. , Knudsen Beatrice , Freeman Michael , Bhowmick Neil , Rogatko Andre , Tseng Hsian-Rong , Chung Leland WK , Scher Kevin , Figlin Robert A. , Posadas Edwin M.
Published: February 2017

208

Background: Cabozantinib is a multi-targeted tyrosine kinase inhibitor (TKI) that has recognized clinical activity in mCRPC. While phase 3 studies did not show a significant improvement in overall survival (OS), patients with VM had improved OS compared to those with only osseous metastases in subgroup analysis. Our group has also identified a subgroup of CTCs strongly associated with the presence of VM (Chen, Cancer 2015). We hypothesized that cabozantinib would yield clinical benefit and changes in vsnCTC counts would reflect disease behavior. Methods: This study was designed as an open label study of cabozantinib 60 mg daily, for mCRPC patients with visceral disease. The primary endpoint is clinical benefit rate (radiographic stable disease + partial response (PR) by RECIST 1.1) at 12 weeks (CBR12). Serum PSA concentrations were not used as a primary endpoint. CTCs were enumerated by NanoVelcro CTC Assay and characterized using published methods. Results: Thirteen patients have completed at least 8 weeks of treatment. In this group, 38% had pulmonary metastases; 77% had hepatic metastases; CBR12 was 92% at the time of this report. A quarter of the patients experienced a PR. Mean time to radiographic progression for responders was 38 weeks (19-57). Discordant responses were noted between VM and bone scans. Grade 3 or higher toxicities were compatible with prior studies and observed in 50% of patients. In this advanced mCRPC and relatively heavily pre-treated population, treatment discontinuation due to toxicity was 33%. Eleven of 13 patients were assessable for CTC and imaging. Of the 11 patients, 7 had vsnCTCs detected at baseline. All 7 patients reported subjective improvement that was associated with a decrease in vsnCTCs by 6-8 weeks. In patients who had a PR, no vsnCTCs were detected at 6 weeks while on active treatment. An increase in vsnCTCs was seen prior to visceral progression. Conclusions: Cabozantinib is a TKI with activity in mCRPC with visceral metastases. Toxicity is consistent with previous reports and manageable. The NanoVelcro vsnCTC assay may be a predictive marker of response. Clinical trial information: NCT01834651.
Genomic and imaging biomarkers associated with cabozantinib therapy in metastatic castrate resistant prostate cancer (mCRPC).
Authors: Vaishampayan Ulka N. , Podgorski Izabela , Heilbrun Lance K. , Smith Daryn W. , Lawhorn-Crews Jawana , Dobson Kimberlee , Fontana Joseph A. , Heath Elisabeth I. , Shields Anthony Frank
Published: February 2017

212

Background: Cabozantinib (C) is a c-met and vascular endothelial growth factor receptor inhibitor that demonstrated remarkable responses on bone scan, but failed to demonstrate overall survival benefit. We studied the dynamics of biomarker changes with imaging and biopsies pre- and post-therapy with C to explore predictors of efficacy. Methods: Eligibility included mCRPC patients (pts) with normal organ function and performance status 0-2. C 60 mg orally was administered daily. Pretherapy and 2 weeks post, 99mTc-labeled bone scans (BS), positron emission tomography with 18F-sodium fluoride (NaF-PET) and 18F-(1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl) thymine (FMAU-PET) scans were conducted. The maximum tumor standardized uptake values (SUVmax) were measured for the 5 most active lesions in at least 3 skeletal areas with each tracer. Tumor biopsies were conducted, and bone markers were measured. Results: 20 evaluable pts, 5 African American and 15 Caucasian were enrolled. Median age was 69 years, 11 had received prior chemotherapy. 16 had received prior abiraterone/enzalutamide or both.5 pts had visceral disease. 11 and 6 pts required dose reduction to the 40 mg and 20 mg daily dose respectively.8 patients had a PSA decline, of which 2 had a decline > 50%. Median PFS and OS for all 20 pts were 4.1 and 11.2 months, respectively and 3 pts were on therapy for 8, 10 and 13 months. Circulating tumor cell count changes did not correlate with PFS or OS. The NaF-PET demonstrated a median change in SUVmax of -56% (range -85 to -5%, n = 11) and -41% (range -60 to -25%, n = 9) for the pts who were clinically stable and remained on therapy for ≥ 4 or < 4 cycles, respectively. The FMAU-PET demonstrated a median change in SUVmax of -44% (-60 to -14%) and -42% (-63 to -23%) for these groups. A 50% decrease in serum BSAP was associated with a hazard ratio (HR) for progression of 0.91 (90% confidence interval [CI]: 0.71 – 1.16). For serum NTx and urine NTx, the analogous HR’s were 0.79 (90% CI: 0.61 – 1.01) and 1.07 (90% CI: 0.66 – 1.73), respectively. Conclusions: Early changes in imaging and bone markers were not predictive of clinical benefit with C. Tissue C-met testing is in process and will be correlated with PFS and OS.
Clinical accuracy of detecting recurrent prostate cancer lesions with F-18-Fluoroethylcholine or Ga-68-PSMA-HBED-CC PET/CT.
Authors: Pfister David J. K. P. , Porres Daniel , Heidenreich Axel , Behrendt Florian , Verburg Frederik
Published: February 2017

218

Background: Ga-68-PSMA-HBED-CC (PSMA) is a novel and promising tracer for highly sensitive PET/CT diagnosis in recurrent prostate cancer (PCA). The aim of the present work was to assess the sensitivity, specificity, positive and negative predictive value (PPV/NPV) per lesion as well as the positive predictive value per patient of PSMA PET/CT in patients with recurrent prostate cancer referred for surgery after a positive PET/CT and to compare this with a collective of patients scanned using the current de-facto PET/CT standard tracer F-18-Fluoroethylcholine (FEC). Methods: In this retrospective study results of PET/CTs and post-surgical histological analysis were compared. 38 patients had FEC and 27 patients had PSMA. We performed a pelvic and/or retroperitoneal lymphadenectomy, if necessary supplemented by resection of locally recurrent lesions in accordance with imaging results. Results: In 30/38 FEC and 22/27 PSMA patients at least one focus of PCA was identified in postsurgical histology, leading to a PPV of 78.9% for FEC and 81.5% for PSMA. In FEC and PSMA patients a total of 378 and 308 lymph nodes and local lesions were removed, respectively. For FEC and PSMA the respective sensitivity was 71.2% and 86.9%, specificity 86.9% and 93.1%, PPV 67.3% and 75.7% and NPV 88.8% and 96.6%. Conclusions: In the present series PSMA PET/CT shows a somewhat better performance than the current de-facto PET/CT standard tracer FEC. Due to the very high NPV of PSMA PET/CT a selective locoregional lymphadenectomy involving only the regions affected on imaging can be discussed.
Very early PSA response to abiraterone in mCRPC patients: A novel prognostic factor to predict overall survival.
Authors: Cavaliere Carla , Caffo Orazio , Ortega Cinzia , D'aniello Carmine , Cecere Sabrina Chiara , Di Napoli Marilena , Della Pepa Chiara , Crispo Anna , Maines Francesca , Ruatta Fiorella , Iovane Gelsomina , Montella Maurizio , Pignata Sandro , Facchini Gaetano
Published: February 2017

219

Background: In the last years the therapeutic scenario of mCRPC has undergone a radical change with the approval of new drugs. AA is approved for the treatment of mCRPC after failure of ADT in whom chemotherapy (CT) is not yet clinically indicated and for treatment of mCRPC progressed on or after docetaxel (DTX) based chemotherapy. The aim of this study is to evaluate the role of early PSA decline as a marker of response for an early detection of therapy success in mCRPC patients treated with AA. Methods: We retrospectively evaluated 87 pts with mCRPC treated with AA in compassionate use in Napoli, Trento, and Candiolo, Italy. Serum PSA levels were performed after 15, 90 days and then monthly, a time course of serum PSA was obtained. The PSA flare phenomenon was evaluated, according to a confirmation value at least one week apart. The Cox proportional hazards model was used to test the effect of several variables on survival outcomes in multivariate analyses. Results: We have collected data of 87 patients between Sep 2011 and Sep 2014; 75/87 were eligible for correlation analysis. PSA decline was observed in 78.6 % (59/75) of pts. Early PSA response ( ≥ 50% from baseline at 15 days) was found in 56%(42/75) evaluated patients and confirmed in 29 of them after 90 days. In early responders patients (PSA RR ≥ 50% at 15 days), we found a significant statistical advantage in terms of PFS at 1 year, HR 0.28,95% CI 0.12-0.65, p = 0.003, and OS, HR 0.21 95% CI 0.06-0.72, p = 0.01. The median OS was 17,1 months(8,8-25,2). PFS at 1 year and OS reached statistical significance also in the evaluation at 90 days, HR: 0.23 95% CI 0.07-0.77, p = 0.02 and HR: 0.14 95% CI 0.03-0.70, p = 0.02 respectively. Our analysis showed a positive correlation between OS and duration of AA treatment, previous chemotherapy treatment, cumulative dose of docetaxel ≤ 675 mg/m² and previous hormonal therapy duration ( ≥ 2.5 months) for metastatic setting in early responders group. Conclusions: A significant proportion (78.6%) of patients achieved a rapid response in terms of decline of PSA. Early PSA RR ( ≥ 50% at 15 days after start of AA) can provide clinically meaningful information and could be considered a surrogate of longer PFS and OS.
EORTC trial 22991: Results of a phase III study comparing 6 months of androgen suppression and irradiation versus irradiation alone for localized T1b-cT2aN0M0 prostate cancer.
Authors: Bolla Michel , Van Den Bergh Alphonsus C.M. , Carrie Christian , Villà Salvador , Kitsios Petros , Poortmans Philip M. , Sundar Santhanam , van der Steen-Banasik Elzbieta M. , Armstrong John , Bosset Jean-Francois , Herrera Fernanda , Pieters Bradley , Slot Annerie , Bahl Amit , Collette Laurence , Maingon Philippe
Published: February 2017

22

Background: Up to 30% patients irradiated for intermediate- or high-risk localized prostate cancer experience relapse biochemically within 5 years. We assessed if biochemical disease-free survival (BDFS) is improved by adding 6 months of androgen suppression (AS) – twice 3-month depot LHRH-agonist to primary irradiation (RT) for intermediate or high risk localized T1b-cT2a N0M0 prostate cancer. Methods: 819 patients staged cT1b-c with PSA ≥ 10 ng/ml or Gleason ≥ 7 or cT2a (UICC TNM 1997) N0 M0 with PSA ≤ 50 ng/ml were randomized between RT or RT+ADT. Centers elected one dose of prostate irradiation: 70, 74, or 78 Gy. Irradiation of pelvic nodes was left to the discretion of each institution. The trial aimed to show an increase of +7.5% in 5-year BPFS (HR=0.714) with 80% power. This requires 274 events in intent-to-treat analysis. HRQoL was assessed by EORTC QLQ-C30+PR25 (ClinicalTrials.gov NCT00021450). Results: Patients were 70 y old in median, 88% had WHO PS 0, 74.8% were intermediate risk, and 24.8% high risk. In the RT arm, 407/409 received RT, in the RT+ADT, 403/410 received RT+ AS and 3 RT. Six patients refused treatment. After a median follow-up of 7.2 years, 201 and 118 events for BPFS were observed in the RT and RT+ AS arm. RT+ AS improved BPFS compared to RT (HR=0.53, CI: 0.42-0.67, P<0.001) irrespective of the radiation dose (heterogeneity P>0.1). The 5-y BPFS increased from 69.3% to 82.5%. Clinical PFS was also statistically significantly improved (205 events, HR=0.63, CI: 0.48-0.84, P=0.001, +7.9% at 5 years). Late genitourinary toxicity was reported by 5.9% vs. 3.6% of the patients, on RT+ AS and RT, respectively (p=0.14), whereas 27.0% vs 19.4% reported severe impairment of sexual function (p=0.010). Overall HRQoL did not differ between the groups. Hormonal treatment symptoms, sexual activity and functioning scales are clinically significantly impaired by AS at month 6 and year 1; from year 2 no marked difference is seen. Conclusions: The addition of 6 months of medical castration to primary irradiation improves BPFS and PFS in intermediate- and high-risk localized T1b-cT2a N0M0 prostatic carcinoma with no persistent detriment on HRQoL or sexual function. Clinical trial information: NCT00021450.
Association of single nucleotide polymorphisms (SNPs) in SULT1E1 with response to treatment with abiraterone acetate (AA) in men with metastatic castration refractory prostate cancer (mCRPC).
Authors: Buckley Tyler Howard , Alex Anitha , Farnham James M. , Gill David , Patel Shiven B. , Teerlink Craig , Albright Frederick S. , Stephenson Robert A , Cannon-Albright Lisa A , Agarwal Neeraj
Published: February 2017

222

Background: Germline variations in genes involved in androgen biosynthesis and metabolic pathways may predict response to AA in men with mCRPC, serve as prognostic and predictive biomarkers, and guide towards more individualized therapy. Methods: 836 single nucleotide polymorphisms (SNPs) from the Illumina OmniExpress genotyping platform within the boundaries of 61 genes reported to be involved in the androgen metabolic pathway were investigated for association with time to treatment failure (TTF) in 68 Caucasian men with mCRPC undergoing treatment with AA. Cox proportional hazard analysis was employed using Gleason score as a covariate and assessing each SNP under an additive genetic model in which the number of minor alleles contributes increasing risk (or protection). Results: Three SNPs in SULT1E1 were associated with TTF on AA therapy after correcting for multiple testing (p < .00007) while controlling for Gleason Score (Table). Conclusions: SNPs in SULT1E1(estrogen sulfotransferase gene) were significantly associated with TTF on AA therapy, and may serve as predictive markers to treatment with AA. Further validation is being performed in a larger cohort of men with mCRPC. [Table: see text]
Association of single nucleotide polymorphism in four genes and response to androgen deprivation therapy (ADT) in men with advanced hormone sensitive prostate cancer (aHSPC).
Authors: Gill David , Alex Anitha , Farnham James M. , Buckley Tyler Howard , Patel Shiven B. , Agarwal Archana M. , Teerlink Craig , Albright Frederick S. , Stephenson Robert A , Cannon-Albright Lisa A , Agarwal Neeraj
Published: February 2017

224

Background: Germline variations in genes involved in androgen biosynthesis and metabolic pathways may predict time to response to androgen deprivation therapy (ADT) in aHSPC, serve as prognostic and predictive biomarkers, and guide towards more individualized upfront therapy. Methods: 706 single nucleotide polymorphisms (SNPs) from the Illumina OmniExpress genotyping platform within the boundaries of 59 genes reported to be involved in the androgen metabolic pathway were investigated for association with time to onset of castration resistance prostate cancer (CRPC) in 171 Caucasian men with aHSPC, i.e. those progressing after definitive treatment (biochemical recurrence alone, or onset of metastatic disease), undergoing treatment with ADT. Cox proportional hazard analysis was employed using Gleason score as a covariate and assessing each SNP under an additive genetic model in which the number of minor alleles contributes increasing risk (or protection). Results: Five SNPs in four genes showed evidence of association with time to CRPC on ADT while controlling for Gleason Score (p < .0002) (Table). Each of these genes had other nearby SNPs with at least nominal (p < 0.05) significance and so, don’t appear to be false positives. Conclusions: Although none of these SNPs exceeded a strict Bonferoni multiple testing correction (p < 0.00007), that threshold is almost certainly conservative as the SNPs and tests are correlated. These results are being validated in a larger cohort and may serve as predictive markers to ADT in this setting. [Table: see text]
Predictive value of bone scan index using computer-aided diagnosis system for bone scans in patients receiving first-line hormone therapy for metastatic hormone-sensitive prostate cancer.
Authors: Miyoshi Yasuhide , Yasui Masato , Yoneyama Shuko , Uemura Koichi , Kawahara Takashi , Hattori Yusuke , Teranishi Jun-ichi , Ohta Jun-ichi , Yokomizo Yumiko , Taguri Masataka , Uemura Hiroji , Yao Masahiro
Published: February 2017

225

Background: Recently, the CHAARTED and STAMPEDE studies showed a survival benefit for docetaxel when started with androgen deprivation therapy (ADT) in men with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC). While GETUG-AFU 15 failed to demonstrate a survival benefit of early chemotherapy. New biomarker for select the candidate for early chemotherapy in mHSPC is warranted. The objective of this study is to evaluate the bone scan index (BSI) using computer-aided diagnosis system for bone scans for predictive factor in patients receiving ADT as first-line hormone therapy for mHSPC. Methods: We identified consecutive 85 mHSPC patients treated with maximum androgen blockade (MAB) as first-line hormone therapy. We analyzed the correlations between progression-free survival (PFS) of MAB and clinicopathological characteristics, including patients’ age, initial PSA levels, Gleason scores, clinical TNM stage, hemoglobin (Hb), lactase dehydrogenase (LDH), c-reactive protein (CRP), and bone scan index (BSI). Statistical analyses were assessed using cox proportional hazards regression models. Results: The median patients’ age was 73 and the median follow-up duration was 11.3months. The median initial PSA value was 270 ng/ml. Median BSI was 2.7 % (range: 0.0-14.6). Clinical or PSA progression occurred in 55 (64.7%) patients. The median time to progression was 12.9 months. In multivariate analysis, three significant risk factors for PFS were identified; patients’ age ( > 73 years old vs ≤ 73; HR 0.53, p = 0.038), initial PSA levels ( > 270 ng/mL vs ≤ 270; HR 0.53, p = 0.038), and BSI ( > 2.7 vs ≤ 2.7; HR 3.0, p < 0.000). We stratified the patients into two cohorts with low risk (0-1 risk factor present) and high risk (2-3 risk factors present). We found a significant difference in PFS among risk groups (median PFS 15.3 months vs 8.5, p < 0.000). Conclusions: Patients’ age, initial PSA levels, and bone scan index were the significant predictive factors for MAB as first-line hormone therapy in patients with mHSPC. These findings might support the decision-making of induction of early chemotherapy for mHSPC.
Association between early PSA increase and clinical outcome in patients treated with enzalutamide for metastatic castration resistant prostate cancer.
Authors: Conteduca Vincenza , Crabb Simon J. , Scarpi Emanuela , Hanna Catherine , Maines Francesca , Joyce Helen , Fabbri Paolo , Derosa Lisa , Massari Francesco , Lolli Cristian , Zarif Sunnya , Jones Robert J. , Caffo Orazio , Elliott Tony , De Giorgi Ugo
Published: February 2017

231

Background: Prostate specific antigen (PSA) decline by 50% from the baseline to 12 weeks (PSA50w12) is currently used to predict response to treatment and clinical outcome of patients with metastatic castration resistant prostate cancer (mCRPC). However, in clinical practice, PSA changes are monitored monthly in several centers. We evaluated the association between PSA changes at 4 weeks and clinical outcome. Methods: We retrospectively evaluated mCRPC patients treated with enzalutamide after docetaxel. Early PSA increase was defined as a PSA level at 4 weeks ≥ 20% (PSA+20w4) from baseline. Early PSA decline was defined as a PSA response at 4 weeks ≥ 30% (PSA30w4) and ≥ 50% (PSA50w4) from baseline.Progression-free survival (PFS), overall survival (OS) and their 95% Confidence Interval (95% CI) were evaluated by the Kaplan-Meier method and compared with the log-rank test. A multivariate analysis was performed including the following variables: PSA+20w4, PSA30w4, PSA50w4 and PSA50w12, baseline PSA, performance status, LDH values, sites of metastases, age. Results: We assessed 193 patients with median age of 73.1 years (range, 42.8 to 90.7). The median follow-up was 11.7 months. PSA+20w4 was associated with shorter PFS (median PFS 2.0 vs. 6.1 months; HR 4.03; 95% CI 2.62-6.19; p < 0.0001) and shorter OS (median OS 5.9 vs. 15.6 months; HR 3.48; 95% CI 2.12-5.69; p < 0.0001). At multivariate analysis, PSA+20w4 remained predictive of both PFS and OS [HR 4.03 (95% CI 0.2.62-6.19; p < 0.0001) and HR 3.48 (95% CI 2.12-5.69; p < 0.0001), respectively], whereas PSA30w4 and PSA50w4 predicted only PFS [HR 0.37 (95% CI 0.21-0.67; p = 0.0009) and HR 0.34 (95% CI 0.19-0.60; p = 0.0003), respectively]. No cases of PSA flare were reported. Conclusions: An early PSA increase, defined as a PSA level at 4 weeks ≥ 20% (PSA+20w4), could be useful to identify patients unlikely to benefit from enzalutamide. Larger studies are needed to confirm PSA+20W4 as an early and cheap biomarker of primary resistance to enzalutamide.
Cardiovascular events in prostate cancer patients: A comparative analysis of German claims data.
Authors: Ruessel Christoph , Walker Jochen , Jacob Josephine , Gedamke Michael , Vosgerau Sebastian
Published: February 2017

232

Background: In addition to the radical prostatectomy and radiotherapy, androgen deprivation therapies (ADT) have been established as a therapy option in patients with high-risk localized and metastatic prostate cancer (PCa). ADT was found to be associated with a higher risk for cardiovascular (CV) events. This retrospective claims-based study investigated whether CV event rates differ following initiation of ADT with gonadotropin-releasing hormone (GnRH) agonists or antagonists and PCa patients not treated with ADT. Methods: Analyses were based on claims data from the research database of the Health Risk Institute. Eligibility criteria included a PCa diagnosis between 2009 and 2013 and the initiation of ADT with GnRH agonists or antagonists or no ADT during follow up. Outcomes of interest included a composite endpoint of myocardial infarction (MI) or ischemic stroke (IS) as well as the occurrence of a CV event. The latter included MI, sequelae of cerebrovascular disease, IS, intracerebral hemorrhage, pulmonary embolism, phlebitis/thrombophlebitis, transient cerebral ischemic attacks and occlusion/stenosis of cerebral arteries. Results: ADT patients suffered from more comorbidities, were older, and were more likely to suffer from CV conditions than patients with no ADT during baseline. Patients treated with GnRH agonists and antagonists were comparable in terms of mean age and burden of comorbidities. The raw event rates for MI/IS and for CV events during follow up were higher in ADT patients than in patients without ADT (Table 1). Patients treated with GnRH agonists suffered more often from a CV event during follow-up than patients treated with antagonists. Conclusions: Our results indicate that ADT with GnRH antagonists is associated with fewer CV events in PCa patients than treatment with GnRH agonists. The results confirm findings from a pooled analysis of six phase III randomized controlled trials (Albertsen P. et al: Eur Urol 65 (2014) 565-573.). [Table: see text]
Impact of pelvic lymph node dissection during radical prostatectomy on 30-day post operative complications: Results from a large national database.
Authors: Pavan Nicola , Rai Samarpit , Soodana-Prakash Nachiketh , Balise Raymond R , Mir Maria Carmen , Nahar Bruno , Ritch Chad , Parekh Dipen , Gonzalgo Mark L.
Published: February 2017

238

Background: Pelvic lymph node dissection (PLND) during radical prostatectomy (RP) is the most effective method for detecting lymph node metastases in patients with prostate cancer. The association between PLND during RP and morbidity, especially thromboembolic adverse events (AEs), remains unclear. We assessed the effect of PLND on 30−day postoperative AEs in patients undergoing RP using the American College of Surgeons’ National Surgical Quality Improvement Program database (NSQIP). Methods: A total of 21,895 men undergoing RP between 2006 and 2013 were classified into two groups according to surgical approach (MIS−RP vs. ORP) and whether PLND was performed. Multivariate logistic regression adjusting for approach and demographic features was performed to assess the impact of PLND for predicting two primary endpoints (overall complications and major complications defined as Clavien−Dindo ≥ 3) and for 17 types of complications. P−values were adjusted to maintain an experiment−wise p < 0.05. Results: MIS−RP and ORP was performed in 17,354 (79.3%) and 4,541 (20.7%) patients, respectively. PLND was performed in 7,579 (43.7%) and 3,597 (79.2%) patients in the MIS−RP and ORP groups, respectively. The overall postoperative complication rate was 8.7% (5.5% for MIS−RP and 21.0% for ORP). PLND was not associated with a higher risk of DVT (OR 0.99; p= 0.98) or PE (OR 1.02; p= 0.91). However, PLND was associated with a higher risk of superficial surgical site infection (OR 1.68; p = 0.013), organ space surgical site infection (OR 1.77; p = 0.02), and perioperative transfusion (OR 1.32; p = 0.002) regardless of surgical approach. PLND was not associated with overall or major AEs on multivariable analysis. ORP was associated with a significantly higher risk of overall (OR 4.64, p < 0.0001) and major (OR 1.6, p = 0.0004) AEs compared to MIS−RP. Conclusions: PLND during RP is associated with a significantly increased risk of certain types of AEs within the 30−day post−operative period. However, there appears to be no significant association between PLND and thromboembolic AEs.
The role of fPSA, [-2]proPSA and the Prostate Health Index for the early prediction of outcome in patients with metastatic castration resistant prostate cancer on therapy with abirateroneacetate.
Authors: Schlack Katrin , Krabbe Laura-Maria , Eminaga Okyaz , Semjonow Axel , Boegemann Martin
Published: February 2017

241

Background: Abiraterone acetate (AA) prolongs overall survival (OS) in pre- and post-chemotherapy setting in patients with metastatic castration resistant prostate cancer (mCRPC). Biomarkers to predict response to therapy are limited. Prostate-specific antigen (PSA) and lactate dehydrogenase (LDH) are commonly used as response-indicators but are often misleading during early therapy. Assays for circulating tumor cells, which can be surrogate for poor survival, are not routinely available at most places. In this retrospective study we evaluated the role of the PSA-derivatives free PSA (fPSA), [-2]proPSA (p2PSA) and the prostate health index (PHI) in addition to PSA as indicators of response during early AA-therapy. Methods: Twenty-five men with mCRPC receiving AA between March 2012 and July 2015 at the University Hospital of Muenster were included and analyzed. The PSA response rate (RR) was monitored according to PCWG2-criteria. Dynamic PSA-, fPSA-, p2PSA- and PHI-changes at 8-12 weeks under therapy were analyzed as predictors of progression free survival (PFS) and OS using Kaplan-Meier-analysis (KMA) and uni- and multivariate cox-regression analysis (UVA and MVA). Results: Twenty men were chemotherapy naïve, 5 pretreated with docetaxel. The PSA RR was 44%. In patients with < or ≥ 12 months of PFS the relative change of median PSA and fPSA at 8-12 weeks compared to baseline differed significantly (p = 0.022 and 0.030). For men with ≤ or > 15 months of OS there was a trend for a difference in relative change of median fPSA (p = 0.058). In KMA declining fPSA at 8-12 weeks was associated with a median OS of 32 months compared to 21 months in men with rising fPSA. In UVA rising PSA and fPSA were non-significant predictors of poor OS (Hazard ratio (HR) = 1.3 and 2.5 (p = 0.717 and 0.159)). In MVA PSA and fPSA were independent predictors of poor survival (HR 6.7 and 12.8 (p = 0.050 and 0.012)). Conclusions: fPSA is easily available and cheap. When added to PSA information, change of fPSA at 8-12 weeks of AA therapy may be a promising therapy control marker to help physicians to make decisions weather to stop or to continue AA therapy in men with mCRPC.
The association of D4, 3-keto-abi (D4A) and response to abiraterone in castration-resistant prostate cancer (CRPC).
Authors: Emamekhoo Hamid , Alyamani Mohammad , Li Zhenfei , Elson Paul , Grivas Petros , Rini Brian I. , Petro Marianne , Stybor Sylvia , Salatino Anthony , Garcia Jorge A. , Sharifi Nima
Published: February 2017

245

Background: Abiraterone (Abi), a potent inhibitor of 17α-hydroxylase/17,20-lyase (CYP17A1), is a standard treatment for men with metastatic CRPC. Abi is converted to D4A by 3β-hydroxysteroid dehydrogenase (3βHSD). D4A inhibits CYP17A1, 3βHSD, and steroid-5α-reductase (SRD5A) and has direct androgen receptor antagonist activity, which together make it a more potent agent than Abi in xenograft models. It is not known if conversion to D4A in patients (pts) correlates with response or resistance to Abi. Methods: Blood was collected (single time point on Abi) from CRPC pts who started Abi during 2011-2015. Abi and D4A were extracted from serum and analyzed by mass spectrometry. The purpose of this ongoing study is to assess the potential correlation between D4A and response to treatment. Results: 32 patients with CRPC had blood collected. 4 pts (12.5%) received ketoconazole and 6 (18.8%) chemotherapy prior to Abi. Median pre-Abi prostate-specific antigen (PSA) was 14.3 ng/ml (0.6-646.1). Median time from initiation of androgen deprivation therapy (ADT) to CRPC was 34.3 months (m) (6-129.6) and median time from CRPC to Abi initiation was 4.8 m (0-14.9). PSA decline > 50% (PSA50) on Abi was seen in 68% (12/31) and 73% (19/26) of pts at 3 and 6 m, respectively. Treatment with Abi was ongoing in 23/32 pts (74%), and discontinued in 8 pts (26%) due to disease progression (no follow up data on 1 pt) with median duration of Abi treatment 14.6 m (2.9-44.4 m) at last follow up. As the absolute concentration of detected levels of Abi and D4A varied significantly among pts, the percentage of the total extracted metabolites was used to assess correlation with response. Abi and D4A comprised 94.3% (73.8-97.4%) and 5.7% (2.6-26.2%), respectively, of total levels. Conclusions: Abi absorption and metabolism significantly vary among pts. Most of these pts had prolonged duration of response to Abi (74% ongoing treatment and median treatment duration 13.3 m in 8 pts that came off treatment). Longer follow up, accrual of pts with shorter duration of response, and sampling at multiple time points on Abi and at progression is ongoing to further evaluate the impact of D4A on treatment response.
Impact of symptomatic skeletal events on healthcare resource utilization, health-related quality of life and pain among patients with castration-resistant prostate cancer and bone metastases.
Authors: McKay Rana R. , Haider Batool , Duh Mei Sheng , Valdarrama Adriana , Nakabayashi Mari , Fiorillo Matthew , Ristovska Ljubica , Wen Lonnie Kent , Kantoff Philip W.
Published: February 2017

247

Background: Prostate cancer patients frequently develop bone metastases (BM), leading to symptomatic skeletal events (SSE). Given the real-world data on SSE are lacking, this study evaluated the impact of SSE on healthcare resource utilization (HRU), health-related quality of life (HRQoL), and pain in patients with castration-resistant prostate cancer (CRPC) and BM. Methods: Electronic medical records (EMR) and clinical database of a tertiary oncology center were used to identify CRPC patients with BM. SSE, including pathologic fracture, radiation to bone, spinal cord compression, and bone surgery, were extracted from medical charts. HRU, such as emergency room (ER), outpatient and inpatient visits, was determined from the EMR. A subset of patients who were alive and had clinic visits from 11/2014-7/2015 completed HRQoL (FACT-P) and pain (BPI-SF) surveys. The impact of SSE on HRU was evaluated using multivariate negative binomial regression. Survey scores were compared using Rank-Sum test and standardized effect sizes (ES); an ES ≥ 0.33 corresponds to meaningful differences between SSE and non-SSE groups. Lower FACT-P and BPI-SF scores suggest reduced HRQoL and less pain, respectively. Results: Of 832 patients, 207 developed ≥ 1 SSE (mean 1.5±0.8); 84% had radiation to bone. The median age at CRPC with BM diagnosis was 68 yrs. and follow-up after diagnosis was 2.1 yrs. Adjusting for baseline factors, the SSE group had significantly higher ER (incidence rate ratio (IRR) = 1.48; 95% confidence interval (CI) = 1.12, 1.95), outpatient (IRR = 1.17; 95% CI = 1.05, 1.30), and inpatient (IRR = 1.74; 95% CI = 1.34, 2.26) visits. Of 107 patients eligible for surveys, 103 responded. The mean FACT-P functional well-being score was 17.5 in SSE and 19.8 in non-SSE group (p = 0.16) with an ES of 0.36. Mean BPI-SF pain severity score was 2.5 in SSE and 1.6 in non-SSE group (p = 0.05) with an ES of 0.47, and that for worst pain was 3.6 and 2.3, respectively, (p = 0.03) with an ES of 0.5. Conclusions: The economic and quality of life burden of SSE amongst CRPC patients with BM is high, underscoring the need for preventive treatments for SSE in this population.
CK13 expression in prostate tumors of patients with bone metastases at diagnosis.
Authors: Liu Sandy
Published: February 2017

257

CK13 Expression in Prostate Tumors of Patients with Bone Metastases at Diagnosis Sandy T. Liu, Radu Cadaneanu, Kevin Lai, Bao Zhang, Haibo Liu, Lihong Huo, Colette Galet, William Aronson, Matthew Rettig, Michael Lewis, Isla P. Garraway; University of California Los Angeles, Los Angeles, CA Background: Biomarkers of lethal prostate cancer (PCa) are needed for appropriate clinical management. Benign stem/progenitor (S/P) cells reside in the basal layer of prostatic ducts/acini and function as cells of origin for PCa. Aggressive tumor cells may co-opt properties of S/P cells, such as mechanisms of resistance to castration. Distinct prostate epithelial populations, including stem-like tubule-initiating cells (TIC), basal cells (BC), and luminal cells (LC) can be isolated from benign prostate tissue. In this study, gene expression analysis was performed on benign prostate to identify TIC markers that may persist in cancer. Methods: Microarray analysis was performed on Epcam+CD44-CD49fHi TIC, Epcam+CD44+CD49fHi BC, and Epcam+CD44-CD49fLoLC using Affymetrix Array. Data was analyzed using Partek Genomics and validated with RT-PCR. Immunohistochemistry (IHC) was performed on 1) prostate tissue microarray (TMA) from 332 prostatectomies 2) pretreatment tissue from stage M1 patients and 3) post-treatment prostate tissue. Results: Affymetrix identified increased cytokeratin 13 (CK13) expression in TIC relative to BC and LC. Rare CK13+ epithelia are seen in ducts/acini of benign prostate tissue. TMA IHC revealed CK13+ cancer cores in 9% of cases, and significantly correlated with recurrence (p = 0.031), progression to castration-resistance (p = 0.05), and metastases (p = 0.009). Biopsy tissue from hormone-naive patients with diffuse bone metastases displayed CK13+ tumors in primary and metastatic foci. Epithelial cells populating residual prostate glands following radiation and ADT also displayed CK13 expression. Conclusions: CK13+ tumors reflect a “stem-like” state, enabling survival in low-androgen conditions and interactions that support invasion/metastases. Further characterization of CK13+ PCa variants could lead to clinical trials investigating agents that may prevent/treat dissemination and progression.
Early abiraterone treatment after surgical castration in in vivo castration resistant prostate cancer (CRPC) tumors in nude mice.
Authors: Thelen Paul , Reupke Verena , Bremmer Felix , Jarry Hubertus
Published: February 2017

263

Background: ADT is the initial therapy for advanced prostate cancer, and androgen biosynthesis inhibitors (abiraterone-acetate, AA) reveal clinical survival benefit for CRPC. On CRPC progression, therapy sequencing towards androgen receptor (AR) antagonism is applied and AA withdrawal / re-challenge strategies (+AA-AA+AA) succeeded in several case reports. Here we established a VCaP-tumor mouse model for a +AA-AA+AA-sequence and external testosterone-boosts (+AA[-AA+T]+AA). Methods: 20 tumor bearing mice (from 106 VCaP in Matrigel) received surgical ADT and then +AA-AA+AA, (AA intraperitoneal 70mg/kg, daily [Janssen-Cilag]), or +AA[-AA+T]+AA (+0.6 µl/kg Nebido [250mg testosterone-undecaonate/ml, Jenapharm]). Tumor growth was monitored with calipers. When tumors grew > 200 mm3, animals were castrated and treatment-sequences began when CRPC growth became evident (n = 15) or early one week after castration (n = 5). Expression analyses were performed with Experion, CSX-96 and ChemiDoc, chemicals, software (BioRad). Steroids were quantified by Dept. Clin. Chemistry. Results: 20 tumor-bearing mice received ADT. To interfere with ADT failure for 15 mice +AA-AA+AA (n = 7) or +AA[-AA+T]+AA (n = 8) commenced when tumors doubled within two weeks. Animals benefited a reduction of up to 210 mm3 receiving +AA-AA+AA, whereas a T-Boost in +AA[-AA+T]+AA revealed a loss of solid tumor mass as mean 42% (+/-21%) liquid effusion. No complete remission was observed, tumors > 1 cm3 were considered dead-of-disease (DOD). Another group (n = 5) was AA-treated one week after castration. There +AA-AA+AA and +AA[-AA+T]+AA resulted for one animal in DOD, however tumors of up to 990 mm3 underwent complete remissions (n = 4) and tumor-free untreated survival. AA-withdrawal is associated with progesterone decrease and DHEA increase. AR (+ AR-Vs) decreases to 95% expression immediately after -AA and to 39% (no AR-Vs) upon +T. Conclusions: Therapy sequences with AA-withdrawal/rechallenge may lead to tumor regression and complete tumor-free survival. Concomitant with tumor regression upon AA-withdrawal, AR overexpression is reduced, which may be boosted with testosterone supplementation.
Surrogacy analysis of prostate-specific antigen (PSA) decline for improved overall survival (OS) with enzalutamide (ENZ) in AFFIRM.
Authors: Armstrong Andrew J. , Saad Fred , Shore Neal D. , Fizazi Karim , Phung De , Dmuchowski Carl Frank , Hirmand Mohammad , Forer David , Scher Howard I. , De Bono Johann S.
Published: February 2017

266

Background: ENZ significantly increased OS for men with metastatic castration-resistant prostate cancer (mCRPC) vs. placebo and significantly decreased PSA levels. However, the prognostic significance and role of PSA falls as a surrogate for OS are not established. Methods: Men in the AFFIRM trial were grouped by maximal unconfirmed PSA decline during the 1st 90 days of treatment in a post-hoc analysis. Each PSA decline criterion was assessed for surrogacy for OS by the proportion of treatment effect (PTE)-explained and Prentice criteria. We also assessed the association of PSA decline with OS, progression-free survival (PFS), and pain response. Results: ENZ improved OS (hazard ratio 0.63, p < 0.001) and was associated with higher rates of PSA declines when compared to placebo (odds ratio > 19.0, p < 0.001). Greater declines in PSA were associated with longer OS, PSA PFS, radiographic PFS, and higher pain response when compared with no PSA decline or PSA increase (table). All decline measures from baseline were highly prognostic for OS and several ( > 0%, ≥ 30%, ≥ 50% declines) explained a proportion of the treatment effect (PTE 1.07–1.29, 95% CI lower bounds > 0.63), in which treatment was no longer significant after adjustment for the decline measures (p > 0.20). Full surrogacy was not demonstrated. Conclusions: In AFFIRM, > 0, ≥30%, and ≥50% PSA declines within 90 days of treatment fulfilled Prentice surrogacy criteria 1–3. Prentice 4, equivalency of survival adjusting for PSA decline outcomes, could not be demonstrated. PSA declines are associated with longer PFS and improved pain response. External prospective validation is needed. Clinical trial information: NCT00974311. [Table: see text]
Body mass index at mCRPC, weight change, and survival in advanced prostate cancer.
Authors: Chow Lydia D. , Ledet Elisa M. , Steinberger Allie E. , Guccione Jeffrey R. , Sartor A. Oliver
Published: February 2017

270

Background: Body mass index (BMI) at diagnosis is associated with increased risk of fatal prostate cancer, but the link between BMI at mCRPC and cancer progression is less clear. Cachexia, often defined as involuntary weight loss > 5% over 6 months, is common in advanced cancers. The goal of this study was to examine the link between BMI at mCRPC and weight change as it relates to cancer progression, the outcomes of survival, and treatment use in a single-institution setting. Methods: 58 mCRPC patients treated at Tulane Hospital were identified, 41 of whom had an overweight BMI at mCRPC (BMI > 25) and 17 with normal BMI at mCRPC (BMI < 25). All patients had a confirmed prostate cancer death. Survival, treatment history, and percent weight change were compared according to BMI status. Rate of percent weight change was defined as the change in weight per day, from date of mCRPC diagnosis to the last treatment stop date or death date (“mCRPC days”). Linear regression, overall survival (OS), and nonparametric analyses were performed. Results: There was no significant difference between the normal and overweight BMI groups in overall survival, from date of diagnosis to death (median = 1835 days vs. 2710 days respectively). Additionally, the difference in survival from mCRPC to death was not statistically significant (median = 630 days vs. 799 days, p = 0.115). Use of Taxotere was not significantly different (47% vs. 68% respectively); however, overweight patients (n = 28) more likely received Abiraterone than normal BMI patients (n = 2) (p-value = 0.0001). The rate of percent weight change was significantly different for normal and overweight patients (mean = –0.050%/day vs. –0.019%/day, p = 0.003). Linear regression analysis showed that mCRPC days had a significant effect on percent weight change (p = 0.0109), and this effect was not significantly different between BMI groups (p = 0.6991). Conclusions: Survival after mCRPC was not significantly different between BMI groups. We observed a significant effect of mCRPC days on percent weight change, with a similar effect for both BMI groups. This outcome is expected, as more time would allow for greater weight changes to occur. Larger studies are needed to fully evaluate these observations.
Comparison of survival of African-American (AA) patients (pts) in docetaxel (D)-based combination therapies in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Karzai Fatima , Madan Ravi Amrit , Ning Yang-Min , Theoret Marc Robert , Arlen Philip M. , Parnes Howard L. , Ojemuyiwa Michelle A. , Strauss Julius , Dawson Nancy Ann , McLeod David G. , Harold Nancy , Couvillon Anna , Cordes Lisa M , Chen Clara , Steinberg Seth M. , Sissung Tristan M. , Price Douglas K. , Gulley James L. , Figg William Douglas , Dahut William L.
Published: February 2017

272

Background: AA pts experience greater prostate cancer (PC) incidence and mortality compared to Caucasian (C) pts but are underrepresented in clinical trials (CTs). Greater representation of AAs is required to explore differences in clinical benefit in advanced disease where recent data has reaffirmed the role of D. Methods: In a retrospective analysis, baseline characteristics, Gleason score (GS), ECOG PS, number of cycles (cys), maximum prostate-specific antigen (PSA) declines, radiographic responses, overall survival (OS) and progression-free survival (PFS) were captured in 2 recent D based CTs. Results: Of 136 pts, 28 (21%) self-identified as Black or AA. Median age of AA pts is 66 (50-78 yrs). Median GS is 8 (5-10). Median ECOG PS is 1 (0-2). 15 pts have bone and soft tissue disease; 13 pts have bone only disease. Median number of cys is 28.5 (1-63). Of 27 evaluable pts, 26 had PSA declines (-26 to -99%). Radiographic responses include 11 (39%) partial responses and 16 (57%) pts with stable disease. Median OS for AAs is 29.0 months (mos) (95% CI: 20.9-34.7 mos); median PFS is 21.5 mos (95% CI: 13.7-28.9 mos). Median OS for all non-AA pts is 24.8 mos (95% CI: 21.8-29.5 mos); median PFS is 16.1 mos (95% CI: 14.1-20.1 mos). The VEGF-634G > C SNP, associated with a more aggressive phenotype of PC, was evaluated in 54 pts. No evidence was found that genotype frequency varies between C and AA pts. Conclusions: In this analysis, AA pts did not have inferior OS (29 mos) or PFS (21.5 mos) outcomes compared to non-AA pts (24.8, 16.1 mos). Further analysis from larger studies is required to determine differential benefits of D for AA pts compared to non-AA pts. Clinical trial information: NCT00089609, NCT00942578.