bluuebunny/crossref_metadata_2025 huggingface dataset:
Histologic determinants of long-term overall survival in patients (pts) with germ cell tumors (GCT).
Authors: Funt Samuel , Patil Sujata , Feldman Darren R. , Motzer Robert J. , Bajorin Dean F. , Sheinfeld Joel , Tickoo Satish , Reuter Victor E. , Bosl George J.
Published: September 2018

4555

Background: GCT display totipotential differentiation ranging from pluripotent embryonal carcinoma to extraembryonic (choriocarcinoma, yolk sac) to somatic cell types (teratoma [T]). We hypothesized that long-term survival after platinum-based chemotherapy (PC) is dependent upon histology. Methods: Advanced GCT pts who received PC from 4/1975 to 5/1996 and had a pre-PC primary tumor specimen available were included. Each pre-PC cell type was reviewed and confirmed. Residual tumor size post-PC was recorded when available. Differences in cumulative incidence (CUI) of death due to disease (DOD) between histologic cell types and other baseline characteristics were evaluated using a competing risks approach and the Fine & Gray test. Results: Pre-PC primary tumor specimens (96% testis, 3% mediastinum) were available from 231 pts. Median age was 29 years (y) and median followup 17 y (range 0.3-35 y). 41 pts had pure seminoma; of the remaining 190 with nonseminomatous GCT (NSGCT), 81 had an element of T (n=29 mature T, n=42 immature T, n=10 both). At PC start, 60% of pts were IGCCCG good risk, 26% intermediate, and 13% poor with no difference for NSGCT based on presence vs. absence of T (p=0.53). Of 72 deaths, 50 were DOD, 20 from other causes, and 2 from unknown causes. The 5, 10, and 15 y CUI of death from any cause was 20%, 23%, and 26%, respectively. CUI of DOD at 5, 10 and 15 y was 18%, 20%, 22%, respectively. CUI of DOD at 2, 5, 10 and 15 y by histologic group is provided in the Table. Presence of T was associated with greater CUI of DOD vs. NSGCT without T (p=0.04) and mature T with a greater CUI of DOD vs. immature T (p=0.03). NSGCT pts with T were also more likely to have residual retroperitoneal disease >1cm after PC vs. those without T (50 vs. 4.2%; p=0.01). Conclusions: With long-term followup, the presence of an element of T, particularly mature T, in mixed NSGCT was associated with a higher risk of DOD than tumors without T, which have the same risk of DOD as pure seminoma. These data suggest that the presence of T in the primary tumor may be an important clinical predictor of long-term outcome in men with GCT. [Table: see text]
Pazopanib exposure-response assessment as adjuvant therapy for patients with localized or locally advanced renal cell carcinoma (RCC) following nephrectomy.
Authors: Sternberg Cora N. , Donskov Frede , Haas Naomi B. , Doehn Christian , Russo Paul , Elmeliegy Mohamed , Banerjee Hiya , Aimone Paola , Voi Maurizio , Motzer Robert J.
Published: September 2018

4564

Background: PROTECT was a Phase 3 randomized placebo-controlled study to evaluate pazopanib efficacy and safety as adjuvant RCC treatment. The starting dose was 800 mg daily, which was reduced to 600 mg in an attempt to improve tolerability. Pazopanib trough concentrations (Ctrough) were collected from 358 patients at the 600-mg starting dose at two timepoints (Week 3/ 5 and Week 16/20). This analysis characterized the relationship between Ctrough and efficacy and safety endpoints. Methods: The relationship between pazopanib Ctrough and disease-free survival (DFS) was explored by Cox regression analysis. DFS of pazopanib Ctrough quartiles was explored using Kaplan-Meier plots. Exposure-safety relationship was explored via summaries of all grade adverse events (AEs), grade 3/4 (G3/4) AEs, and AE-related treatment discontinuation by Ctrough quartiles. Results: The geometric mean (geo-CV%) of Ctrough at 600-mg dose was 31.4 (57%) µg/mL and 25.3 (70%) µg/mL for Week 3/5 and Week 16/20, respectively. At Week 16/20, Ctrough values overlapped among patients receiving 400-, 600-, and 800-mg doses. Cox regression analysis showed pazopanib Ctrough at Week 3/5 as a significant covariate for DFS after adjusting for TNM staging and Fuhrman Nuclear grading (HR: 0.58, 95% CI, 0.42, 0.82; p = 0.002). Longer DFS was observed in higher Week 3/5 Ctrough quartiles (median DFS by quartile—Q1: 41.89 months, Q2-Q4: median DFS not reached). Incidence of all-grade AEs, as well as G3/4 hypertension, increased as Ctrough increased. Treatment discontinuation due to hypertension among pazopanib-treated subjects was low (3.1% vs < 1% in the placebo group). Ctrough was not correlated to G3/4 ALT increase. Incidence of other G3/4 AEs plateaued at higher Ctrough. No relationship was observed between Ctrough and treatment discontinuation due to AEs. Conclusions: Pazopanib Ctrough levels in PROTECT were consistent with levels associated with efficacy in the advanced setting. Higher pazopanib Ctrough correlated with longer DFS. Higher pazopanib exposure did not increase the incidence of G3/4 AEs, with the exception of hypertension, which was adequately controlled and managed. Clinical trial information: NCT01235962.
Long-term response and time to response to pazopanib (PAZ) and sunitinib (SUN) in metastatic renal cell carcinoma (mRCC): COMPARZ subanalysis.
Authors: Tannir Nizar M. , Porta Camillo , Gruenwald Viktor , Choueiri Toni K. , Ahmad Qasim , Carrasco Alfonso Marlene , Dezzani Luca , Han Jackie , Sternberg Cora N.
Published: September 2018

4572

Background: COMPARZ (NCT00720941) was a phase 3, randomized, controlled, open-label trial that demonstrated comparable efficacy of first-line PAZ and SUN, but favorable safety and quality of life profiles for PAZ in 1110 patients with mRCC (NEJM 2013;369:722). The objectives of this study were to identify patients from COMPARZ who exhibited a long-term response (LTR) to PAZ and SUN, determine time to response, and describe the clinical characteristics of patients who achieved LTR. Methods: Patients in the intention-to-treat population of COMPARZ were analyzed for differences in LTR (≥10 months [mos]) as measured by responder rate with either complete response or partial response (CR/PR) and PFS rate, and time to response. We also compared the clinical characteristics between long-term and shorter-term responders within and between each treatment arm. Results: The overall percentage of long-term responders with CR/PR (PAZ = 14%, SUN = 13%) and PFS (PAZ = 31.4%, SUN = 33.6%) in the PAZ and SUN groups were similar. This similarity was observed regardless of the cut-off for long-term duration of response. However, a shorter time to achieve CR/PR was observed in the overall population with PAZ (11.9 weeks [95% CI, 11.3–12.1] vs 17.4 weeks; [95% CI, 12.7–18.0]). Analysis conducted to identify baseline clinical characteristics that may be related to LTR will be reported. Conclusions: These exploratory subanalyses in long-term responders support the overall efficacy results with PAZ and SUN, which were reported in the COMPARZ trial. However, the results here demonstrate that the time to response was shorter with PAZ versus SUN. Clinical trial information: NCT00720941.
Impact of geographic region on overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC): Results from a pooled clinical trials database.
Authors: Fay Andre Poisl , McKay Rana R. , Lin Xun , Simantov Ronit , Choueiri Toni K.
Published: September 2018

4583

Background: Health determinants vary according to the geographic region and may impact the outcomes of mRCC patients treated on clinical trials of targeted therapy. We investigate the OS by geographic region of mRCC patients treated in the targeted therapy era. Methods: We conducted a pooled analysis of mRCC patients treated on phase II and III clinical trials. Clinical characteristics and survival data were collected. Statistical analyses were performed using the Kaplan-Meier method and log-rank test in univariate analysis. Results: Overall, 4736 patients were included in the analysis. Patient characteristics differed according to geographic region (table). No statistically significant differences in OS were observed when comparing US/Canada (USC, reference) to other regions: Latin America (LA), Asia/Oceania/Africa (AOA), and Eastern Europe (EE). OS differed among patients enrolled on trials in the USC compared to Western Europe (WE) (20.3 vs.17.4 months, respectively; HR: 1.15; 95%CI 1.03-1.3 p = 0.015). All grade treatment-related adverse events (AE) were reported more frequently in USC. There were no significant differences in grade 3-5 AEs between groups. Conclusions: We highlight that despite differing baseline characteristics, OS was similar among most geographic regions. Factors such as disease biology, access to care, AE reporting, and quality of care that may contribute to potential differences in outcomes among regions need to be further characterized. [Table: see text]
Phase 3 prognostic analysis of the automated bone scan index (aBSI) in men with bone-metastatic castration-resistant prostate cancer (CRPC).
Authors: Armstrong Andrew J. , Edenbrandt Lars , Bondesson Eva , Anand Aseem , Nordle Orjan , Carducci Michael Anthony , Morris Michael J.
Published: September 2018

5006

Background: Quantitative measures of metastatic bone disease are needed in men with mCRPC. We recently demonstrated the validity/reproducibility of a computational approach to bone scan imaging that employs artificial intelligence called the automated BSI (aBSI), which quantifies the percent of skeletal mass involved by cancer. We aimed to extend the prognostic validation of aBSI in a multinational prospective phase 3 clinical study of men with bone-metastatic CRPC. Methods: Whole-body bone scans were acquired at screening in a placebo-controlled phase 3 trial of men with mCRPC and bone metastases and treated with tasquinimod/placebo (n = 1,245). The prospective aBSI biomarker analysis plan was locked in Sept 2014 prior to treatment unblinding. All scans generated at 241 trial sites in 37 countries were assessed for image quality and analyzed using the EXINI boneBSI v.2 software and were blindly associated with outcomes. Baseline aBSI was evaluated for its independent prognostic association with overall survival (OS), radiographic progression-free survival (rPFS), and symptomatic skeletal related events (SSEs). Results: The aBSI-population (721 pts) was representative of the entire trial population based on patient characteristics at screening and OS outcomes. Median aBSI was 1.07 (SE 0.05). The aBSI-population was divided into quartiles (n = 180-181) with aBSI-levels of 0 - 0.3 (Q1); > 0.3 - 1.1 (Q2); > 1.1 - 4.0 (Q3); and > 4.0 (Q4) and median OS ranging from 35 months (Q1) to 13 mo (Q4) (p < 0.0001). Baseline aBSI was significantly associated with OS (HR 1.2 per doubling of BSI; p < 0.0001) and remained independently associated with OS after adjustment for treatment, PSA, CRP, LDH and albumin. Baseline aBSI was also strongly associated with rPFS (p = 0.0005), time to symptomatic progression (p < 0.0001), and time to SSE (p = 0.001). Conclusions: This analysis represents the first phase 3 evaluation of aBSI as a clinically validated prognostic biomarker for OS, rPFS, and SSEs in men with bone-metastatic CRPC, providing independent prognostic information over commonly measured clinical characteristics. Clinical trial information: NCT01234311.
Circulating tumor cell (CTC) number as a response endpoint in metastatic castration resistant (mCRPC) compared with PSA across five randomized phase 3 trials.
Authors: Heller Glenn , Mccormack Robert Thomas , Kheoh Thian , Smith Matthew Raymond , Dreicer Robert , Saad Fred , De Wit Ronald , Aftab Dana T. , Hirmand Mohammad , MacLean David B. , Fizazi Karim , De Bono Johann S. , Scher Howard I.
Published: September 2018

5007

Background: Radiographic progression and overall survival (OS) are the traditional clinical benefit measures for mCRPC trials. Reliable indicators of response that occur early are a critical unmet need in practice and clinical research. We explored a week 13 CTC and prostate-specific antigen (PSA) endpoint relative to baseline in 5 prospective randomized phase 3 registration trials that enrolled 5912 pts. OS was the primary endpoint. Methods: CTC number (CellSearch) and PSA values in patients who survived at least 13 weeks were evaluated as response endpoints in COU-AA-301, AFFIRM, ELM-PC-5, ELM-PC-4 and COMET-1. Pts with missing values at week 13 were considered non-responders. The endpoints considered are shown in Table 1. Results: The discriminatory strength of the response endpoints with respect to OS was estimated using the weighted c-index. To summarize discrimination results for each measure, the mean and the standard deviation based on the weighted c-indices from the 5 studies were computed. Conclusions: CTC0 and CTC conversion endpoints had the highest discriminatory power for OS relative to the % decline in CTC or PSA endpoints. The percent of pts eligible and evaluable for the CTC0 endpoint was significantly higher than the conversion endpoint, 75% vs. 51%, respectively. These two absolute measures of CTC can be considered meaningful response indicators in mCRPC clinical trials. [Table: see text]

[Table: see text]
Need for re-evaluation of current guidelines based on results from germline genetic testing in prostate cancer.
Authors: Nicolosi Piper L.W. , Michalski Scott T. , Freschi Brandy , O'Leary Erin , Quintana Rita , Wilson Ian , Powers Martin P. , Sartor Oliver
Published: September 2018

5009

Background: Inherited risk for prostate cancer (PCa) is potentially associated with more aggressive disease. Recent data indicate that DNA repair gene abnormalities may be much more common than previously appreciated, especially BRCA2, ATM, CHEK2, BRCA1, RAD51D, and PALB2. Herein, we investigate the efficacy of a targeted gene panel in men with PCa and evaluate clinical factors in relationship to current guidelines for genetic screening. Methods: DNA sequencing and exon-level copy number analysis were performed in 1158 PCa patients (pts) between 2013 and 2016 at a commercial diagnostic laboratory. The genes requisitioned varied but consistently included 14 genes on a hereditary PCa panel, most of which were DNA repair genes. Evaluation included Gleason scores and eligibility for genetic screening based on any NCCN testing criteria in pts with positive findings (pathogenic, likely pathogenic, and risk allele). Results: Pathogenic findings were identified in 199 of 1158 (17.2%) pts, 13 pts (1.0%) had two variants. Roughly 75% of detected variants were in genes on the hereditary PCa panel, of which 34.4% were BRCA1/2. Positive variants in HOXB13, a gene associated only with PCa risk, were identified in eight (3.8%) pts. DNA mismatch repair variants, alterations with substantial known therapeutic implications, were detected in 1.7% of samples. A total of 12.4% of pts with Gleason scores of ≤6, compared with 15.4% of those with scores of ≥7 had a pathogenic variant. Within this cohort, 126 (63%) patients with positive results were eligible for genetic testing based on currently available NCCN guidelines, whereas 73 (37%) would not have qualified. Conclusions: Current NCCN guidelines and Gleason scores cannot be used to reliably stratify PCa pts for the presence/absence of pathogenic germline variants. Most positive results identified in this study have important management implications for pts and their families. The percentage of pts with germline variants who did not meet current genetic screening criteria underscores the need for revisiting current guidelines which cannot, at this time, reliably be used to predict pathologic findings on genetic testing.
Clinical outcome of metastatic castration-resistant prostate cancer (mCRPC) patients (pts) with a post-treatment circulating tumor cell (CTC) of 0 vs CTC > 0: Post hoc analysis of COU-AA-301.
Authors: Scher Howard I. , Heller Glenn , Yu Margaret K. , Kheoh Thian , Peng Weimin , De Bono Johann S.
Published: September 2018

5015

Background: Assessment of radiographic response by RECIST in the majority of mCRPC pts is limited by the lack of measurable disease. Changes in CTC counts (CTCs) enumerated using Veridex CellSearch from unfavorable at baseline (BL [≥ 5 cells/7.5 mL]) to favorable (≤ 4) are prognostic for survival, and the test is FDA cleared as an aid in the monitoring of metastatic PC. The CTC cutpoint of ≥ 5 excludes many pts from response assessment. Examining CTCs alone and in combination with other biomarkers as a potential surrogate for clinical benefit was a secondary objective of COU-AA-301, a phase 3 trial of abiraterone acetate + prednisone vs prednisone alone in mCRPC. Methods: Pts from both treatment (tmt) groups with BL CTC > 0 were combined to assess CTC = 0 as a response criterion. Association between CTC response, defined as BL CTC > 0 and post-BL CTC = 0, and clinical outcomes was assessed. CTCs were determined at BL and 4, 8, and 12 wks. Pts with BL CTC > 0 and missing post-tmt CTCs were considered nonresponders. Radiographic response was first assessed at Wk 12. Overall survival (OS) was estimated using the Kaplan-Meier method. Results: Among739 pts with BL CTC > 0, 141 had measurable disease. At Wk 12, 19% (141/739) of pts were CTC responders and 81% (598/739) were CTC nonresponders. Among CTC responders, 74% (104/141) had stable disease or better by RECIST; 26% (37/141) were either not evaluable or had disease progression by RECIST. Median OS was 23.8 and 10.0 mos for CTC responders (n = 141) and nonresponders (n = 598), respectively. Among pts with liver and/or lung metastases, 86% (24/28) of CTC responders at Wk 12 had stable disease or better by RECIST; 14% (4/28) had disease progression by RECIST. Median OS was 19.9 and 7.1 mos for CTC responders (n = 28) and nonresponders (n = 127), respectively. Similar results were observed in Wk 8 CTC responders. Conclusions: For mCRPC pts with BL CTC > 0, CTC response on tmt (CTC = 0) is associated with longer survival and could be considered a response criterion. Additional analysis is required to fully characterize the relationship between CTC = 0 and objective response by RECIST in pts with measurable disease. Clinical trial information: NCT00638690.
Extended versus limited pelvic lymphadenectomy during radical prostatectomy for intermediate- and high-risk prostate cancer: Early outcomes from a randomized controlled phase III study.
Authors: Lestingi Jean Felipe Prodocimo , Guglielmetti Giuliano , Pontes Jr Jose , Mitre Anuar Ibrahim , Sarkis Alvaro , Bastos Diogo Assed , Riechelmann Rachel , Mattedi Romulo Loss , Cordeiro Mauricio , Coelho Rafael , Srougi Miguel , Nahas William Carlos
Published: September 2018

5018

Background: The role of extended pelvic lymph node dissection (ePLND) in treating prostate cancer (PCa) patients remains controversial, mainly by the lack of RCTs. Methods: Patients with D'Amico intermediate or high risk PCa, absence of bone metastasis and no previous treatment were prospectively computer randomised to undergo extended or limited PLND (1:1) during radical prostatectomy. Limited PLND (lPLND) included the obturator chain bilaterally; ePLND involved bilaterally chains: obturator, external-, internal-, common-iliac and pre-sacral. Surgical specimens and each chain were analyzed separately, according to College of American Pathologists. All patients signed a free and informed consent and local ethics committee approved the study. The primary endpoint was biochemical recurrence-free survival, analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01812902. Results: Since May 2012 until August 2016, 291 patients were randomly assigned, 145 to ePLND and 146 to lPLND. Preoperative data were comparable between groups. Median follow-up was 35.2 months. EPLND increased significantly operative time (54 minutes), estimated blood loss (100 mL), length of hospital stays (1 day) [p≤0.001], transfusion rate [p = 0.05] and postoperative complications according to Clavien scale [p = 0.03]. There was no difference in Pathologic Gleason grade, T stage or positive surgical margin. On ePLND and lPLND groups, 59.3% and 61.7% were staged ≥ pT3a, respectively. EPLND and lPLND yielded median (mean) 17 (19.8) and 3 (4.1) nodes, respectively (p < 0.001). EPLND showed 6.3 times more lymph node metastases (p < 0.001) and only it was able to show positive nodes in intermediate risk. There were no difference in biochemical recurrence (PSA ≥ 0.2 ng/mL) using Kaplan-Meyer method (p = 0.4), Radiotherapy, Androgen Deprivation Therapy, bone metastases or death. Conclusions: Extended lymphadenectomy in intermediate- and high-risk prostate cancer patients is associated with better tumor staging, increased morbidity and no oncological benefits in this initial short follow-up time. Clinical trial information: NCT01812902.
Adjuvant androgen deprivation (AD) +/- mitoxantrone + prednisone (MP) in patients with high-risk prostate cancer (PC) post radical prostatectomy (RP): Phase III intergroup trial S9921.
Authors: Hussain Maha , Tangen Catherine M. , Thompson Ian Murchie , Swanson Gregory P. , Wood David Peter , Sakr Wael , Dawson Nancy Ann , Haas Naomi B. , Flaig Thomas W. , Dorff Tanya B. , Lin Daniel W. , Crawford E. David , Quinn David I. , Vogelzang Nicholas J. , Glode L. Michael
Published: September 2018

5019

Background: Patients (pts) with high-risk PC post RP are at risk of systemic relapse with related morbidity/mortality. Adjuvant AD can reduce this risk. In 1999, based on available data, we hypothesized that adjuvant MP + 2 years (ys) of AD can further reduce mortality. Methods: Eligible pts had cT1-T3, N0 PC with post RP > = 1 high risk factors defined as Gleason sum (GS) ≥ 8, pT3b, pT4, pN+, GS 7 + positive margin or any of these preoperative findings (in pts with neoadjuvant AD): preoperative PSA of > 15 ng/ml, bx GS score > 7, or PSA of > 10 ng/ml + bx GS > 6. Pts had to have post RP PSA = < 0.2 ng/ml, were stratified by T, N, GS, and adjuvant radiation plan and randomized: Arm 1 AD (bicalutamide + goserelin for 2 ys) or Arm 2 AD + 6 cycles m 12 mg/m2 + P 5mg BID. Primary endpoint: overall survival (OS). Median OS was estimated to be 10 ys in AD arm requiring 680 pts/arm to detect a hazard ratio (HR) of 1.30 with 92% power and one-sided α = 0.05. Results: 983 pts (961 eligible intent to treat) with median age 60 ys and median PSA 7.6 ng/ml were randomized to AD or AD + MP from 10/99 -1/07 when the DSMC recommended stopping accrual due to higher leukemia rate in Arm 2. 16% had N1 (Group “Gr” 1), 61% GS ≥8 or pT3b (Gr 2),23% other risk factors (Gr 3). Median time to testosterone recovery was 9.5 months. Median follow-up (f/u) 11.2 ys. Conclusions: OS was higher than anticipated in both arms; MP did not improve OS and increased other malignancy risk. These data illustrate that systemic therapy benefit cannot be extrapolated from different disease stages and the importance of adequate f/u in adjuvant PCa trials. The remarkable DFS and 10 y OS, irrespective of risk extent, may be result of risk definition, and/or 2 ys AD. Pending definitive data 2 ys adjuvant AD for high-risk PCa post RP is a reasonable option to consider. Clinical trial information: NCT00004124. [Table: see text]
Stereotactic ablative radiation therapy for the treatment of oligometastatic prostate cancer.
Authors: Tran Phuoc T. , Moyer C. Leigh , Phillips Ryan , Radwan Noura , Ross Ashley , Reyes Diane K. , Wright Jean , Antonarakis Emmanuel S. , Song Daniel Y. , Deville Curtiland , Walsh Patrick C. , DeWeese Theodore L. , Carducci Michael Anthony , Schaeffer Edward M. , Pienta Kenneth J. , Eisenberger Mario A.
Published: September 2018

5020

Background: The importance of local treatment in oligometastatic prostate cancer (OPC) is unknown. Stereotactic ablative radiotherapy (SABR) is highly focused, high-dose radiation that is well suited for treatment of oligometastases. Here we report on the safety and preliminary clinical outcomes of SABR in a modern cohort of OPC men. Methods: Eighty four men who satisfied criteria of OPC diagnosed on imaging underwent consolidative SABR were then followed prospectively on our IRB approved registry by our GU multidisciplinary team. We collected demographic, clinical, toxicity and efficacy information. We examined the first 66 men in this preliminary report to allow for a minimum of 4.5 months follow-up. SABR was delivered in 1-5 fractions of 5-18 Gy. Kaplan-Meier method was used to assess local progression-free survival (LPFS), biochemical progression-free survival (bPFS; PSA nadir+2), distant progression free survival (DPFS), ADT-free survival (ADT-FS) and time-to-next intervention (TTNI). Results: Of the 66 OPC patients analyzed, 25 (38%) men presented as synchronous OPC and the remaining 41 had recurrent OPC. Median and mean follow-up was 61 and 66 weeks, respectively. Patient and disease factors as listed in the Table. Crude Grade 1 and 2 acute toxicities were 36% and 11%, respectively, with no Grade > 2 toxicity. SABR was delivered to 134 metastases: 89 bone (66%), 40 nodal (30%) and 5 (4%) visceral metastases. Overall LPFS at 1-year was 92%. The bPFS and DPFS at 1-year were 69% and 69%, respectively. Median TTNI was not reached yet. Of the 18 men with hormone sensitive prostate cancer who had their ADT deferred, 11/18 (56%) remain free of disease following SABR (1-year ADT-FS was 78%) and in 17 castration resistant men, 11 had > 50% PSA declines with 1-year TTNI of 30% with a median of 45 weeks. Conclusions: Consolidative SABRfor OPCis feasible and well tolerated. The preliminary clinical outcomes in our series is limited by heterogeneity and size but our data suggests that this approach is worthy of further prospective study. [Table: see text]
Circulating tumor cells (CTCs) N-terminal androgen receptor expression to identify patients (pts) with castrate resistant prostate cancer (CRPC) who are more sensitive to chemotherapy.
Authors: Slovin Susan F. , Knudsen Karen E. , Halabi Susan , Carbone Emily , Fernandez Celina , Chen Yu , Autio Karen A. , Rathkopf Dana E. , Kampel Lewis J. , Morris Michael J. , Arauz Gabrielle , Graf Ryon P , Kelvin James , Dittamore Ryan Vance , De Leeuw Renee , Sullivan Amanda , Tse Kin , Molina Ana M. , Scher Howard I. , Kelly William Kevin
Published: September 2018

5034

Background: Loss of the retinoblastoma tumor suppressor (RB) function was identified as a major means to develop CRPC; the expression of the androgen receptor (AR) is under stringent RB control; and tumors devoid of RB function are hypersensitive to treatment with chemotherapy. Exploratory analysis evaluated baseline N-terminal AR expression in CTCs in men with chemotherapy-naïve CPRC and correlated to changes in PSA, leading us to inquire if this biomarker may identify pts sensitive to chemotherapy. Methods: In a multicenter phase II randomized trial of approved doses of abiraterone acetate/prednisone (AA-Arm 1) or combination AA and standard doses of cabazitaxel (AA/CBZ-Arm 2). Patients on AA received CBZ upon progression. Baseline CTCs were obtained on all pts and expression of N-terminal AR expression was performed by Epic Sciences. Positive AR N-terminal expression (AR+) was based on the presence of at least 1 CTC or CK- cell with AR N-terminal signal expression above the 3.0 positivity threshold. Serial PSAs were determined at baseline and every 3 weeks with routine labs and imaging every 12 weeks. Results: To date, 42 of 80 pts have been enrolled: 22 pts to AA, and 20 pts to AA/CBZ. Both regimens were well tolerated with 8/42 (19%) pts experiencing treatment-related grade 3 or 4 toxicities. Blood from 35 patients underwent CTC analysis. Seventy-seven percent of pts (27/35) had detectable CTCs; 11 of 35 pts (31%) had AR overexpression. Of the pts with AR+ CTCs, 1/5 pts treated with AA, and 5/6 pts treated with AA/CBZ had a PSA decline > 50% from baseline. Conclusions: Real-time CTC analysis of N-terminal AR expression was feasible and data suggests that this may identify a cohort of pts who may benefit from the combination of CBZ with AA. Further studies are ongoing to evaluate whether cellular heterogeneity and RB expression in CTCs play a role in identifying pts who would benefit from chemotherapy. The trial is coordinated by the Prostate Cancer Clinical Trials Consortium, LLC and funded by Sanofi US Services Inc. and Prostate Cancer Foundation. Clinical trial information: NCT02218606.
Assessment of quality of life (QOL), cognitive function and depression in a randomized phase II study of abiraterone acetate (ABI) plus prednisone (P) vs enzalutamide (ENZA) for metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Khalaf Daniel , Sunderland Katherine , Eigl Bernhard J. , Finch Daygen L. , Oja Conrad D. , Vergidis Joanna , Parimi Sunil , Zulfiqar Muhammad , Gleave Martin , Chi Kim N.
Published: September 2018

5036

Background: ABI + P and ENZA treatments are associated with side effects that may impair QOL. ENZA has been associated with cognitive and memory impairment. There has been no direct comparison between these agents and their effect on these domains. Methods: Randomized phase II trial of ABI + P vs ENZA as 1st-line therapy for mCRPC (ClinicalTrials.gov: NCT02125357). FACT-P QOL questionnaire, patient health questionnaire (PHQ-9) and Montreal Cognitive Assessment (MoCA) were completed throughout the study. The proportion of patients with a clinically significant change in FACT-P (10 points total FACT-P score, 3 points FACT-P subscales), worsening of PHQ-9 depression symptom severity (none = 0-4, mild = 5-9, moderate = 10-14, moderate-severe = 15-19, severe ≥20) and decline in MoCA cognitive impairment level (normal = 27-30, mild = 18-26, moderate = 10-17, severe ˂ 10) at week 12 was compared between study arms for this analysis. Results: From 202 patients (pts) accrued, there were 162, 145 and 142 pts with baseline and 12-week FACT-P, PHQ-9 and MoCA assessment. Median baseline FACT-P, PHQ-9 and MoCA scores were similar in both arms. From baseline to 12 weeks, the median total FACT-P score improved in the ABI + P arm (115 to 128, P = 0.02), but there was no change in the ENZA arm (114 to 114, P = 1.00). There was a higher rate of significant worsening for the physical well-being (PWB) subscale for ENZA vs ABI + P (TABLE), but not for the other FACT-P subscales. There was a higher rate of worsening in depression severity in the ENZA arm (TABLE), although worsening to a moderate-severe/severe level occurred in only 2 patients. There was also a trend for worsening in cognitive impairment for the ENZA arm (TABLE). Conclusions: These data suggest there are distinct differences between ABI + P vs ENZA and their effects on QOL, mood symptoms and cognitive function. Clinical trial information: NCT02125357. [Table: see text]
Phase 1 study of the PSMA-targeted small-molecule drug conjugate EC1169 in patients with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Morris Michael J. , Vogelzang Nicholas J. , Sartor Oliver , Armour Alison , Groaning Michael , Robarts Adam , Petrylak Daniel Peter , Tolcher Anthony W. , Gordon Michael S. , Babiker Hani M.
Published: September 2018

5038

Background: Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancers, but not in most normal tissues, making it a potential therapeutic target. We are conducting a two-part phase 1 dose escalation/expansion study of EC1169, a PSMA-targeted conjugate of the microtubule inhibitor tubulysin B hydrazide in mCRPC. The utility of the PSMA-targeted companion imaging agent 99mTc-EC0652 is also being evaluated as a patient selection tool. The safety, efficacy, and imaging-based PSMA selection strategy are being investigated in Part A (dose escalation) and Part B (2-stage, 2-cohort expansion). Methods: Part A pts were eligible if they progressed on abiraterone or enzalutamide, and were treated with a taxane. EC1169 was administered as an IV bolus on days 1, 8 every 21 days. Part B pts are enrolled in 1 of 2 cohorts, mCRPC taxane naïve (cohort 1, 45 pts) and taxane exposed (cohort 2, 40 pts). Prior to treatment, pts undergo a 99mTc-EC0652 SPECT scan. The primary endpoint of Part B is median radiographic progression-free survival (rPFS). Other study evaluations are OS, PSA, and CTC-based biomarkers. Results: Part A is now complete: the RP2 dose is 6.5 mg/m2, on the basis of non-DLT transaminitis. 20 Part A/B pts have been treated at the RP2 dose (7 taxane naïve, 13 taxane exposed). Median age is 69 (range: 59-82). Median number of cycles is 2 (range: 1-7). 10 pts (50%) reported at least 1 treatment related AE. Most treatment related AEs are Gr1 and 2; G3 thrombocytopenia, fatigue, and constipation have occurred in 1 pt each. No Grade 4 treatment related AEs have been reported. No DLT or toxicity requiring dose reductions occurred. Four taxane-exposed pts in Part B have reached their first 9 wk radiographic assessment, of which two have soft tissue disease. One of those two patients (50%) has achieved an unconfirmed RECIST PR. Conclusions: The RP2 dose of EC1169 is 6.5 mg/m2. EC1169 has been well tolerated in 20 pts at the RP2 dose. Imaging with 99mTc-EC0652 suggests excellent disease localization supporting a PSMA-targeted therapeutic strategy. There is evidence of anti-tumor activity in both the dose escalation and expansion cohorts. Clinical trial information: NCT02202447.
Comparison of biochemical recurrence free survival after radical prostatectomy triggered by grade reclassification on active surveillance, and men newly diagnosed with similar grade disease.
Authors: Diniz Clarissa P. , Carter Ballentine , Epstein Jonathan I. , Mamawala Mufaddal
Published: September 2018

5047

Background: Evaluate the biochemical recurrence free survival (bRFS) in men after radical prostatectomy (RP) triggered by Gleason score (GS) grade reclassification (GR) during active surveillance (AS) in order to inform patient decisions. Methods: We conducted a retrospective analysis of men undergoing RP from 1995 - 2015 at Johns Hopkins and identified 4 groups; 94 men in AS that underwent RP following GR from Gleason score (GS) 6 to GS ≥ 7(3+4) [grade groups ≥ 2], 3,504 men that underwent IRP following a diagnosis of grade groups ≥ 2, 56 men in AS that underwent RP following GR to GS 7(3+4) [grade group 2], and 1,979 men that underwent IRP following a diagnosis of grade group 2. The outcome of interest was bRFS, assessed using Kaplan Meir analysis and a multivariate Cox regression model. Results: Men on AS had a lower PSA density distribution (0.11 vs. 0.13, p = 0.022; 0.12 vs. 0.12, p = 0.043), and a higher proportion of low volume cancers (46.2% vs. 15.3%, 46.4% vs. 16.7%, both p < 0.001) as compared to the IRP groups for both biopsy grade groups ≥ 2 and biopsy grade group 2, respectively. The proportions of men with biochemical recurrence (BCR) in the AS and IRP groups were 13.8% vs. 29.1% (p = 0.008 for grade groups ≥ 2) and 8.9% vs. 21.7% (p = 0.022 for grade group 2), respectively. One, 5, 10-year bRFS for men in the AS group vs the IRP group was 97.9%, 76.6%, 69.0% vs 85.5%, 65.1% ,54.2%%, respectively for biopsy grade groups ≥ 2 (log-rank test, p = 0.009), and 96.4%, 89.6%, 89.6% vs 91.2%, 74.0%, 63.9%, respectively for biopsy grade group 2 (log-rank test, p = 0.071). For biopsy grade groups ≥ 2, there was no significant difference in BCR between groups after adjustment for age at treatment, biopsy extent of cancer, and PSA density; HR = 0.78 (95% CI 0.43 – 1.43, p = 0.426). Conclusions: AS patients that are reclassified to grade groups ≥ 2 have no greater risk of treatment failure as compared to men newly diagnosed with similar grades. These data could help inform decisions regarding management of low grade prostate cancer.
Predictors of post-surgical race-specific prostate cancer progression.
Authors: Cullen Jennifer , Kuo Huai-Ching , Hurwitz Lauren , Rosner Inger L. , Rebbeck Timothy , D'Amico Anthony Victor , Lu-Yao Grace L.
Published: September 2018

5048

Background: Disparity in prostate cancer (CaP) incidence and mortality for African American (AA) versus Caucasian American (CA) men may reflect tumor biology, comorbidity, treatment, follow-up care, and/or health care access. In a racially diverse cohort of patients undergoing radical prostatectomy (RP), this study examined how race, comorbidity, and PSA doubling time (PSADT) impact CaP progression. Methods: Enrollees in the Center for Prostate Disease Research (CPDR) Multi-Center National Database from 1989-2014 who underwent RP within 12 months of CaP diagnosis were eligible. Biochemical recurrence (BCR) was defined as PSA ≥0.2 ng/mL post-RP. Comorbid conditions included coronary artery disease (CAD), cerebral vascular incident (CVI), Type II diabetes (DB), hypertension (HT), elevated cholesterol (EC), lung disease (COPD), prostatitis (PS), renal insufficiency (RI) and other cancer (OC). Multivariable Cox proportional hazards (PH) analysis was used to examine comorbid conditions (yes vs. no) and PSADT ( < 3, 3-8.9, 9-14.9, and ≥15 mos) to predict BCR, controlling for age at RP, D’Amico risk stratum, pathology features, and adjuvant treatment. Results: A total of 6,785 patients were eligible; 22% AA and 78% CA. Median age and follow-up was 62 and 6.1 years, respectively. Across race, comparable median follow-up time, distributions of pathologic features and adjuvant treatments were observed. However, AA vs. CA patients had greater HT (53 vs. 39% p < 0.0001), DB (17 vs. 7%, p < 0.0001), and RI (3 vs. 1%, p = 0.002). Alternatively, CA vs. AA patients had greater CVD (10 vs. 7%, p = 0.0008) and OC (3 vs. 0.5%, p < 0.0001). Cox PH analysis showed poorer BCR-free survival for AA vs. CA men (HR = 1.28, CI = 1.11, 1.48, p = 0.0009) adjusting for D’Amico risk stratum, pathology, and treatment. PSADT, not comorbidity, was a critical predictor of BCR, with poorest outcome at extremes: HR PSADT < 3 vs. > = 15 months = 41.5, CI = 33.6, 51.3, p < 0.0001). Conclusions: Despite comparable health care access and distribution in clinical risk stratum and pathology features, race persisted in predicting poor CaP outcome. Disparate comorbidity for AA and CA men did not eliminate this difference. PSADT remained the most striking determinant of poor BCR-free survival.
HSD3B1 genotype and response to androgen deprivation therapy for biochemical recurrence after radiotherapy for localized prostate cancer.
Authors: Hearn Jason W.D. , Xie Wanling , Nakabayashi Mari , Almassi Nima , Reichard Chad A. , Pomerantz Mark , Kantoff Philip W. , Sharifi Nima
Published: September 2018

5050

Background: The enzyme encoded by the HSD3B1(1245C) variant allele has been shown to promote castration-resistant prostate cancer by increasing intratumoral dihydrotestosterone synthesis. In the setting of biochemical recurrence (BCR) following prostatectomy, inheritance of the variant allele has been associated with inferior clinical outcomes for men treated with androgen deprivation therapy (ADT). Whether the same is true in the context of BCR after radiotherapy (RT) is unknown. Methods: We determined HSD3B1 genotype retrospectively in men treated with ADT for post-RT BCR using an established biorepository at a large academic center. We analyzed time-to-progression (TTP), time-to-metastasis (TTM), and overall survival (OS) according to HSD3B1genotype using an additive genetic model with the log-rank trend test. Multivariable analyses (MVA) were performed to adjust for known prognostic factors with Cox regression. Results: We identified 218 men treated with ADT for BCR after RT, of whom 213 (98%) were successfully genotyped (46%, 45% and 9% carrying 0, 1, and 2 variant alleles, respectively). Median follow-up was 7.9 years (yrs). Demographic and treatment factors were similar across genotypes. Median TTP was 2.3 (95% CI: 1.6, 3.1) yrs in men who inherited 0 variant alleles, 2.3 (1.5, 3.3) yrs with 1 variant allele, and 1.4 (0.7, 3.3) yrs with 2 variant alleles (P = 0.683). Median TTM diminished with the number of variant alleles inherited (7.4 [6.7, 9.7], 5.8 [4.9, 6.5] and 4.4 [3.0, 5.7] yrs, respectively (P = 0.030). No difference in OS was detected (P = 0.305). On MVA with 0 variant alleles as the reference, the adjusted hazard ratio (HR) for metastasis was (1.19 [0.74, 1.92]; P = 0.480) for 1 allele and (2.01 [1.02, 3.97]; P = 0.045) for 2 alleles. MVA did not demonstrate significant differences in TTP or OS. Conclusions: The HSD3B1(1245C) allele that enhances dihydrotestosterone synthesis is associated with time-to-metastasis in men treated with ADT for BCR after RT for prostate cancer. Notably, 49% of men had received prior ADT as part of local therapy and 56% received an anti-androgen during ADT for BCR, which may blunt the effect of the variant allele.
Association of CTC detection by AdnaTest with outcome on enzalutamide in chemotherapy-naïve castration-resistant prostate cancer: Exploratory results from PREMIERE—A SOGUG trial.
Authors: Font Pous Albert , Vazquez-Estevez Sergio , Gonzalez del Alba Aranzazu , Mellado Begoña , Fernandez Calvo Ovidio , Mendez Maria Jose , Juan Fita María José , Rodriguez Sanchez Angel , Pérez-Valderrama Begoña , Gallardo Enrique , Santander Carmen , Sáez M Isabel , Puente Javier , Alonso Teresa , Fernandez Perez Maria Piedad , Martínez Alberto , Lopez-Andreo Maria Jose , Grande Enrique , González-Billalabeitia Enrique , Castellano Daniel
Published: September 2018

5052

Background: Circulating tumor cells (CTCs) enumeration using CellSearch correlates with clinical outcome in prostate cancer, but is limited for gene expression analysis. AdnaTest ProstateCancer is a commercially available CTC immune-enrichment and PCR-related detection method that allows gene expression studies (Antonarakis E, NEJM 2014). It has demonstrated incremental detection of CTCs in patients with no CTCs identified by CellSearch (Samoila A, ASCO 2013) but needs to be clinically qualified. There is a strong need for studies to assess the association with the clinical outcome in CRPC. Methods: Between February and November 2015, 98 asymptomatic or oligo-symptomatic chemotherapy-naïve mCRPC pts were recruited in 16 institutions. Although initially designed to study the predictive value of TMPRSS2-ETS, data emerging after the trial was initiated led the group to prioritize alternative predefined exploratory biomarkers, including plasma AR (Grande E, ASC0 2017 #) and CTC characterization (Grande E, ESMO 2016). Outcome measures included PSA-PFS (sPFS), radiographic PFS (rPFS) and OS. Cox regression was used for survival analyses and Fisher’s exact test for PSA response. Results: Ninety-eight patients had CTC blood samples available. CTCs were detected at baseline, 12 weeks and progression in 36% (35/98), 27% (26/95) and 78% (32/41), respectively. The CTC conversion rate (positive to negative after 12 w) was 43% (15/35). All CTC conversions had ≥50% decline in PSA (15/15) whereas only 35% (7/20) of pts with persistent CTCs. At first interim analysis, with a median follow-up of 10.6 months, detection of CTCs at baseline was associated with worse sPFS (median, 7.59 m versus NR, HR, 3.67; 95% CI 1.90-7.10; P < 0.001), rPFS (median, 12.9 m versus NR; HR, 7.61; 95% CI, 2.80-20.64; P < 0.001) and OS (medians NR, HR, 9.51; 95% CI, 1.11-81.52; P = 0.0398). CTC positive pts were less likely to have a ≥90% decline in PSA (OR, 2.88; 95% CI, 1.13-7.72; P = 0.02). Conclusions: CTC detection using AdnaTest is associated with an adverse outcome in chemotherapy-naïve asymptomatic or oligo-symptomatic mCRPC pts. Clinical trial information: NCT02288936.
A 17-gene panel for prediction of adverse surgical pathology in the setting of MRI-guided prostate biopsy.
Authors: Salmasi Amirali , Said Jonathan W. , Raman Steven , Shindel Alan W , McCullough Debbie , Bailey Helen , Rothney Megan , Marks Leonard S. , Febbo Phillip G. , Reiter Robert Evan
Published: September 2018

5063

Background: A 17 gene panel (Oncotype Dx Genomic Prostate Score, GPS) has been validated as an independent predictor of adverse pathology (AP, defined as pathological GS 4+3 or higher and/or pT3+) in men treated with radical prostatectomy (RP) for prostate cancer (PCa). Multiparametric Magnetic Resonance Imaging (mpMRI) may help guide prostate biopsies. We explored synergies between GPS and mpMRI to aid in PCa management decisions. Methods: A cohort of men with NCCN Low and Intermediate-Risk PCa who were managed with RP was identified from a clinical database. Patients were required to have had a simultaneous mpMRI-guided and systematic biopsy and to have undergone RP within 6 months. Biopsy tissue of the highest Gleason pattern was used for calculation of GPS. The primary endpoint was AP. Secondary endpoints included the range of GPS within UCLA prostate MRI risk groups and median GPS when there was discrepancy between MRI and systematic biopsy Gleason Score (GS). Logistic regression models were fit to evaluate the relationship between GPS (per 20 units) and AP. Results: 134 men met criteria for the primary endpoint. Median age was 62 years (range 46-77). NCCN Low & Intermediate-Risk PCa was present in 16%, and 84% of men, respectively. Biopsy GS 3+3/3+4/4+3 was present in 19%, 67%, and 13%, respectively. In a univariable model, GPS was associated with AP (OR 3.8, 95% CI 2.1 to 7.4, p < 0.001). After adjustment for highest biopsy GS and clinical T-stage, GPS remained significantly associated with AP (OR 3.4, 95% CI 1.8 to 6.8, p = 0.0004). A wide and overlapping distribution of GPS was noted across UCLA MRI prostate risk groups, indicating that GPS provides information that is distinct from what can be determined from mpMRI. When there was a discrepancy between mpMRI and systematic biopsy GS, mpMRI targeted lesions with higher GS had higher median GPS (33, range 13-70) than systematic biopsies with higher GS (median GPS 25, range 15-55). Conclusions: GPS provides independent and complementary prognostic information to mpMRI-guided biopsies. The combination of mpMRI for biopsy guidance and GPS for molecular analysis may optimize prediction of AP and improve patient selection for treatment versus surveillance.
The accuracy of multiparametric magnetic resonance imaging (mpMRI) using PI-RADS v2 in disease upgrading on re-biopsy among patients with low-risk prostate cancer (PCa) on active surveillance (AS): A Brazilian perspective.
Authors: Viana PÃºblio C. C. , Horvat Natally , Guglielmetti Giuliano , Coelho Rafael , Nahas William Carlos , Park Rubens , Bezerra Regis , Bastos Diogo Assed , Rodrigues Thiana , Vargas Hebert Alberto
Published: September 2018

5084

Background: The current selection criteria to AS is critical and it becomes even more relevant in Latin America, given the higher proportion of high risk cancers. The objective of this study is to analyze the accuracy of mpMRI using PI-RADS v2 in predicting the risk of upgrading on re-biopsy (UR) in men with low-risk PCa on AS. Methods: In this Institutional Review Board approved prospective study, patients with low-grade PCa selected for AS at our institution underwent mpMRI at least 6 weeks after the baseline 12-core random prostate biopsy (BSB), from March 2014 to March 2016. One blinded abdominal radiologist evaluated the exams regarding presence of dominant lesion and assigned the PI-RADS v2 score. MRI-target transrectal ultrasound-guided re-biopsies were performed in all patients within 6-12 months after the BSB. Standardized 12-core biopsy was performed and additional cores were taken from suspicious areas on mpMRI. Results: One hundred and nine patients were included, 93 (85.3%) patients had a dominant lesion on MRI. mpMRI were classified as PI-RADS 1, 2 or 3 in 67 (61.5%) patients, and as PI-RADS 4 or 5 in 42 (38.5%) patients. UR occurred in 42 (38.5%) patients. Out of these, 39 (92.8%) had radical prostatectomy, 6 (15.4%) T2a, 24 (61.5%) T2b, and 9 (23.1%) T3a. The diagnostic performance of mpMRI for PCa upgrading after re-biopsy was summarized in table 1. Patients assigned as PI-RADS 4 or 5 presented a significantly higher risk for UR compared with patients with PI-RADS 1, 2 or 3 (73.8% vs 16.4%, p < 0.001). Logistic regression analyses demonstrated that PI-RADS 4 or 5 remained a significant predictor of UR (OR: 37.366, p < 0.0001). Conclusions: We demonstrated in our population that mpMRI using PI-RADS v2 is a significant predictor for upgrading on re-biopsy in patients on AS and could be used to guide TRUS biopsy, increasing the accuracy of current clinical criteria for AS. [Table: see text]